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Genetics for Surgeons
Review of leading medical and surgical journals shows that the most frequent area of publication is papers with a genetic or molecular biological component – and inherited diseases contribute to a substantial proportion of the surgical workload. It is vital that today’s surgeon can recognize a positive history of disease in a family. This allows genetic testing and precise diagnosis, which, in turn, will lead to presymptomatic screening of at-risk members of a family, and allow prevention strategies to be implemented.
Remedica genetics series
Written in non-technical language, this book is a readable and accessible reference that covers the genetic disorders that surgeons can expect to meet in general surgical practice. The detailed appendix and glossary provide an introduction to the nomenclature and technology of molecular biology, and offer a useful starting point for those who wish to extend their knowledge and understanding of this rapidly evolving field.
Praise for the Genetics for… series “An outstanding reference and educational tool.” Jeffrey C Wang, Chief, Spine Service, UCLA Department of Orthopedic Surgery (Genetics for Orthopedic Surgeons)
“An excellent reference book for any health care practitioner who wishes to incorporate molecular genetics into the management of his or her patients. I wholeheartedly recommend it both as an educational and reference tool.” Andrew Lotery, Assistant Professor of Ophthalmology, University of Iowa (Genetics for Ophthalmologists)
ISBN 1-901346-69-2
9 781901 346695
Patrick J Morrison, Roy AJ Spence
Contents • Introduction • Principles of genetics for surgeons • Common surgical conditions with a hereditary tendency • Systemic cancers (benign and malignant tumors) • Topics surgeons and anesthetists should both know • Further reading • Glossary
Genetics for
Surgeons Patrick J Morrison Roy AJ Spence Series Editor Eli Hatchwell
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Genetics for Surgeons
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The Remedica Genetics for… Series Genetics for Cardiologists Genetics for Dermatologists Genetics for Endocrinologists Genetics for Hematologists Genetics for ENT Specialists Genetics for Oncologists Genetics for Ophthalmologists Genetics for Orthopedic Surgeons Genetics for Pediatricians Genetics for Pulmonologists Genetics for Rheumatologists Genetics for Surgeons
Published by Remedica 32–38 Osnaburgh Street, London, NW1 3ND, UK 20 N Wacker Drive, Suite 1642, Chicago, IL 60606, USA E-mail:
[email protected] www.remedicabooks.com Publisher: Andrew Ward In-house editors: Thomas Moberly and Cath Harris Design and artwork: AS&K Skylight © 2005 Remedica While every effort is made by the publishers and authors to see that no inaccurate or misleading data, opinions, or statements appear in this book, they wish to make it clear that the material contained in the publication represents a summary of the independent evaluations and opinions of the authors and contributors. As a consequence, the authors, publishers, and any sponsoring company accept no responsibility for the consequences of any such inaccurate or misleading data, opinions, or statements. Neither do they endorse the content of the publication or the use of any drug or device in a way that lies outside its current licensed application in any territory. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher. Remedica is a member of the AS&K Media Partnership. ISBN 978 1 901346 69 2 ISSN 1472 4618 British Library Cataloguing-in Publication Data A catalogue record for this book is available from the British Library.
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Genetics for Surgeons Patrick J Morrison, MD, FRCPCH, FFPHMI Honorary Professor of Human Genetics University of Ulster Honorary Reader in Cancer Genetics Queen’s University Belfast Consultant in Clinical Genetics Belfast City Hospital Trust Belfast UK Roy AJ Spence, OBE, MA, MD, FRCS Honorary Professor of Biomedical Science University of Ulster Honorary Professor of Surgery Queen’s University Belfast Departments of Medical Genetics and Surgery Belfast City Hospital Trust Belfast UK Series Editor Eli Hatchwell Investigator Cold Spring Harbor Laboratory USA
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Acknowledgments We would particularly like to thank our wives Anne and Diana for their patience and the length of time spent burning the midnight oil. We also thank our patients for asking us appropriate questions and our colleagues in general surgery who encouraged us to write this text.
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Introduction to the Genetics for… series Medicine is changing. The revolution in molecular genetics has fundamentally altered our notions of disease etiology and classification, and promises novel therapeutic interventions. Standard diagnostic approaches to disease focused entirely on clinical features and relatively crude clinical diagnostic tests. Little account was traditionally taken of possible familial influences in disease. The rapidity of the genetics revolution has left many physicians behind, particularly those whose medical education largely preceded its birth. Even for those who might have been aware of molecular genetics and its possible impact, the field was often viewed as highly specialist and not necessarily relevant to everyday clinical practice. Furthermore, while genetic disorders were viewed as representing a small minority of the total clinical load, it is now becoming clear that the opposite is true: few clinical conditions are totally without some genetic influence. The physician will soon need to be as familiar with genetic testing as he/she is with routine hematology and biochemistry analysis. While rapid and routine testing in molecular genetics is still an evolving field, in many situations such tests are already routine and represent essential adjuncts to clinical diagnosis (a good example is cystic fibrosis). This series of monographs is intended to bring specialists up to date in molecular genetics, both generally and also in very specific ways that are relevant to the given specialty. The aims are generally two-fold: (i)
to set the relevant specialty in the context of the new genetics in general and more specifically
(ii)
to allow the specialist, with little experience of genetics or its nomenclature, an entry into the world of genetic testing as it pertains to his/her specialty
These monographs are not intended as comprehensive accounts of each specialty — such reference texts are already available. Emphasis has been placed on those disorders with a strong genetic etiology and, in particular, those for which diagnostic testing is available.
Introduction
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The glossary is designed as a general introduction to molecular genetics and its language. The revolution in genetics has been paralleled in recent years by the information revolution. The two complement each other, and the World Wide Web is a rich source of information about genetics. The following sites are highly recommended as sources of information: 1.
PubMed. Free on-line database of medical literature. http://www.ncbi.nlm.nih.gov/PubMed/
2.
NCBI. Main entry to genome databases and other information about the human genome project. http://www.ncbi.nlm.nih.gov/
3.
OMIM. On line inheritance in Man. The On-line version of McKusick’s catalogue of Mendelian Disorders. Excellent links to PubMed and other databases. http://www.ncbi.nlm.nih.gov/omim/
4.
Mutation database, Cardiff. http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html
5.
National Coalition for Health Professional Education in Genetics. An organization designed to prepare health professionals for the genomics revolution. http://www.nchpeg.org/
6.
Finally, a series of articles from the New England Journal of Medicine, entitled Genomic Medicine, has been made available free of charge on their website. http://www.nejm.org.
Eli Hatchwell Cold Spring Harbor Laboratory
Genetics for Surgeons
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Preface This text is written in non technical language in three main sections: • a general overview of the principles in genetics • a section on common genetic disorders that surgeons will encounter • a third section on familial cancers, which, in the case of breast, bowel, and ovarian cancers, account for around 10% of the cancers that surgeons encounter. A fourth section deals with the topics that surgeons and anesthetists should both know, while the glossary at the end of the book allows a quick reference to increasingly common genetics terms. Surgeons can update themselves at the excellent Online Mendelian Inheritance in Man website (www.ncbi.nlm.nih.gov/omim). Within this book, Mendelian inheritance in man (MIM) numbers are given at the top of each condition for easy access. We hope this book is a readable and accessible reference for general surgical practice. Patrick J Morrison and Roy AJ Spence
Preface
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To our wives Anne and Diana, our children Richard and Peter and Robert, Andrew, and Katherine, and our patients and colleagues.
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Contents Section 1. Principles of Genetics for Surgeons Changing Times in Modern Surgical Practice Investigation of Familial Disease Genetic Counseling Penetrance Expression Diagnostic and Presymptomatic Testing Practical Approaches to Genetic Testing Section 2. Common Surgical Conditions with a Hereditary Tendency 1. Gastrointestinal Tract Familial Pancreatitis Cholecystitis Pyloric Stenosis Hiatus Hernia Crohn’s Disease Ulcerative Colitis Celiac Disease Abdominal Wall Defects Spleen Disorders Intestinal Atresias 2. Skin Tuberose Sclerosis Neurofibromatosis Type I Neurofibromatosis Type II Multiple Lipomatosis Cystic Hygroma Sebaceous Cysts 3. Cardiac Marfan’s Syndrome Noonan’s Syndrome Type I Down’s Syndrome Cardiac Myxoma Structural Cardiac Defects
Contents
1 2 2 4 5 6 6 9 13 16 17 18 19 20 21 23 24 25 26 27 30 33 34 35 36 37 39 40 41 42
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4. Respiratory Cystic Fibrosis Pneumothorax Ehlers–Danlos Syndrome Pectus Excavatum and Pectus Carinatum Kartagener’s Syndrome α -1 Antitrypsin Deficiency Lung Cancer Congenital Airway Problems 5. Hematologic Hemochromatosis Hemophilia Acute Myeloid Leukemia Chronic Myeloid Leukemia Chronic Lymphocytic Leukemia Non Hodgkin’s Lymphoma Hodgkin’s Lymphoma Multiple Myeloma 6. Neurologic Duchenne Muscular Dystrophy Hereditary Motor and Sensory Neuropathy Huntington’s disease Fragile X Syndrome Facioscapulohumeral Muscular Dystrophy Dupuytren’s Contracture Congenital Dislocation of the Hip Spina Bifida and Neural Tube Defects Hydrocephalus Cataract Section 3. Systemic Cancers (Benign and Malignant Tumors) 1. Endocrine Multiple endocrine neoplasia type I Multiple endocrine neoplasia type IIA Multiple endocrine neoplasia type IIB Thyroid Cancer Cowden Disease von Hippel-Lindau Syndrome Familial Paraganglioma Syndrome Familial Pheochromocytoma
43 44 45 46 46 47 47 49 51 52 53 54 55 56 57 58 59 60 61 63 64 65 65 66 68 68 71 73 74 76 78 80 81 84 86 Genetics for Surgeons
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2. Breast Breast Cancer (BRCA1) Breast Cancer (BRCA2) Breast Cancer (BRCA3 and BRCA4) Ataxia–Telangiectasia Li–Fraumeni Syndrome 3. Colon Hereditary Non Polyposis Colon Cancer Familial Adenomatous Polyposis Peutz–Jeghers Syndrome Autosomal Recessive Colon Cancer Juvenile Polyposis Syndromes Gastric Cancer Pancreatic Cancer Tylosis and Esophageal Cancer 4. Urogenital Papillary Renal Cancer Birt–Hogg–Dubé Syndrome Cutaneous Leiomyoma Syndrome Ovarian and Other Gynecologic Cancers Prostate Cancer Testicular Cancer 5. Skin Gorlin’s Syndrome Familial Atypical Mole Melanoma Syndrome Squamous Cell Carcinoma 6. Brain Gliomas Meningiomas Primitive Neural Ectodermal Tumors Pituitary Tumors Retinoblastoma
Contents
89 92 96 97 98 100 103 105 107 108 109 110 112 113 114 115 116 119 120 122 124 125 127 129 130 131 132
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Section 4. Topics Surgeons and Anesthetists Should Both Know Pheochromocytomas Malignant Hyperthermia Muscle Diseases Chloride Ion Channel Disease Sodium Ion Channel Disease Inherited C1 Esterase Inhibitor Deficiency
135 136 137 138 139 140 141
Section 5. Further Reading
143
Section 6. Glossary
145
Section 7. Abbreviations
195
Section 8. Index
197
Genetics for Surgeons
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1 1. Principles of Genetics for Surgeons
Changing Times in Modern Surgical Practice 2 Investigation of Familial Disease 2 Genetic Counseling 4 Penetrance 5 Expression 6 Diagnostic and Presymptomatic Testing 6 Practical Approaches to Genetic Testing 9
Principles of Genetics for Surgeons
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Principles of Genetics for Surgeons Inherited diseases contribute to a substantial proportion of the surgical workload. Recognition of a positive history of disease in a family will allow genetic testing and precise diagnosis, leading to the ability to screen at-risk members of a family presymptomatically and allow screening and prevention strategies to be implemented.
Changing Times in Modern Surgical Practice Review of leading medical and surgical journals shows that papers with a genetic or molecular biology component represent the most frequent area of publication. Some of these papers will involve childhood or prenatal diagnostic issues; an increasing proportion involve adult-onset single disorders, such as neurologic disease or familial cancers. In the future, complex multifactorial (or polygenic) diseases, such as cardiovascular and respiratory diseases, will become more prevalent, and already the ethical issues involved are complex and widely discussed. Surgeons need to know about genetics and how this field interacts with modern surgical practice.
Investigation of Familial Disease The first important step is to complete an accurate family tree. This can be done by working closely with the patient and his/her relatives, and asking relevant and specific questions about both sides of the family. In a case of suspected hereditary breast cancer, for example, initial questioning may not reveal any particular relevant history. A woman may know that her mother had no relatives with cancer and think this is sufficient, but not realize that her father’s two sisters and paternal aunt with breast cancer are also relevant in a disorder with autosomal dominant inheritance. If cancers in two organ systems, such as breast and ovarian, can be linked in a family history, this may suggest that mutations in a gene, such as
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BRCA1 or BRCA2, may have caused both cancers (either in the one affected relative or in different relatives within a family). In familial cancers, as with other hereditary diseases, asking about all relevant factors is the key. In hereditary colon cancer, for instance, the focus should be on identifying cancers of all sites and types, the age of onset, patterns in particular organ systems, the association with multiple adenomas or polyps in a particular part of the colon, and the histological type (an excess of mucoid and signet cell features in hereditary non polyposis colon cancer [HNPCC] often links colon cancers to endometrial cancers in HNPCC, or multiple colonic polyps with extracolonic effects such as retinal pigmentation or jaw cysts in familial adenomatous polyposis). If a germline mutation is present in the family, molecular testing may guide the surgeon by verifying the genotype of the cancer. Prompt referral to a surgeon for screening and referral to a geneticist to discuss the complex issues of consent for genetic testing, and the investigation of other family members, is essential. Cases are often new mutations (that is, the parents have not carried the faulty gene). In such cases, genetic testing of the parents can be reassuring and save screening other members of the family. Over the last 10 years, modern genetic techniques have raised complex issues of consent in families. The duty of the surgeon to his/her patient is to inform the patient that the disease is hereditary and that there are implications for other family members. Not all members, however, will want to know about the condition or will wish to have a genetic test, particularly if there are serious health implications and the condition has no treatment (as is the case, for example, with Huntington’s disease and some of the other hereditary neurogenetic diseases). Because of such sensitivities, prompt referral of the index case to a clinical geneticist will allow the genetics team to discuss these issues with the family, allowing referral back to the surgeon for screening and surveillance in the case of hereditary cancers and to other relevant professionals for treatment in the case of other conditions such as cystic fibrosis, or reassurance of the patient if the risks are low.
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Patients must give their consent for a genetic test. This is usually fully informed written consent and requires that patients know and understand the concepts of hereditary transmission of the disease to offspring and siblings, the physical characteristics and progression of the condition within the family, and the ethical and social issues involved (including insurance, employment, family dynamics, and the fact that testing is a voluntary process).
Genetic Counseling Counseling is sometimes regarded with suspicion. Genetic counseling involves imparting information to couples to inform them of the hereditary risks of disease and enable them to make choices about screening, diagnostic or predictive testing, and various lifestyle choices. Genetic screening also extends to prenatal and preimplantation diagnosis, with various types of embryo screening. Most individuals need time to assimilate genetic information and may need more than one appointment with the counselor, as they need to take in information that affects not only themselves, but also their whole family. Assessing the reasons why a patient is attending the clinic is important, because choices affect people in different ways. Risk assessment is important. Most people have a varied perception of risk and what constitutes high and low risk. If considering the risk of a congenital anomaly, couples may consider having further children a priority, and want to know the inherent risk of this congenital anomaly recurring, and what prevention or treatment is available. The Glossary explains the use of “recurrence” in genetics (rather than “reoccurrence” in surgery). Prenatal diagnostic testing may be an important part of their agenda in wanting reassurance in a future pregnancy. If a patient has a late-onset disease, they may not want to know if they have the gene (eg, in Huntington’s disease, for which no treatment is available). However, some patients, although aware there is no treatment, may want to have the certainty that a genetic test can give rather than living with the anxiety of not knowing. If they carry a gene for a hereditary cancer, such as ovarian cancer, careful screening or
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preventative surgery may be options, or the patient may not want to know that they carry a specific gene. Individuals often seek genetic testing soon after becoming aware of a condition in their family and may be anxious about testing. They may need simple reassurance about the hereditary nature of the condition, or more in-depth counseling about the condition itself and its features, diagnosis, potential screening or treatments, and long-term outlook. Insurance should also be covered in the discussion of genetic testing. In 2001, the UK Association of British Insurers, a body that covers over 95% of insurers, agreed a 5-year moratorium on genetic testing. This allows information on testing and use of family history to be collected. At present, insurers cannot force an applicant to take a genetic test, but may ask for results to be declared and are entitled to adjust premiums if the genetic risk is increased. So far, the only approved genetic test is for Huntington’s disease, but others are under scrutiny, including those for familial breast and colon cancers. For Huntington’s disease, insurers cannot use the information when assessing applications for mortgage purchases under £500,000 or health insurance under £300,000. Over these amounts, or for other insurance cover such as long-term care or critical illness, the insurer may increase the premium. Several insurers, however, do not use the family history in setting tariffs, and restrict questions to relevant health effects such as blood pressure and smoking history. In contrast, in the USA where a private insurance system predominates, insurers will often cover the cost of genetic testing and screening programs. Access to genetic testing is more difficult if no health insurance cover is in place, but unfair discrimination against patients with abnormal genetic test results is forbidden.
Penetrance Penetrance describes whether gene carriers of a condition develop features of the condition (see Glossary). Incomplete penetrance occurs in most disorders. Conditions with extremely high penetrance are rare. One such example is Huntington’s disease, where penetrance is around 99% – that is, virtually everyone who carries the Huntington’s disease
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gene will develop the condition if they live long enough. Conditions such as hereditary colon cancer caused by mismatch repair genes (such as MLH1) vary in that male gene carriers for MLH1 have around an 80% chance of developing colon cancer by 70 years of age. This means that, for genetic counseling, around one fifth of patients will not develop colon cancer, even though they may carry the gene. Counselors therefore need to ensure that patients know that such apparent skipping of disease does not mean that their children will not carry the gene, but that they still have a 50% chance of doing so. Penetrance varies between sexes; in female MLH1 carriers, penetrance is only around 70% by 70 years of age, possibly due to a protective effect from factors such as estrogen and other hormones.
Expression The expression of a gene is different to penetrance. Expression is a measure of the physical signs found in those who are penetrant for a particular gene. For instance, male MLH1 carriers may only express colon cancer, whereas female carriers may exhibit varied expression, with tumors in the ovary or uterus. This is sex-modified expression. Another example of variable expression occurs in a gene causing polydactyly: most gene carriers have one extra finger, but three extra fingers would be variable expression.
Diagnostic and Presymptomatic Testing Presymptomatic testing is different to diagnostic testing. A person who exhibits the clinical symptoms of Huntington’s disease may need a test to confirm the diagnosis or to exclude the possibility of other neurologic disorders, other causes of chorea, and other movement disorders. Such tests are not to be taken lightly because of the familial implications, and informed written consent is required for most later onset genetic tests. If the disorder is known in the family, presymptomatic or predictive testing is offered to “at-risk” symptomless persons to predict whether that individual carries the gene. Reassurance or future life planning, screening or preventative treatment, and the relief of uncertainty are the major reasons for such testing.
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Genetic testing is not usually undertaken in children under 18 years of age unless they are particularly mature, there is a good reason, or they have a potentially treatable condition. Exceptions would include some early-onset hereditary cancers, such as multiple endocrine neoplasia type II, in which thyroidectomy at 5 years of age may be curative.
Technical Aspects of Presymptomatic Gene Testing Screening for some genes can be very fast, such as in cystic fibrosis, where mutations in most segments of the gene are easily identified. Some larger genes, such as the dystrophin gene in Duchenne muscular dystrophy (DMD) or the BRCA2 gene in familial breast cancer, take much longer, partly due to their size and partly because no common mutation exists that allows easy screening in particular populations. Often an affected person’s blood needs to be tested to be absolutely sure of the exact mutation present in a family. This may be difficult if a boy with DMD has died before female relatives are aware of the diagnosis and seek genetic testing, or in familial breast cancer if the index relative is deceased. Testing of pathological material such as retained biopsy tissues is possible in some cases, but long storage in fixed materials makes this technically difficult and freshly extracted DNA is usually best (for instance, from blood or a cheek swab). Negative or normal results often mean that although the person is not at high risk, their risk falls back to the population risk of a new mutation or the population risk of the somatic incidence of the disease. In DMD, non mutation carrier females have a 1 in 3,000 chance of a new sporadic case of the condition – this is a low risk that will not usually deter couples from having a child. Non carriers of a breast cancer mutation still have a risk of breast cancer similar to the population risk (1 in 11 in the UK and US). This is sufficiently high to ensure that they still need to participate in a national breast screening program (such as that in the UK, where every woman is invited for mammographic screening every 3 years after 50 years of age until 65 years, with extension to 70 years recently approved).
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Such programs are controversial, although the evidence suggests that programs that are well established have better detection and survival rates. Because patients with a known family mutation who test negative for that mutation are at lower risk than their relatives, continuing breast screening at an early age is not necessary. It is prudent to make sure that patients in this situation do not go away with the thought that their normal gene test has left them with a zero risk of breast cancer, but rather with a risk close to 10% (albeit much lower that the BRCA1 gene carriers risk of up to 80%). Unfortunately, not all patients with a family history of disease are able to have a mutation identified, either because of limitations in gene screening or because the genes themselves have not yet been identified. For example, in the case of a familial breast cancer history, screening should be carried out for the appropriate duration and can be discontinued if a gene is subsequently identified in the family, and the patient tests negative for that gene. Most regional genetic centers have established protocols for testing common genetic disorders, especially late-onset diseases. In the UK, services are organized into regional centers within the National Health Service. Often patients can only have a genetic test if they see a geneticist, because of the complexities described above. Not all centers have laboratories that screen all the currently available genetic tests – a recent review of genetic testing within the UK has started a process of organizing laboratories to provide UK-wide availability of certain tests within specific labs. This seems a sensible approach to rationalize the service as demands and gene discoveries continually increase. Costs for common genetic tests such as cystic fibrosis and DMD are low, as mutations are easily detectible. In the case of cystic fibrosis, a common mutation, ∆F508, is present in 70%–80% of cases. In large genes such as BRCA1 and BRCA2 where no common mutations exist (except in the Ashkenazi Jewish populations and some countries in which there are a substantial number of founder
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mutations), searching has to be done by sequencing the entire gene. This can be very time consuming in small hospital laboratories, and may take months or even years. In the UK, high throughput sequencing facilities are slowly being introduced into clinical practice. Current commercial laboratories can screen and sequence the entire BRCA1 and BRCA2 genes in 3–4 weeks, at a cost of around $3,000. Costs for specific mutation analysis in smaller hospital laboratories are much lower, but reflect the longer time scale, and range from around $200 to $500 for specific mutations or screening of smaller genes. Universities or other academic institutions will often have a research program that can identify mutations more easily in complex or large genes, but these still need to be confirmed in an accredited service laboratory before the results can be given to patients. In the USA, genetic testing is not as cohesive, but individual laboratories may offer a wider range of genetic tests locally. Genetic counseling is widely accessible in both the UK and the USA.
Practical Approaches to Genetic Testing Case scenario
The following referral letter is sent to the regional genetics centre.
Dear Doctor, Please see and advise this 38-year-old lady, who is anxious as her sister has developed breast cancer at an early age and there is a mother who had an abdominal tumour. Yours sincerely Dr Local Practitioner
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Plan of action
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Most genetic centers will organize initial contact with the patient via a genetic counselor or nurse specialist – they can either telephone the patient to obtain a clearer family history or, in the case of a cancer referral (as here), will often send a written proforma for the patient to complete. This allows details of living or deceased relatives to be given and, with their permission, a cancer registry should be contacted to obtain a deceased patient’s tumor type or clinical records. It is important to verify the exact causes of cancers, as full details may not be known by the family. In this case, the pedigree shown in Figure 1 was constructed from the proforma. Pedigrees are labeled by Roman numerals at the lefthand side to indicate the generation, and by individual numbers under the symbol (circles for females, squares for males – see Glossary). The proband or index case – ie, the patient referred and seen first – is arrowed. Here, the proband is number III.8 or patient 8 in generation 3. The cancer registry confirmed that her sister (III.1) had an adenocarcinoma of the breast at 35 years of age. Discussion with the patient also revealed an affected aunt, and case records and pathology reports confirmed that both her mother (II.5) and maternal aunt (II.2) had ovarian cancer diagnosed at 44 and 42 years of age, respectively. This mixture of cancers is very suggestive of BRCA1 or BRCA2 (see p. 89), and is clearly additional information to that provided by the referring practitioner. This does not mean that the referring practitioner was wrong – only that the patient, having had more time to check details with her family members and with the genetic service checking diagnoses with the availability of clinical notes and registry data, can develop a more precise and accurate family tree. Often, some “abdominal” cancers turn out to be benign (such as uterine fibroadenomas) or colon cancers may be primarily ovarian with subsequent spread. This may allow reassurance of some patients without need for a clinic appointment in the former case or, in the latter case, explanation of why breast–ovarian gene tests are being ordered, rather than colon gene tests. The next step is to organize genetic testing. In families where several genes may be suspected, the first step is usually to analyze blood from an affected relative, as blindly analyzing the proband may not
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BRCA1
1
2
3
4
Figure 1. The pedigree of a family constructed from the proforma.
show any genetic changes – this may be because there are no changes in a particular gene, or the person may not be a carrier for a particular change. In this case, the sister (III.1) had a genetic test for BRCA1, which was shown to have a missense mutation in exon 11 – a significant change in the centre of the gene (if the test had been normal, the lab would have proceeded to analyze BRCA2 and other breast genes). With the knowledge that this is almost certainly the cause of the breast cancer in the sister, presymptomatic gene testing for the particular BRCA1 mutation may be offered to all members of the family. As BRCA1 is an autosomal dominant gene (see Glossary), both male and female members of the family are at risk of carrying the gene, although males are at low risk for breast cancer and zero risk for ovarian cancer. The next step is counseling for the proband, who elected to have a genetic test and was found not to carry the same mutation as her sister, thus reducing the proband’s cancer risk to that of the general population (note, this is not zero risk). Counseling was then offered to other members of the family, including all brothers and sisters. The proband’s brother (III.3) underwent predictive testing “to clarify the risks for my two
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daughters”. His mutation test confirmed he carried the same abnormal gene mutation as his affected sister. Genetic testing of his daughters is possible and is usually offered when the children are mature enough to understand the implications (16–18 years onwards unless treatment is available at an earlier age, such as in familial polyposis or multiple endocrine cancers [see p. 73], where preventative surgery in childhood may be helpful). In this case, his 20-year-old daughter (IV.1) underwent testing and was shown not to be a mutation carrier and reassured. Her 16-year-old sister (IV.2) may seek testing when she is older. The proband’s children (IV.3 and IV.4) do not need testing as they will inherit their mothers normal BRCA genes and the chance of a new spontaneous mutation is small. The affected sister (III.1) has risks of further breast cancer and other cancers, including ovarian cancer, so further genetic counseling for screening advice can be given. This scenario illustrates the interplay between the referral physician and genetic counselors, clinical genetic physicians, and eventually referral to the surgeon for screening – the affected patient will need further surveillance and other at-risk mutation members may be referred to other clinicians for screening. In the case of autosomal recessive disorders (see Glossary) such as cystic fibrosis, screening family members takes place not only for reassurance and identification of carrier status, but also to allow prenatal screening and options for choice within pregnancy.
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2 2. Common Surgical Conditions with a Hereditary Tendency
1. Gastrointestinal Tract Familial Pancreatitis 16 Cholecystitis 17 Pyloric Stenosis 18 Hiatus Hernia 19 Crohn’s Disease 20 Ulcerative Colitis 21 Celiac Disease 23 Abdominal Wall Defects 24 Spleen Disorders 25 Intestinal Atresias 26 2. Skin Tuberose Sclerosis 27 Neurofibromatosis Type I 30 Neurofibromatosis Type II 33 Multiple Lipomatosis 34 Cystic Hygroma 35 Sebaceous Cysts 36
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3. Cardiac Marfan’s Syndrome 37 Noonan’s Syndrome Type I 39 Down’s Syndrome 40 Cardiac Myxoma 41 Structural Cardiac Defects 42 4. Respiratory Cystic Fibrosis 43 Pneumothorax 44 Ehlers–Danlos Syndrome 45 Pectus Excavatum and Pectus Carinatum 46 Kartagener’s Syndrome 46
α -1 Antitrypsin Deficiency 47 Lung Cancer 47 Congenital Airway Problems 49 5. Hematologic Hemochromatosis 51 Hemophilia 52 Acute Myeloid Leukemia 53 Chronic Myeloid Leukemia 54 Chronic Lymphocytic Leukemia 55 Non Hodgkin’s Lymphoma 56 Hodgkin’s Lymphoma 57 Multiple Myeloma 58
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6. Neurologic Duchenne Muscular Dystrophy 59 Hereditary Motor and Sensory Neuropathy 60 Huntington’s disease 61 Fragile X Syndrome 63 Facioscapulohumeral Muscular Dystrophy 64 Dupuytren’s Contracture 65 Congenital Dislocation of the Hip 65 Spina Bifida and Neural Tube Defects 66 Hydrocephalus 68 Cataract 68
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Familial Pancreatitis MIM
167800
Clinical features
Upper abdominal pain and vomiting and raised amylase levels. The features are similar to those of sporadic pancreatitis. The abdominal pain often radiates through to the patient’s back and vomiting can be persistent. The attacks usually settle with intravenous fluids and pain relief.
Genes
PRSS1 (cationic trypsinogen), SPINK1 (serine protease inhibitor, Kazal type, 1)
Chromosomal location
7q35
Prevalence
Around 2%–3% of cases of pancreatitis have a familial basis.
Inheritance
Autosomal dominant, with around 80% penetrance.
Age at onset
Approximately 14 years of age onwards, with frequent attacks of abdominal pain requiring hospital admission. Onset of carcinoma is around the mid fifties.
Diagnosis
Magnetic resonance imaging, cholangiopancreatography, and endoscopic ultrasound are gradually replacing endoscopic retrograde cholangiopancreatography. Intraepithelial neoplasia may be a premalignant change in chronic pancreatitis
Genetic testing
Routinely available for PRSS1. A total of 80% of patients develop chronic pancreatitis, while 40% of all patients proceed to carcinoma.
Screening
Those at risk should be under regular surveillance, but no specific screening protocol exists. Trials using magnetic resonance scanning to screen patients are in progress.
Mutational spectrum
Heterogeneity exists. Some cases are associated with BRCA2 (breast cancer 2) mutations, particularly when there are previous cases of pancreatic carcinoma and breast carcinoma in the family history. Pancreatic insufficiency also occurs in cystic fibrosis and Shwachman–Diamond syndrome (MIM 260400, chromosome 7q11).
Counseling issues
It is now thought that acute and chronic pancreatitis are part of a spectrum of disease, rather than two separate entities.
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Cholecystitis MIM
Not listed
Clinical features
The patient presents with right upper quadrant pain radiating through to the back with nausea. Intravenous fluids and antibiotics are required. See Figure 1.
Figure 1. A gallstone.
Gene
Unknown
Chromosomal location
Unknown
Prevalence
Around 50%–70% of cholecystitis patients have a family history of the disease, but the proportion may be much higher for earlier onset cases.
Inheritance
Autosomal dominant with incomplete penetrance.
Age at onset
Onset is generally earlier than in sporadic cases (generally 20–30 years of age, compared with 40–50 years in sporadic cases).
Diagnosis
Clinical examination and ultrasound.
Genetic testing
Not available. No genes have as yet been linked or identified.
Screening
At present, there are no clear guidelines for first-degree relatives, but patients should be promptly referred to a specialist if abdominal pain or other relevant symptoms appear.
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Figure 2. Cholangiocarcinoma.
Counseling issues
Symptoms in family members should be promptly investigated. There is an increased risk of cholangiocarcinoma (see Figure 2) in BRCA2 gene carriers, and increased risk of bile duct cancers in Peutz–Jeghers syndrome, although there does not appear to be a definite association between familial cholecystitis and cancer of the gall bladder.
Pyloric Stenosis MIM
179010
Clinical features
Projectile vomiting, visible peristalsis, and palpable abdominal tumor.
Gene
Unknown
Chromosomal location
Unknown
Incidence
Around 5 per 1,000 births
Inheritance
Autosomal dominant with variable penetrance.
Age at onset
Predominantly in the neonatal period, but cases have been described with onset in middle age.
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Diagnosis
Ultrasound
Genetic testing
Not available
Screening
Pediatric assessment in the neonatal period with abdominal ultrasound.
Mutational spectrum
Heterogeneity exists. Some families had suggested linkage to NOS1 (nitric oxide synthase 1). Other families display the presence of a lingual frenulum or other congenital malformations. There may also be an association with chromosomal abnormalities.
Counseling issues
In familial cases, inheritance is most commonly autosomal dominant. However, penetrance is incomplete (around 40%–50%). Further cases do occur in families with an isolated case. Recurrence risks in this situation vary depending on gender: at least 10% in sporadic cases for male siblings and around 2% for female siblings. If congenital malformations are present, check the chromosome analysis in case a chromosomal rearrangement is the cause of both the malformation and the pyloric stenosis.
Hiatus Hernia MIM
142400
Clinical features
Gastroesophageal reflux, occasional dysphagia and chest symptoms.
Gene
Unknown
Chromosomal location
13q14 and others
Prevalence
1%–2% of hiatus hernia or gastroesophageal reflux.
Inheritance
Autosomal dominant with variable penetrance.
Age at onset
Childhood or early adulthood (often earlier than sporadic cases).
Diagnosis
Refer to a gastrointestinal specialist for endoscopy, radiology, and pH monitoring.
Genetic testing
Not available. Some large dominant families have suggested linkage to chromosome 13q14.
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Screening
Assessment of all family members by endoscopy from early adulthood.
Counseling issues
Careful counseling and explanation of autosomal dominant inheritance if two or more affected members in the family. There is a small risk of cancer of the esophagus.
Crohn’s Disease MIM
266600
Clinical features
Intermittent diarrhea, abdominal pain, malabsorption, and many systemic features (such as eye signs). See Figure 3.
Gene
NOD2 (nucleotide-binding oligomerization domain 2), CARD15 (caspase-recruitment domain-containing protein 15)
Chromosomal location
16q12, 5q31
Prevalence
100 per 100,000 births
Inheritance
Autosomal dominant. This is a complex trait linked to autoimmune disease.
Age at onset
Two peaks: one during the teenage years and early twenties, and a second during middle age.
Diagnosis
Small bowel series, colonoscopy, and biopsy.
Genetic testing
Genetic testing is available for NOD2 and CARD15, but usually only on a research basis. Mutations within the OCTN (organic cation transporter) genes increase the risk of Crohn’s disease and may be helpful in distinguishing patients at high risk.
Screening
Not easily done. Seek advice from a gastrointestinal specialist. Genetic testing may refine this process in the future.
Mutational spectrum
Heterogeneity exists and other inflammatory bowel disease genes have been identified.
Counseling issues
The phenotype in patients with NOD2 is associated to a greater degree with fistulization, ileal disease, stenosis, and resection. Around 45% of Crohn’s disease is linked to NOD2 with at least
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Figure 3. A barium enema demonstrating extensive Crohn’s colitis with typical “rose thorn” ulcers.
one affected allele. Approximately 10% of Crohn’s disease cases have an affected relative. Relatives have a 10-fold risk of developing Crohn’s disease.
Ulcerative Colitis MIM
191390
Clinical features
Bloody diarrhea, weight loss, acute or chronic illness, and many systemic features. See Figure 4.
Genes
IBD1 (inflammatory bowel disease 1), IBD2, IBD3
Chromosomal location
16p12–q13, 12p13, 6p, 10q23
Prevalence
200 per 100,000
Inheritance
Polygenic trait
Age at onset
Many patients are young (early twenties), but the disease may present later.
Diagnosis
Colonoscopy and biopsy. It may be difficult to exclude Crohn’s disease.
Genetic testing
Genetic testing is available for IBD genes through interested research institutions. However, the predictive power of testing is not known at present. IBD2 is often associated with ulcerative colitis, but the diagnosis currently remains clinical and endoscopic.
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Figure 4a. Ulcerative colitis. A barium enema demonstrating the fine granular appearance of ulcerative colitis.
Figure 4b. A resection specimen (colon)
Screening
No real screening program currently exists for relatives, although one is being considered in the UK.
Mutational spectrum
Heterogeneity exists. Several environmental factors and genes are involved.
Counseling issues
One mutation in IBD1 may predispose to ulcerative colitis, two mutations may predispose to Crohn’s disease, and there may be a link or common pathway between the two disorders.
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Celiac Disease MIM
212750
Clinical features
Chronic gastrointestinal symptoms, including weight loss, metabolic bone disease, and anemia. These symptoms are often insidious; patients may simply present with vague ill health.
Gene
No specific gene, but associated with the HLA complex.
Chromosomal location
HLA gene, 5q31–33, 11q
Prevalence
1 in 266. This is one of the most common genetic diseases known, although penetrance is often incomplete and mild cases go unrecognized.
Inheritance
Polygenic or multifactorial genetic susceptibility.
Age at onset
Variable, onset at any age.
Diagnosis
Small intestinal biopsy, improvement on gluten-free diet.
Genetic testing
Not available for any particular mutation. However, HLA typing is available for the DQ2 and DQ8 haplotypes, which are associated with 98% of cases.
Screening
Serological and endomysial antibody testing. Pathological duodenal biopsy is used to confirm the diagnosis.
Mutational spectrum
Heterogeneity exists with loci on 11q and 5q31–q33 involved in non-HLA cases.
Counseling issues
In a family with one case, the sibling recurrence risk for celiac disease is 10%. There is 70% concordance in identical twins.
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Abdominal Wall Defects MIM
130656 (Beckwith–Wiedemann syndrome [BWS]. Also known as: exomphalos, macroglossia, and macrosomia) 230750 (gastroschisis) 164750 (exomphalos/omphalocele)
Clinical features
Gastroschisis or exomphalos may be isolated defects, or associated with other congenital malformations or part of chromosomal defects. Additional defects are seen in 15% of gastroschisis and 50% of exomphalos cases. In BWS, the omphalocele or exomphalos is associated with ear-lobe creases and punctate ear lesions. Around 97% of cases have macroglossia and 80% have organ overgrowth (macrosomia). There is an increased risk of malignancy, especially hepatoblastoma and Wilms’ tumor.
Gene
CDKN1C (cyclin-dependent kinase inhibitor 1C; BWS)
Chromosomal location
11p15.5
Prevalence
60 per 100,000 births
Inheritance
Complex, autosomal dominant. In BWS, imprinting and uniparental disomy may occur (see Glossary).
Age at onset
In utero or at birth.
Diagnosis
Examination at birth or picked up on fetal ultrasound from 15 to 16 weeks into pregnancy.
Genetic testing
Genetic testing is available for BWS in supraregional centers, and amniocentesis should be offered prenatally if this is not an isolated defect.
Screening and counseling
Chromosome analysis is indicated in BWS, or if other malformations are present. Mutations in BWS will allow screening of parents to determine the risk to further offspring. Hypoglycemia is common in BWS in the neonatal period and blood glucose should be monitored.
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Spleen Disorders MIM
208530 (asplenia) 271400 (hyposplenia) 306955 (heterotaxy syndrome) 601086 (laterality disorders)
Clinical features
Polysplenia syndrome (essentially “bilateral” left sidedness) is associated with cardiac malformations and polysplenia: bilateral spleens in each side of abdomen with accessory or rudimentary splenic tissue. Asplenia is associated with “bilateral” right sidedness (Ivemark triad of spleen agenesis, heart defects, and situs inversus) and is more common in males than females (in polysplenia there is equal sex incidence). The cardiac defects are more severe in asplenia than in polysplenia and aberrant mesenteric attachments are found. Cardiac failure causes early death. Lung mirror imaging occurs with both conditions, with similar lobe formation and number. Heterotaxy syndrome consists of dextrocardia, situs inversus, and asplenia or polysplenia. There may be a midline liver. Patients with asplenia are prone to life-threatening infections.
Gene
Unknown
Chromosomal location
Xq26.2 (heterotaxy syndrome)
Prevalence
Rare
Inheritance
Autosomal recessive and autosomal dominant inheritance have been suggested for both asplenia and polysplenia. Some patients may have a sporadic developmental growth defect. Heterotaxy syndrome (laterality sequence where one side of the body is affected) is sex-linked, although autosomal recessive and autosomal dominant laterality disorders exist.
Age at onset
Congenital
Diagnosis
Radiologic imaging of abdomen with CT, ultrasound, and magnetic resonance imaging.
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Genetic testing
Not available
Screening
Radiological imaging (ultrasound) should be conducted in relatives if a hereditary form is suspected.
Counseling issues
Both asplenia and polysplenia have occurred in the same family, suggesting that this is determined by laterality genes dealing with body symmetry. The recurrence risk in an isolated case with no family history is around 5%.
Intestinal Atresias Esophageal Atresia The prevalence of esophageal atresia is 1 in 30,000 births. Over 60% of cases are associated with chromosomal or developmental syndromes, including Edwards’ syndrome (trisomy 18) and VATER syndrome (acronym of Vertebral defects, Anal atresia, TracheoEsophageal fistula, and Renal dysplasia) (see Figure 5). The remaining cases are not genetic, and are mainly sporadic. Recurrence risks for siblings are around 1%.
Figure 5. A pathological specimen with esophageal atresia and tracheoesophageal fistula.
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Duodenal Atresia This is a rare defect. It is usually sporadic, but may be associated with trisomy 21 (Down’s syndrome). The recurrence risk is around 1 in 100 for isolated cases.
Anal Atresia This is rare and usually sporadic. It is associated with congenital malformation syndromes, including chromosomal defects and VATER syndrome. The risk of recurrence is around 1 in 100 for isolated cases, and 1 in 50 for VATER syndrome.
Biliary Atresia This is associated with Alagille syndrome (intrahepatic cholestasis, with paucity of intralobular bile ducts) and may also be associated with chromosomal disorders and intrauterine infections (particularly viral hepatitis). It is generally sporadic. Familial intrahepatic cholestasis disorders are usually autosomal recessive.
Meckel’s Diverticulum Bowel duplications and malrotations including an aberrant appendix and Meckel's diverticulum are usually sporadic, although there are rare reports of familial Meckel’s diverticulum consistent with autosomal dominant inheritance. In isolated cases, the recurrence risk is negligible.
Tuberose Sclerosis (also known as: tuberose sclerosis complex [TSC]) MIM
191100 (TSC1), 191092 (TSC2)
Clinical features
Often adenoma sebaceum (NB, not adenomas and not sebaceous, but actually facial angiofibromas [see Figure 6]), epilepsy, and skin hypopigmentation. The skin features were first described as hypopigmented macules and a facial rash, but also include confettilike hypopigmentation, shagreen patches, periungual fibromas, and dental enamel pits (see Figures 7–9). Cardiac rhabdomyomas in
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Figure 6. Facial angiofibromas.
Figure 7. Hypopigmented macules.
Figure 8. A shagreen patch.
Figure 9. A periungual fibroma on the nailbed of a right big toe.
early age are also associated and may cause arrhythmias. Renal angiomyolipomas (seen in 65% of cases) present with advancing age. Renal cell carcinoma is seen in 3% of cases. Retinal hamartomas (phakomas) are generally asymptomatic. Subependymal giant cell astrocytomas occur in 1% patients, often causing obstructive hydrocephalus. TSC1 is present in 45% of cases, while TSC2 occurs in 55% of cases. Genes
TSC1 (tuberous sclerosis 1 gene; also known as hamartin), TSC2 (also known as tuberin)
Chromosomal location
9q34 (TSC1), 116p13.3 (TSC2)
Prevalence
1 in 12,000
Inheritance
Autosomal dominant (60% sporadic in TSC1; 32% sporadic in TSC2)
History
Described by Bourneville in 1880 and by Pringle in 1890. Also known as epiloia. In 1908, Vogt described the classical triad of mental retardation, seizures, and adenoma sebaceum. More recently, Gomez defined the clinical criteria. The name “tuberose sclerosis” stems from the tubers seen in the cerebral cortex, best
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Figure 10. Periventricular calcification in tuberose sclerosis.
shown by brain magnetic resonance imaging. Periventricular calcification is also characteristic (see Figure 10). Epilepsy occurs in 60% of patients and learning disability in around 40% (particularly in patients with mutations in TSC2). Age at onset
Symptoms vary with age of presentation: epilepsy may appear in the neonatal period, with hypopigmented macules and other skin problems appearing in early childhood – often as early as 1 year. Facial angiofibromas generally appear at around 9–10 years of age onwards. Learning disability appears in adolescents, and renal disease in adults (especially with TSC2). Only 4% of cases present with epilepsy in adulthood and there may be no other features, or only one feature (such as periungual fibroma). A total of 1% of patients (characteristically females of reproductive age) develop lung adenomatoid malformation (or lymphangioleiomyomatosis of the lungs). This consists of diffuse proliferation of smooth muscle cells. Surgical treatment may produce some relief, but if there is persistent development then lung transplantation is the only permanent form of therapy.
Diagnosis
Mainly clinical, with confirmation possible on genetic testing. Gomez described the clinical diagnostic criteria – patients must have at least two major features (from: facial angiofibroma or forehead plaque; periungal fibroma; shagreen patch; retinal hamartomas; cortical tubers; subependymal nodules; subependymal giant cell astrocytomas; cardiac rhabdomyoma; renal angiomyolipoma; and more than three hypomelanotic macules).
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Genetic testing
Genetic testing is available for TSC1 and TSC2. Although time consuming (around 10–14 months) and expensive, this is particularly useful in some situations, such as in prenatal diagnosis (if the mutation in the family is known in advance) or when there is no family history (because of the disease’s low penetrance) to allow diagnosis of familial cases or clarify risks to siblings and children.
Screening
Woods lamp should be used to check for skin signs, rigorous clinical examination to check for dental pits, and ultrasound scan of renal tracts to check for angiomyolipomas. If these are present, rescan every 1 or 2 years. Use computed tomography or magnetic resonance imaging of the brain to check for cortical tubers. Relatives who are at risk should have a detailed clinical examination and genetic testing or computed tomography screening of the brain and ultrasound screening of the renal tracts.
Mutational spectrum
Few cases are thought to exist other than those caused by mutations in TSC1 and TSC2.
Counseling issues
If a mutation is found, but the parents are normal, there is a 5%–10% risk of germline mosaicism in any further children (see Glossary). Behavioral therapy can be helpful in dealing with autistic-like problems, sleep disorders, and hyperactivity.
Neurofibromatosis Type I (also known as: NF1) MIM
162200
Clinical features
More than six café-au-lait spots (CALS, seen in 95% of cases) (see Figure 11), neuromas, fibromas, and neurofibromas. Axillary freckling (Crowe’s sign, 80%), Lisch nodules (pigmentation of the iris, 80%) (see Figure 12), macrocephaly (40%), learning difficulties, ranging from patients with mild learning difficulties who can be given normal schooling (20%–30%) to moderate patients with special educational needs, hyperactivity, and a lack of concentration (up to 20%).
Gene
NF1 (neurofibromin 1)
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Figure 11. Café-au-lait spots.
Figure 12. A Lisch nodule.
Chromosomal location
17q11.2
Prevalence
1 in 4,400
Inheritance
Autosomal dominant. New mutations are present in >50% of cases.
History
Robert W Smith, Professor of Surgery in Dublin, described cases in 1849. In 1882, Friedreich Daniel Von Recklinghausen was the first to recognize that the tumors originated from connective tissue around the nerve. Crowe, who described the axillary freckling, added cases in 1956.
Age at onset
Macrocephaly develops in infancy and CALS usually appears by 6 years. Neurofibromas and Lisch nodules develop with age, and peripheral neurofibromas may appear around puberty.
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Figure 13. Plexiform neuroma.
Diagnosis
A clinical diagnosis. The defined criteria are two or more of the following: • six or more CALS (>1.5 cm postpuberty or >0.5 cm prepuberty) • two or more neurofibromas or one or more plexiform neuromas (see Figure 13) • axillary or groin freckling
Genetic testing
Available, but time consuming and expensive. Rarely used in practice as most cases are new mutations.
Screening
Annual basis for general review of growth, blood pressure, and visual field examination. Annual ophthalmic examination until 10 years of age to check for optic gliomas. Complications such as scoliosis, epilepsy, and pheochromocytomas (seen in <5% of cases) should be assessed.
Heterogeneity
Most cases are NF1 or NF2, although schwannomatosis may exist as a separate presentation.
Counseling issues
Regular assessment is important. Malignant tumors occur in 10%–15% of cases and include optic nerve gliomas, astrocytomas, rhabdomyosarcoma, chronic myeloid leukemia, and pheochromocytomas. Nerve sheath tumors occasionally turn malignant. Vestibular schwannomas (acoustic neuromas) are not seen in NF1, but are a characteristic feature of NF2 (next entry).
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Neurofibromatosis Type II (also known as: NF2) MIM
101000
Clinical features
Classical central neurofibromatosis with vestibular schwannomas, other malignant central nervous system tumors (including meningioma), and spinal tumors (including ependymomas).
Gene
NF2 (neurofibromin 2; also known as schwannomin and merlin)
Chromosomal location
22q12.1
Prevalence
1 in 35,000
Inheritance
Autosomal dominant; 50% of cases are new mutations. Around 10% of cases present in the first 10 years of life. Thirty percent of de novo cases are mosaic; their children have a <50% risk.
Age at onset
The average age at presentation is the early twenties; 10% of cases present by 10 years of age.
Diagnosis
Clinical examination and genetic analysis of NF2. This is useful as it allows presymptomatic gene testing in families. Family members should be screened for vestibular schwannomas by magnetic resonance imaging and ear, nose, and throat examinations.
Genetic testing
Available through the clinical genetics team in supraregional genetic laboratories. Full gene sequencing takes 10–12 months.
Screening
Should be conducted on an annual basis from birth, with eye examination for subcapsular lenticular opacity, neurologic, and skin examination. After 10 years of age, audiologic testing should be conducted; from 14 years onwards, magnetic resonance imaging screening should be carried out at 2-yearly intervals. Most patients develop central nervous system tumors by 30 years.
Mutational spectrum
Heterogeneity is rare. If the gene test is normal, consider a diagnosis of NF1.
Counseling issues
Genetic testing is possible. Because of the risk of vestibular schwannomas and malignant tumors, this is one of the few disorders where testing can be recommended in childhood.
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Multiple Lipomatosis MIM
151800, 151900
Clinical features
Multiple symmetric lipomatosis with predominance in the neck, chest, and upper back, or multiple asymmetric lipomatosis involving the arms and legs.
Gene
Unknown
Chromosomal location
12q15
Prevalence
Underestimated in the population, the true figure not known.
Inheritance
Autosomal dominant
History
A variant called Dercum’s disease (adiposis dolorosa, MIM 103200) with painful lipomas, obesity, and sparse pubic hair was described by Francis Dercum, an American professor of nervous diseases, in 1888. Launois and Bensaude first described this disorder definitively in 1898.
Age at onset
Around 35 years of age.
Diagnosis
Clinical examination shows lipomatosis with autosomal dominant inheritance.
Genetic testing
Not available at present as no major gene has been isolated.
Mutational spectrum
Heterogeneity probably exists. The multiple symmetric lipomatosis condition appears to be different from both multiple asymmetric lipomatosis and Dercum’s disease.
Counseling issues
The disease has a benign course, but cosmesis is major factor to consider.
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Cystic Hygroma MIM
257350
Clinical features
Large cystic mass in the nuchal region (see Figure 14). This may regress during early pregnancy. After birth, it may be noticeable as neck webbing (contraction of the tissue around the neck region) (see Figure 15). Girls with Turner syndrome have congenital lymphoedema, short stature, short fourth metacarpal and metatarsal bones (see Figure 16), ovarian dysgenesis, and cardiac abnormalities (including coarctation of the aorta).
Gene
X chromosome (Turner syndrome), and other unknown genes.
Chromosomal location
Monosomy of the X chromosome.
Prevalence
Turner syndrome: 1 in 2,000 births. Other types are rare.
Inheritance
Autosomal recessive, sporadic, or chromosomal.
Figure 14. Cystic hygroma.
Figure 15. Neck webbing in Turner syndrome due to cystic regression.
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Figure 16. A short fourth metacarpal.
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History
Henry Turner, an American endocrinologist, described cystic hygroma in 1938. This was the first sex chromosomal disorder to be described.
Age at onset
Usually congenital or noted prenatally on an ultrasound scan.
Diagnosis
Ultrasound scan 15–18 weeks prenatally. Ultrasound of the neck and transillumination postnatally.
Genetic testing
Genetic testing is available for Turner syndrome (45X), but not for rare recessive types. Chromosomal analysis will confirm 45X, if all or part of the X chromosome is missing. If both X chromosomes are present, consider autosomal recessive variants.
Screening
Nuchal thickness scanning during weeks 10–14 of pregnancy, ultrasonography during weeks 15–18, and cardiac Doppler ultrasound at ≥20 weeks for aortic and other cardiac defects in utero.
Mutational spectrum
Heterogeneity exists. Some forms are rare and recessive; others are linked to Turner syndrome.
Counseling issues
If recessive, there is a one in four recurrence risk. The prevalence of Turner syndrome decreases with maternal age. This is unlike other age-related aneuploidies (disorders in which patients have an extra autosomal chromosome, such as Down’s syndrome – trisomy 21), in which the risk increases exponentially with higher maternal age. Girls with Turner syndrome will need hormonal therapy around puberty and discussion of assisted fertility techniques when considering reproductive options. Pregnancies can occur in Turner syndrome with appropriate assistance. In the majority of cases of 45X, some Y chromosome fragments are present so screening for gonadal malignancies is necessary. Refer the patient to a clinical geneticist, specialist gynecologist, and endocrinologist for management.
Sebaceous Cysts MIM
184500 (steatocystoma multiplex)
Clinical features
Oval benign tumors on the back, trunk, and thigh.
Gene
Unknown
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Chromosomal location
17q12–q21
Prevalence
The sporadic type is extremely common. The exact prevalence of hereditary types is unknown.
Inheritance
Sporadic, autosomal dominant
Age at onset
Middle age and beyond
Diagnosis
Clinical with histological confirmation
Genetic testing
Not available
Screening
None available
Counseling issues
Inheritance may be autosomal dominant in some families.
Marfan’s Syndrome MIM
154700
Clinical features
Skeletal problems, including arachnodactyly, pectus deformities of the chest, joint laxity, and scoliosis (see Figure 17). Cardiac abnormalities include mitral or aortic regurgitation, a dilated aortic root, and aortic aneurysms. Ocular abnormalities are common, and include myopia and, occasionally, lens dislocation. Connective tissue weakness can cause hernia, lumbar striae, pneumothorax, and a narrow, high-arched palate.
Figure 17. Marfanoid habitus.
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Gene
FBN1 (fibrillin 1)
Chromosomal location
15q21
Prevalence
1 in 14,000 births
Inheritance
Autosomal dominant
History
Described by Bernard Marfan, the foundation Professor of Pediatrics in Paris, in 1896.
Age at onset
Congenital forms occur, but are rare and have severe cardiac involvement. Most forms are obvious; patients present with tall stature in childhood and heart defects.
Diagnosis
Clinical examination and defined criteria requiring the major involvement of two organ systems and minor involvement of a third system.
Genetic testing
Genetic testing is available for FBN1 mutations and several have been described, with no major common mutation.
Screening
Should include annual ophthalmic examination and regular echocardiographic screening to detect aortic root dilatation. Strenuous or very competitive sports (eg, weightlifting) should be avoided due to potential heart and joint problems.
Mutational spectrum
Heterogeneity exists with FBN2 mutations found in Beal’s syndrome (congenital contractural arachnodactyly) and is similar to Marfan’s syndrome, but without the cardiac features. Other causes of a Marfanoid habitus include familial ectopia lentis (MIM 129600), Ehlers–Danlos syndrome, familial mitral valve prolapse, and multiple endocrine neoplasia type IIB.
Counseling issues
As for other disorders with autosomal dominant inheritance. Careful examination and fulfilling of the criteria are important to exclude other conditions listed above. Penetrance is variable, and not all families have the eye changes or the tall stature.
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Noonan’s Syndrome Type I MIM
163950
Clinical features
Short stature and a short, webbed neck. Cardiac anomalies (particularly pulmonary stenosis, atrial septal defect, ventriculoseptal defect, patent ductus arteriosus, and hypertrophic cardiomyopathy), and chest deformity (pectus carinatum superiorly and pectus excavatum inferiorly), wide-spaced nipples, and a characteristic dysmorphic facial appearance with ptosis of the eyelids and wiry hair (see Figure 18).
Gene
PTPN11 (protein-tyrosine phosphatase nonreceptor-type, 11)
Chromosomal location
12q24
Inheritance
Autosomal dominant
Age at onset
Neonatal onset with cardiac problems and feeding difficulties.
Diagnosis
Clinical with confirmation on genetic testing in difficult cases.
Genetic testing
Available in research centers.
Screening
Cardiac problems are the most severe. Screen with echocardiography.
Counseling issues
Autosomal dominant inheritance with variable penetrance, so the affected parent should be screened for latent cardiac problems. Around 10% of affected individuals have learning and schooling problems, and coagulation abnormalities can be a problem.
Figure 18. Wiry hair and a low hairline, characteristic of Noonan’s syndrome.
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Down’s Syndrome MIM
190685
Clinical features
Various malformations, including simian creases (see Figure 19). Several surgical problems, including congenital heart disease, increased incidence of goiter, umbilical and groin hernias, and macroglossia.
Gene
Complete trisomy of chromosome 21
Chromosomal location
Chromosome 21
Prevalence
1 in 600 live births
Inheritance
Chromosomal: 95% of cases are the result of age-related nondysjunction, 3% result from familial translocation (where two or more chromosomes have segments shared or exchanged), and 2% are mosaic cases. In mosaic cases, some cell lines have normal chromosomes and others have the extra cell line – this may allow a milder phenotype, particularly if brain tissue has the normal chromosome complement and blood has the extra cell line.
History
Described by Langdon Down, an English physician, in 1887.
Age at onset
Congenital, although rare milder mosaic cases may not be recognized until adolescence.
Diagnosis
Chromosome analysis will confirm a diagnosis suspected on clinical grounds.
Figure 19. A simian crease.
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Screening
Prenatal diagnosis by maternal serum screening (in the first or second trimester), ultrasound (neck-fold thickness, nasal bone appearance, and structural markers in the first and second trimester), and amniocentesis (from 15 weeks onwards).
Counseling issues
Recurrence risks by age are available for parents wishing to have a further child after one child with Down’s syndrome. Typical risks are around 1 in 100, but around 1 in 10 if the affected child has translocation Down’s syndrome.
Cardiac Myxoma MIM
160980 (Carney complex type I [CNC1]; also known as NAME or LAMB syndromes) 605244 (Carney complex type II [CNC2])
Clinical features
Spotty pigmentation, cardiac and other myxomas, endocrine tumor – also known by the acronyms NAME (Nevi, Atrial myxoma, Myxoid neurofibromata, Ephelides) and LAMB (Lentigines, Atrial myxoma, Myxoid tumors, Blue nevi)
Gene
PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, α; CNC1). Unknown for CNC2.
Chromosomal location
17q23–q24 (CNC1), 2p16 (CNC2)
Prevalence
Extremely rare
Inheritance
Autosomal dominant
Age at onset
Atrial myxomas develop during childhood.
Diagnosis
A distinctive combination of dermatological and cardiac clinical features is suggestive of the diagnosis. Confirmed by cardiac echocardiography and gene testing.
Genetic testing
Available for PRKAR1A on a research basis. Around 50% of patients have CNC1. In patients who do not have CNC1, linkage analysis may allow testing for the CNC2 locus on 2p16 in large families, but this is only available on a research basis.
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Screening
Gene carriers for cutaneous tumors and cardiac echocardiography in childhood. Endocrine problems, including Cushing’s syndrome and Sertoli cell tumors of the testis, have been reported.
Mutational spectrum
Heterogeneity exists. At least two CNC types and gene loci are known and further types may exist.
Structural Cardiac Defects Mitral Valve Individuals with familial mitral valve prolapse (MIM 157700) have displacement or billowing of the mitral valve leaflets into the left atrium. Complications include fatal arrhythmias, endocarditis, and even sudden death. Inheritance is autosomal dominant, with one locus on 16p11.2 (myxomatous mitral valve prolapse 1 [MMPV1]), a second on 11p15.4 (MMPV2), and an X-linked type on Xq28. Heterogeneity exists, with several families described. Associations with connective tissue disorders, Ehlers–Danlos syndrome, cutis laxa, pseudoxanthoma elasticum, osteogenesis imperfecta, and Marfan’s syndrome should be excluded.
Aortic Valve Aortic stenosis associated with Williams’ syndrome, a chromosomal microdeletion defect of the ELN (elastin) gene on chromosome 7. Some patients with Noonan’s syndrome may also have aortic valve defects.
Pulmonary Valve Rarely has a familial cause. Noonan’s syndrome is associated with pulmonary stenosis.
Tricuspid Valve Tricuspid atresia is common in 1%–3% of cardiac defects. Familial autosomal dominant disease is rare, but has been reported (MIM 605067).
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Atrial Septum Isolated atrial septal defect (ASD) is often familial – one locus on 6p21.3 (ASD1, MIM 108800) is autosomal dominant. It is also associated with numerous congenital malformation syndromes, including Holt–Oram syndrome (autosomal dominant inheritance and cardiac or limb defects), due to mutations in the NKX2-5 gene
Ventricular Septum Hereditary isolated ventricular septal defects are rare, but when they do occur they are often associated with congenital malformation syndromes (including Down’s syndrome and arteriovenous canal defects). The GATA4 (GATA-binding protein 4) gene on 8p22–p23 is associated with autosomal dominant septal defects, including atrial septal defect and pulmonary valve thickening.
Patent Ductus Arteriosus This is the second most common cardiac defect, occurring in 1 in 3,000 live births. After prematurity, genetic causes are common, but most are found in congenital malformation syndromes. Familial forms exist and can be either autosomal dominant (MIM 607411) or autosomal recessive. The recurrence risk in siblings is around 5%.
Cystic Fibrosis MIM
219700
Clinical features
Respiratory difficulties leading to repeated chest infections, pancreatic insufficiency, meconium ileus, and reduced fertility.
Gene
CFTR (cystic fibrosis transmembrane conductance regulator)
Chromosomal location
7q31.2
Incidence
1 in 2,500 births in northwest Europe. Around 1 in 25 of the western European population is a gene carrier.
Inheritance
Autosomal recessive
Age at onset
Infancy. Occasionally, presentation is with pancreatic insufficiency with pale, smelly stools and malabsorption.
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Diagnosis
Sweat electrolytes (sodium and chloride) >60 mmol/L. Mutation testing confirming mutations in CFTR is commonly available.
Genetic testing
Genetic testing is available for mutations in CFTR. Several common mutations exist, depending on the population. The ∆F508 mutation is found in 70% of carriers.
Screening
Neonatal screening by heel prick for immunoreactive trypsin. Raised sweat electrolytes on sweat testing. Confirmation by CFTR genotyping.
Counseling issues
Affected patients who are compound heterozygotes (eg, have two different mutations, such as ∆F508 or R117H) may show varying degrees of severity, depending on the mutations. The R117H mutation associated with the poly T (5T) variant is more common in pancreatic insufficiency. With the poly T (7T) variant, the R117H mutation is associated with congenital bilateral absence of the vas deferens, and is a cause of infertility in affected males, who require assisted reproductive techniques. Carrier screening is widely available and prenatal diagnosis is possible in at-risk pregnancies.
Pneumothorax MIM
173600
Clinical features
As sporadic pneumothorax. The patient develops a sudden onset of chest pain and shortness of breath.
Gene
Unknown
Chromosomal location
Unknown
Prevalence
Rare (1%–2% of pneumothoraces)
Inheritance
Autosomal dominant, more common in males
Age at onset
Similar to the population onset – generally young adults, 18–25 years of age.
Diagnosis
Chest examination and X-ray
Screening
Prompt treatment if symptoms appear
Counseling issues
Genetic testing is available in regional centers for the FBN (fibrillin) gene mutation in patients who may have Marfan’s syndrome
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(allowing this to be excluded). Autosomal recessive pulmonary lobe agenesis is rare, but can occur with various lobes missing at birth. Other causes include Ehlers–Danlos syndrome and, in theory, any disorder of connective tissue. Some autosomal dominant families exist without known FBN mutations, so a separate entity does exist.
Ehlers–Danlos Syndrome (also known as: EDS) MIM
130000 (type I)
Clinical features
The cardinal features include hyperextensible skin (soft and easily bruised), dystrophic scarring, joint laxity, and internal organ rupture (particularly arterial and bowel, and especially in type IV). Subtypes include EDS II (with symptoms similar to EDS I, but milder), EDS III (joint hypermobility), EDS IV (severe bruising, thin skin, prominent veins, vascular rupture), EDS V (X-linked), and EDS VI (eye involvement).
Gene
COL5A1, COL5A2, COL1A1
Chromosomal location
9q34
Prevalence
Rare
Inheritance
Autosomal dominant
History
Described by Edward Ehlers, an eminent Danish dermatologist, in 1901, followed by further description by Henri Alexandre Danlos, a French physician, in 1908.
Age at onset
Childhood onset of skin lesions and joint laxity.
Diagnosis
Dermatological examination, for characteristic lesions and elastic skin and joint laxity.
Screening
Symptomatic for skin and vascular problems.
Counseling issues
Mostly autosomal dominant, but the differentiation of types is mainly clinical. X-linked and, possibly, autosomal recessive types may exist.
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Pectus Excavatum and Pectus Carinatum MIM
169300
Clinical features
Abnormal shape of the ribcage: depressed in pectus excavatum (“funnel chest”) and prominent or peaked in pectus carinatum (“pigeon chest”).
Gene
Unknown
Prevalence
Rare
Inheritance
Autosomal dominant
Age at onset
Congenital
Counseling issues
Both pectus excavatum and pectus carinatum can sometimes be inherited as isolated autosomal dominant conditions. Marfan’s syndrome and other connective tissue disorders should be excluded.
Kartagener’s Syndrome (also known as: immotile cilia syndrome, primary ciliary dyskinesia) MIM
244400
Clinical features
Chronic bronchitis leading to bronchiectasis, chronic sinusitis, and situs inversus, including dextrocardia. The underlying defect is probably in the dynein arms, which link the microtubules of normal cilia.
Gene
Unknown
Chromosomal location
9q21–p13
Prevalence
Rare
Inheritance
Autosomal recessive
History
Described by Manes Kartagener, a Swiss physician, in 1933.
Age at onset
Dextrocardia is often noted in infancy. Respiratory symptoms start in childhood and worsen with age.
Diagnosis
Clinical features and abnormal cardiac position on chest X-ray.
Screening
Regular chest examination – consult a chest specialist for screening frequency and advice on management.
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Mutational spectrum
Heterogeneity exists with families tentatively linked to various loci. Genetic testing is not yet available.
Counseling issues
Immotile cilia often result in infertility.
α -1 Antitrypsin Deficiency MIM
107400
Clinical features
Loss of elasticity of the lung leading to frequent chest infections. Made worse by smoking. Liver disease and cirrhosis are associated features.
Gene
AAT (α-1 antitrypsin)
Chromosomal location
14q32.1
Incidence
1 in 1,000 neonates in northern Europe
Inheritance
Autosomal recessive
Age at onset
Adolescence
Diagnosis
Lung disease in young adolescents, particularly if aggravated by smoking. Most cases are caused by homozygosity for the ZZ mutation or compound heterozygosity for the ZS mutation.
Genetic testing
Widely available for mutations in AAT.
Counseling issues
Homozygotes for the ZZ or SS mutations and compound heterozygotes for the SZ variants will have more severe disease. The normal phenotype (MM) does not exclude the condition. Carriers are strongly recommended to cease smoking.
Lung Cancer MIM
211980
Clinical features
Respiratory symptoms. In syndromic causes such as Li–Fraumeni syndrome, early-onset lung cancer occurs with associated childhood leukemia and sarcoma. Small-cell or anaplastic lung cancer often occurs without a history of smoking. See Figures 20 and 21.
Gene
Several postulated, but none yet identified.
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Figure 20. A chest X-ray showing lung cancer of the upper right lobe.
Figure 21. Chest X-rays showing massive pleural effusion in a patient with irresectable lung cancer.
Chromosomal location
Unknown
Prevalence
Lung cancer is the most common cancer in western countries.
Inheritance
Various familial susceptibilities have been noted, including a predisposition for some smokers and their families to develop lung cancer while others do not.
Age at onset
Variable. When the disease is in familial clusters, onset is generally earlier than that seen in the general population.
Screening
Not easily available. Mutations in CYP1A1 (cytochrome P450, subfamily I, polypeptide 1) may alter nicotine metabolism and increase the risk of cancer.
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Mutational spectrum
Heterogeneity exists, but no major genes have yet been identified. However, some nicotine-metabolizing polymorphisms are likely to have a familial basis. Nasopharyngeal cancer is a separate entity, and a locus at 3p21 has recently been identified in some families with an autosomal dominant type.
Counseling issues
Stopping smoking (with appropriate support) will have the biggest effect on an individual’s risk. There is a greater than 30% increase in risk if there is a family history. The DRD2 (dopamine D2 receptor) gene contains a variant 32806 C/T mutation that is associated with a better response to nicotine patches in women with the T allele (but not men), showing that nicotine addition may be hereditary and explaining some of the increased risk of lung cancer in families.
Congenital Airway Problems Laryngeal Atresia MIM
150300 Laryngeal stenosis and atresia may occur. Complete or partial laryngeal atresia (including laryngeal webs) occasionally occur in families as an autosomal dominant trait. If there is complete laryngeal atresia or severe stenosis, presentation can be with fetal ascites (see Figure 22), and is usually sporadic or due to 22q deletion syndrome (cardiac defects with cleft lip and palate and dysmorphic facies are associated).
Tracheoesophageal Fistula and Tracheal Agenesis Autosomal dominant. Patients may present with isolated tracheal agenesis, but the disease usually involves cardiac or esophageal abnormalities. Three forms are recognized: type I (partial atresia with a normal short segment of distal trachea arising from the anterior esophageal wall), type II (complete agenesis with normal bronchi with the carina connecting with the esophagus), and type III (complete agenesis with bronchi originating directly from the esophagus). Tracheoesophageal fistula may be associated with VATER syndrome (acronym for Vertebral defects, Anal atresia or stenosis, Common Surgical Conditions with a Hereditary Tendency
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Figure 22. Ascites in a fetus
Figure 23. Polydactyly.
due to laryngeal atresia.
TracheoEsophageal fistula, Radial defects, and renal anomalies; MIM 192350). Cases are usually sporadic. All patients should be checked for chromosome abnormalities, as several rare deletions or chromosomal rearrangements may be found, including 22q deletion syndrome.
Cleft Lip and Palate Various modes of inheritance and several syndromic and non syndromic causes all exist. In cases that result from syndromic causes, patients show features such as lip pits or extra fingers or toes (see Figure 23). Those that result from non syndromic causes show pure isolated clefting. A bilateral cleft lip with a cleft palate is more likely to have a genetic basis than a single cleft palate. Genetic counseling is recommended if there is a syndromic cause or if more than one family member is affected. If the patient has an isolated cleft palate, recurrence risks are unlikely to exceed 1%–2% (but beware of the rare X-linked variety in males). Van der Woude syndrome (MIM 119300) is an autosomal dominant entity in which lip pits are found in the lower lip inner vermilion border. It accounts for around 2% of cases of cleft palate. A bilateral cleft lip and palate in at least two members of a family suggests a strong hereditary component and a recurrence risk of 20%–40%.
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Hemochromatosis MIM
235200
Clinical features
Iron overload with hepatic cirrhosis, diabetes, and cardiomyopathy and joint problems.
Gene
HFE (hemochromatosis gene)
Chromosomal location
6p21.3
Incidence
1 in 500 in European populations. Around 1 in 10 of the UK population are gene carriers.
Inheritance
Autosomal recessive with variable penetrance.
History
First named by Friedreich von Recklinghausen in 1889. (See the section on neurofibromatosis type I [p. 30] for his description of neurofibromatosis.)
Age at onset
Early to middle age in males. Onset is postmenopausal in females, due to the protective effect of menstruation.
Diagnosis
Elevated transferrin saturation levels and reduced iron binding capacity.
Genetic testing
Widely available for HFE.
Mutational spectrum
Heterogeneity exists. Rare juvenile and autosomal dominant forms account for 2%–3% of cases. Cases that are due to HFE have the common mutation C282Y in 90% of cases. Heterozygotes for the C282Y and H63D mutations may also develop hemochromatosis. H63D homozygotes are unaffected.
Counseling issues
Biochemical testing for transferrin and for both iron and iron-binding capacity measurements is useful, as not all cases are fully penetrant. Genotyping of families may help to confirm or exclude the diagnosis in equivocal cases. Where the genotype is known, mutation screening can be offered to family members. Treatment is by venesection. The penetrance is highly variable, with clinically unaffected homozygotes recognized.
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Hemophilia (includes: hemophilia A, factor VIII deficiency; hemophilia B, Christmas disease, factor IX deficiency) MIM
306700 (hemophilia A) 306900 (hemophilia B)
Clinical features
These depend on the level of factor deficiency. Spontaneous hemorrhage occurs if factor levels are <1% of normal; hemorrhage and hemarthroses occur following trauma if factor levels are 5%–25% of normal. There is usually no significant bleeding if factor levels are >25% of normal.
Genes
Factor VIII (hemophilia A), factor IX (hemophilia B)
Chromosomal location
Xq28 (hemophilia A), Xq26–q27.3 (hemophilia B)
Prevalence
1 in 5,000–10,000 males (hemophilia A); 1 in 50,000 males (hemophilia B)
Inheritance
Sex-linked recessive
History
Queen Victoria was a gene carrier for hemophilia A and passed the disease into the German and Russian Royal families at the end of the 19th century. Erik Von Willebrand, a Finnish physician, described Factor IX deficiency in 1931.
Age at onset
Congenital. Usually noticed in infancy after excessive bruising from falls or cuts.
Diagnosis
Measurement of blood clotting factors, including factors VIII or IX. This is now routinely available.
Genetic testing
Available for both genes, but only in specialist centers.
Screening
Families may be screened for mutations in the appropriate gene.
Counseling issues
A common inversion mutation is in intron 22 of the factor VIII gene and accounts for around 40% of cases. No common mutations exist in factor IX deficiency. Treatment is by specific factor replacement. Joint replacement surgery is occasionally needed, and usually successful.
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Acute Myeloid Leukemia (also known as: AML) MIM
151380
Clinical features
Anorexia, lassitude, weight loss, night sweats, massive splenomegaly, all due to bone marrow failure or infiltration by leukemia cells.
Genes
Associated with Fanconi anemia, neurofibromatosis type I, RUNX1 (runt-related transcription factor 1), GATA1 (GATA-binding protein 1), PTPN11 (protein-tyrosine phosphatase, nonreceptor-type, 11), and others.
Chromosomal location
21q22, 16q21–q23.2
Prevalence
AML is the common acute leukemia in adults. (Acute lymphocytic leukemia or acute lymphoblastic leukemia [MIM 159555] is the main acute leukemia in childhood, with a peak incidence at 4 years of age. A strong hereditary basis of acute lymphocytic leukemia has not been identified.)
Inheritance
There is increasing evidence that an inherited predisposition exists. Autosomal dominant cases have been reported.
Age at onset
Generally, families with more than one case have onset after 60 years of age, as in other AML cases.
Genetic testing
Available for RUNX1 (a rare marker for acute leukemia), but only on a research basis in some centers. Gene testing is not yet available for other types.
Screening
Family members should be aware that they will have an increased risk of lymphoproliferative disease. However, familial cases are rare and no particular screening strategy is indicated, other than prompt referral to a medical practitioner if symptoms arise.
Genetic counseling
Exclude disorders such as Fanconi anemia (an autosomal recessive disorder with anemia, limb defects, and leukemia, due to chromosome instability) and neurofibromatosis type I. Down’s syndrome patients have an increased incidence of early-onset AML involving GATA1 and other genes on chromosome 21. Some patients with AML, juvenile myelomonocytic leukemia, and myelodysplastic syndromes have been found to have mutations in PTPN11 that
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cause Noonan’s syndrome (syndrome of dysmorphic facies, ptosis with wiry hair, and cardiac defects).
Chronic Myeloid Leukemia (also known as: CML) MIM
151410
Clinical features
Anorexia, lassitude, weight loss, night sweats, and splenomegaly, all due to bone marrow failure or infiltration by leukemic cells.
Gene
Associated with the Philadelphia (Ph) chromosome (see Figure 24).
1
2
3
6
7
8
13
14
15
19
20
9
4
5
10
11
12
16
17
18
21 22 x t(9;22)(q34;q11) in CML
y
Figure 24. Karyotype showing 9;22 (Philadelphia) chromosome translocation.
Chromosomal location
9q34, 22q11
Inheritance
Generally sporadic
Age at onset
Variable, but rarely before 10 years of age.
Genetic testing
Now widely available for the Ph chromosome, which is a prognostic marker for the treatment of CML (better prognosis as levels of Ph reduce). It is caused by the fusion of the BCR (breakpoint cluster region) and ABL (Abelson murine leukemia viral oncogene homolog) genes on chromosomes 9 and 22. This event causes the formation of a fusion oncogene, which is found in over 90% of CML cases.
Screening
Chromosome analysis for the Ph chromosome is used in affected patients to predict treatment success. It is not useful in relatives.
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Chronic Lymphocytic Leukemia (also known as: CLL) MIM
151400
Clinical features
Patients present with tiredness, anaemia, and enlarged (often massive) lymph nodes in the neck, axillae, and groin.
Gene
Unknown, although overexpression of BCL2 (B-cell CLL/lymphoma 2) is associated and sequence variation in the ATM (ataxia–telangiectasia mutated) and P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) genes has been suggested as a risk factor.
Chromosomal location
12q24, 18q21.3
Prevalence
The most common form of leukemia – around 30% of all leukemia cases.
Inheritance
There is increasing evidence that an inherited predisposition exists, with some autosomal dominant cases now well documented. As in other lymphoproliferative disorders, anticipation is a well-recognized finding in CLL
Age at onset
Generally, families with more than one case have onset after 60 years of age, as in other CLL cases. Onset before 30 years is rare.
Genetic testing
Not available
Screening
Awareness that family members will have an increased risk of lymphoproliferative disease. Familial cases are rare and no particular screening is indicated, other than prompt referral to a medical practitioner if symptoms arise.
Genetic counseling
If more than one member of a family is affected, or if there is a history of other lymphoproliferative diseases in the family (especially Hodgkin disease), the risk to relatives is increased. No definite genes have been identified, so counseling is difficult.
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Non Hodgkin’s Lymphoma MIM
605027
Clinical features
Painless enlargement of lymph nodes. See Figures 25–27.
Gene
Unknown
Chromosomal location
2q33–q34
Prevalence
Around 1%–2% of cases have a strong family history.
Inheritance
Autosomal dominant cases reported. Some of these show anticipation – ie, progressively earlier onset of the disorder in succeeding generations.
Age at onset
Generally, families with more than one case have an earlier onset presentation than sporadic cases.
Figure 25. (l) A patient with a large non Hodgkin’s lymphoma deposit in the neck. Figure 26. (r) A young man with non Hodgkin’s neck lymph node enlargement.
Figure 27. A child with Burkitt’s lymphoma of the cheek.
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Genetic testing
Not available
Screening
Family members should be aware that they will have an increased risk of lymphoproliferative disease. Familial cases are rare, and no particular screening is indicated other than prompt referral to a medical practitioner if symptoms arise. If there are two or more affected individuals in a family, then annual consultation with a primary-care physician should be given to at-risk relatives, with physical examination (particularly for lymphadenopathy) and full blood count analysis. Magnetic resonance imaging and computed tomography are currently under evaluation as research tools.
Hodgkin’s Lymphoma MIM
236000
Clinical features
Often solitary and painless lymphadenopathy; may be accompanied by sweating and itching.
Gene
Unknown
Chromosomal location
2p
Prevalence
Around 1% of cases have a strong family history.
Inheritance
Autosomal dominant cases have been reported.
Age at onset
Families with more than one case have an earlier onset presentation, particularly for cases with an onset before 45 years of age. There is a 7-fold increased risk for siblings if there is early presentation (before 45 years) in the family.
Genetic testing
Not currently available, although a possible locus on chromosome 2p looks promising.
Screening
Awareness that family members will have an increased risk of lymphoproliferative disease. Familial cases are rare. No particular screening procedure is indicated in cases with onset in a family member over 45 years of age, other than prompt referral to a medical practitioner if symptoms arise. In cases with onset before 45 years, yearly consultation with a primary-care physician with full blood count and physical examination may be useful.
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Multiple Myeloma MIM
254500
Clinical features
Patients present with bone pain and anaemia. Pathological fractures are common. See Figure 28.
Gene
Unknown
Chromosomal location
Unknown
Inheritance
Some autosomal dominant families have been documented.
Age at onset
Generally families with more than one case have onset after 60 years of age, as in other myeloma cases.
Genetic testing
Not available
Screening
Awareness that family members will have an increased risk of lymphoproliferative disease. However, familial cases are rare and screening of family members is not indicated, other than prompt referral to a medical practitioner, if symptoms arise.
Genetic counseling
There is no difference between the sporadic and hereditary forms with respect to sex, age, or clinical presentation. There is a small, but definite, increased risk to siblings, especially if other family members are affected or if they have a relative with prostate or brain cancer.
Figure 28. A skull X-ray of a patient with multiple myeloma. Multiple lucent deposits can be seen.
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Duchenne Muscular Dystrophy MIM
310200 (Duchenne type) 300376 (Becker type)
Clinical features
Contractures of tendo-Achilles, muscle pseudohypertrophy (see Figure 29), and weakness, predominantly proximal, with delay in walking. This has a slow, relentless progression so that the patient will be wheelchair-bound by their early teens (or by mid to late adulthood in Becker type). Treatment by regular physiotherapy, or by Achilles tenotomy in late childhood, may help with walking.
Gene
DMD (dystrophin)
Chromosomal location
Xp21.2
Prevalence
1 in 5,000 males (Duchenne); 1 in 18,500 males (Becker)
Inheritance
Sex-linked recessive. “Manifesting” female carriers occasionally occur (females who carry one copy of the gene and have mild symptoms or weakness).
History
Following a description by Meryon in 1852, Guillaume Duchenne described this disorder in 1861. In 1879, Gower described the pseudohypertrophy and the classic maneuver of rolling over and rising from the floor from lying flat by using the hands to help with leverage. The milder type was described by Becker in 1957.
Age at onset
Childhood. Usually between 3–5 years of age, although onset of the Becker type is later (starting around 5 years, but may be as late as 50 years).
Figure 29. Calf hypertrophy in a boy with Duchenne muscular dystrophy.
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Figure 30. Dystrophic muscle showing the absence of a dystrophin stain.
Diagnosis
Raised serum creatine phosphokinase (levels >10,000 U/L are almost diagnostic). Muscle biopsy confirms dystrophic change and absence of dystrophin in Duchenne type (see Figure 30). Reduced dystrophin staining in the Becker type.
Genetic testing
Available for mutations in DMD. Around 70% of boys have deletions, 5% have duplications, and the remainder have point mutations (which are difficult to detect).
Screening
Perform genetic tests and measure the creatine phosphokinase level in at-risk males. Conduct carrier testing in at-risk females.
Counseling issues
Prenatal diagnosis is available. Carrier testing should be offered in all families. Around a third of mutations are de novo in boys, but a third can be de novo in the mother and give rise to germline mosaicism risks. The average life expectancy in the Duchenne type is 15–25 years. Life expectancy is variable in Becker type, but ranges from 40 to 60 years.
Hereditary Motor and Sensory Neuropathy (includes: Charcot–Marie–Tooth [CMT] disease, peroneal muscular atrophy) MIM
118220 (CMT1 type 1A [CMT1A]) 118200 (CMT type 1B [CMT1B]) 302800 (CMT X-linked [CMTX])
Clinical features
60
Wasting of the intrinsic muscles of the hand, especially thenar and hypothenar eminences, with wasting and atrophy of the peroneal muscles.
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PMP22 (peripheral myelin protein 22), P0, CX32 (connexin-32; also known as GAP junction protein, β-1 [GJB1]), various others
Chromosomal location
17p11 (CMT1A), 1q32 (CMT1B), Xq13 (CMTX)
Prevalence
1 in 2,500
Inheritance
Autosomal dominant (several types, including CMT1A and CMT1B). Autosomal recessive and sex-linked (CMTX).
History
Described by Jean Charcot, the French neurologist (who created the famous neurologic clinic at the Salpêtrière clinic in Paris), along with his pupil, Pierre Marie, in 1886. Howard Tooth, an English neurologist, described the condition the same year, indicating that it was a peripheral neuropathy.
Age at onset
Variable, from early childhood to middle age. The average is 12 years of age.
Diagnosis
Neurophysiologic testing will confirm the muscle wasting and weakness.
Genetic testing
Available for the common dominant types CMT1A and CMT1B and the X-linked dominant type CMTX (CX32).
Screening
Genetic testing will help to clarify the exact subtype. Around 60%–80% of cases are CMT1A. Several rare dominant and recessive types exist.
Mutational spectrum
Heterogeneity exists, with genes for several of the dominant and recessive types still to be identified.
Counseling issues
This is complex. Most centers will test for CMT1A, CTM1B, CMTX, and CMT2, but other types need careful counseling. A related disorder, hereditary neuropathy with pressure palsies (MIM 162500), is caused by a deletion of the region duplicated on chromosome 17p in CMT1A.
Huntington’s Disease MIM
143100
Clinical features
Triad of movement disorder (including choreiform movements), psychiatric dysfunction (including mood swings, irritability, inertia,
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and depression), and cognitive dysfunction. There is often shrinkage of the basal ganglia and, in particular, atrophy of the caudate nucleus occurs before atrophy of other parts of the brain (see Figure 31). Gene
A CAG expansion (see Glossary) in the huntingtin gene.
Chromosomal location
4p16.3
Prevalence
1 in 10,000
Inheritance
Autosomal dominant
History
Described by George Huntington, a general practitioner in Ohio, in 1872.
Age at onset
Classically early middle life (35–50 years of age), but about 10% of cases have onset before 20 years and around 25% of cases have onset after 50 years.
Figure 31. Caudate nucleus shrinkage shown on computed tomography.
Diagnosis
Autosomal dominant choreiform disease with relentless progression is classic. Few therapies are available. Fetal neural transplantation, in which fetal cells are injected into the caudate and putamen, looks promising in early trials, but is controversial.
Genetic testing
Available for triplet expansion of CAG repeats within the huntingtin gene.
Screening
Presymptomatic genetic testing is available for those at risk.
Counseling issues
Complex testing protocol because of the ethical implications of testing for a late-onset disorder with no treatment.
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Fragile X Syndrome MIM
309550
Clinical features
Mental retardation, long face, large testicles, and behavioral difficulties.
Gene
FMR1 (fragile site mental retardation 1)
Chromosomal location
Xq28
Prevalence
1 in 4,000 males. This is the most common cause of mental retardation in males.
Inheritance
X-linked (female gene carriers may have mild expression of features).
Age at onset
Childhood, with behavioral problems and developmental delay.
Diagnosis
Testing by molecular genetics for FMR1 is widely available. Variable-sized CCG expansion within the gene is diagnostic. Generally, the larger the expansion, the worse the condition. The chance of a premutation (around 55–200 repeats) expanding to a full mutation is positively associated with the size of the repeat (~95% by 90 repeats).
Screening
At-risk family members may have genetic testing. National screening in the neonatal period is under consideration in some countries, including the UK.
Mutational spectrum
Heterogeneity exists. Other causes of mental handicap are common, but genetic testing is not usually available. In FMR1 mutationnegative cases, a routine chromosome analysis should be carried out to exclude chromosomal anomaly. Referral for specialist genetic assessment is appropriate.
Counseling issues
Females may be gene carriers and show mild expression. Males with a small expansion (a “premutation”) may be normal, but transmit the premutation to all daughters, who will be unaffected by overt learning difficulties. Women with premutations have an increased chance (16%) of menopause before 40 years of age.
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Facioscapulohumeral Muscular Dystrophy (also known as: FSHD. Includes: Landouzy–Dejerine muscular dystrophy) MIM
158900
Clinical features
Progressive weakness, particularly of the scapula (with winging), face, upper arm, and hip girdle. Affected individuals have a normal life expectancy, but often require a stick to assist with walking and a small proportion (10%–20%) will require a wheelchair.
Gene
Unknown, but FSHD can be identified by a rearrangement of DNA repeat sequence at 4q35.
Chromosomal location
4q35
Prevalence
5–10 per 100,000
Inheritance
Autosomal dominant. Around 10%–30% of cases are new mutations. Penetrance is approximately 95% by 20 years of age.
History
Described by Joseph Landouzy, a French physician, and Joseph Dejerine, a French neurologist, in a paper in 1886.
Age at onset
Childhood weakness of scapulae and difficulty with reaching up to high shelves.
Diagnosis
Clinical, with support from electromyography. Genetic testing is routinely possible and confirms the clinical diagnosis in over 95% of cases.
Screening
Genetic testing for rearrangement in families will help clarify the diagnosis and potential age of onset.
Counseling issues
Surgery with scapular fixation will repair and help the shoulder weakness and allow the patient to reach their arms up (to high shelves, to change light bulbs, etc). However, surgery is only used in a small number of cases, mostly for occupational reasons (eg, electricians), as it requires a plaster cast for some weeks with resulting inconvenience, particularly if a bilateral operation is carried out.
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Dupuytren’s Contracture MIM
126900
Clinical features
Thickening and contraction of the palmar fascia causing flexion contractures of the fingers, particularly the fourth and fifth. It is also associated with Peyronie's disease of the penis (MIM 171000) in 20% of cases and popliteal fasciitis. Sporadic forms are associated with diabetes, alcoholism, and liver disease.
Gene
Unknown
Chromosomal location
Unknown
Prevalence
Very common – occurs in around 20%–30% of the Caucasian population over 65 years of age.
Inheritance
Autosomal dominant (males more than females)
History
Guillaume Dupuytren, the leading French surgeon of the early 19th century, described this in 1832, realizing that the defect lay in the palmar fascia. Ling suggested a dominant inheritance in 1963. A suggestion of Viking ancestry has been made.
Age at onset
Middle age
Diagnosis
Clinical
Counseling issues
Surgical release of the contracture is possible. The risk for firstdegree relatives is approximately 70%.
Congenital Dislocation of the Hip (also known as: CDH) MIM
142700
Clinical features
Dislocation of the hip noted at birth on neonatal examination. Figure 32 shows an X-ray of the pelvis of an adult man whose CDH was missed as a child.
Gene
Unknown
Chromosomal location
Unknown
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Figure 32. X-ray of congenital dislocation of the hip in an adult man with a missed diagnosis at birth. Note the failure of the acetabulum to develop.
Prevalence
Around 1 in 1,000 in the Caucasian population. More common in females.
Inheritance
Autosomal dominant and autosomal recessive forms are suspected.
Age at onset
Birth
Diagnosis
Clinical examination, with ultrasound or magnetic resonance imaging for accurate diagnosis.
Screening
A hip examination before discharge from hospital in the neonatal period is routine in several countries.
Counseling issues
May be part of joint laxity syndromes, including Ehlers–Danlos and Larsen syndromes. Common in breech deliveries and Caesarean sections. A recurrence risk of 5% for siblings is usually quoted.
Spina Bifida and Neural Tube Defects MIM
182940
Clinical features
Any partial formation of the neural tube, ranging from spina bifida occulta (see Figure 33), through spinal lipoma to open or closed meningomyelocele (see Figure 34) or anencephaly.
Gene
Unknown
Chromosomal location
Unknown
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Figure 33. Spina bifida occulta.
Figure 34. Meningomyelocele.
Prevalence
1 in 500–800 in high-risk areas such as the northwest of the British Isles, or on the Indian subcontinent, where the role of genetic and environmental factors (research is still unsure which) is much higher than elsewhere; 1 in 3,000 in the rest of Europe and the USA.
Inheritance
Multifactorial, including some rare autosomal recessive and X-linked families.
Age at onset
Congenital. Prenatal diagnosis is available by ultrasound and serum screening.
Diagnosis
By prenatal ultrasound: elevated serum or amniotic fluid α-fetoprotein. Clinical diagnosis at birth or by ultrasound or X-ray of the spine.
Genetic testing
Available for the MTHFR (methylene tetrahydrofolate reductase) gene, as reduced folate is a risk factor for neural tube defects, but no gene has yet been identified for pure neural tube defects.
Screening
Advice to avoid recurrence is high-dose folic acid (4–5 mg) periconceptually (2–3 months before conception to around 3 months after conception).
Mutational spectrum
Heterogeneity exists, and several syndromic causes need to be excluded.
Counseling issues
In the majority of cases, advising the mother about diet and taking folic acid should reduce the risk of recurrence. The risk of recurrence is around 1 in 100 if there is just one case in the family. If there are two affected members in a family, the risk increases to around 1 in
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10; if there are three affected family members, the risk of recurrence is around 1 in 4, as there is a strong genetic component.
Hydrocephalus MIM
307000 (X-linked hydrocephalus)
Clinical features
The X-linked type typically affects males, with early onset of prenatal hydrocephalus and adducted thumbs. Most cases of hydrocephalus are due to congenital causes, acquired infection, or trauma.
Gene
L1CAM (L1 cell adhesion molecule)
Chromosomal location
Xq28
Prevalence
Present in around 1 in 30,000 male births.
Inheritance
Sporadic, X-linked, autosomal dominant (rare).
Age at onset
Congenital, some rare later onset types.
Diagnosis
Cranial imaging – ultrasound in the neonatal period or magnetic resonance imaging after 2–3 months of age.
Genetic testing
Available for L1CAM in specialist centers on a research basis.
Screening
Possible during pregnancy by serial ultrasonography.
Counseling issues
Genetic types should be suspected in males with prenatal onset with adducted thumbs and gene testing considered for L1CAM. Rare autosomal dominant types occur. Screening for congenital infections is useful.
Cataract MIM
115650 (autosomal dominant) 302200 (X-linked)
Clinical features
Lens opacities
Gene
Various
Chromosomal location
14q24 (autosomal dominant), Xp (X-linked)
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Prevalence
A very common condition. The incidence increases with age and with illnesses such as diabetes.
Inheritance
Autosomal dominant, autosomal recessive, and X-linked recessive.
Age at onset
Recessive cataracts generally have an early onset (from birth to early childhood). Dominant cataracts may commence from early adulthood into later life.
Diagnosis
Ocular examination combined with slit-lamp examination by an ophthalmologist.
Genetic testing
Available in research laboratories for some types.
Screening
Regular ophthalmic examination
Mutational spectrum
Heterogeneity exists
Counseling issues
Genetic counseling to exclude a syndromic form, especially in infancy- or childhood-onset types. Exclude other causes of cataracts that may also run in families, including diabetes. Occasionally, cataracts are the result of rare mitochondrial defects. These cataracts are asssociated with retinopathy and muscle weakness.
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3 3. Systemic Cancers (Benign and Malignant Tumors)
1. Endocrine Multiple Endocrine Neoplasia Type I 73 Multiple Endocrine Neoplasia Type IIA 74 Multiple Endocrine Neoplasia Type IIB 76 Thyroid Cancer 78 Cowden Disease 80 von Hippel-Lindau Syndrome 81 Familial Paraganglioma Syndrome 84 Familial Pheochromocytoma 86 2. Breast Breast Cancer (BRCA1) 89 Breast Cancer (BRCA2) 92 Breast Cancer (BRCA3 and BRCA4) 96 Ataxia–Telangiectasia 97 Li–Fraumeni Syndrome 98
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3. Colon Hereditary Non Polyposis Colon Cancer 100 Familial Adenomatous Polyposis 103 Peutz–Jeghers Syndrome 105 Autosomal Recessive Colon Cancer 107 Juvenile Polyposis Syndromes 108 Gastric Cancer 109 Pancreatic Cancer 110 Tylosis and Esophageal Cancer 112 4. Urogenital Papillary Renal Cancer 113 Birt–Hogg–Dubé Syndrome 114 Cutaneous Leiomyoma Syndrome 115 Ovarian and other Gynecologic Cancers 116 Prostate Cancer 119 Testicular Cancer 120 5. Skin Gorlin’s Syndrome 122 Familial Atypical Mole Melanoma Syndrome 124 Squamous Cell Carcinoma 125 6. Brain Gliomas 127 Meningiomas 129 Primitive Neural Ectodermal Tumors 130 Pituitary Tumors 131 Retinoblastoma 132
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Multiple Endocrine Neoplasia Type I (also known as: MEN1) MIM
131100
Clinical features
All the “P”s: parathyroid hyperplasia or adenomas, pancreatic polypeptidoma or pancreatic islet cell tumors (gastrinoma, insulinoma, glucagonoma, vasoactive intestinal polypeptidoma), and pituitary prolactinoma. Primary hyperparathyroidism is seen in 95% of patients (see Figure 1) and over 50% of islet cell tumors are gastrinomas, causing severe peptic ulceration – hypergastrinemia leads to the Zollinger–Ellison syndrome.
Gene
MEN1 (menin)
Chromosomal location
11q13
Prevalence
1 in 30,000–60,000
Inheritance
Autosomal dominant, with 50% penetrance by 20 years of age and 95% by 50 years.
History
First described by Wermer in 1954, with a separate description of peptic ulceration and pancreatic disease by Zollinger and Ellison in 1955. Now, both are combined in the diagnosis of MEN1.
Age at onset
Most commonly from adolescence to early middle life.
Diagnosis
Clinical history and examination will usually suggest the diagnosis.
Figure 1. Skull X-ray showing changes of hyperparathyroidism.
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Genetic testing
Available for MEN1 in selected supraregional centers. Genetic testing helps with targeting screening and management. Results take around 3–4 months.
Screening
Annual testing of serum calcium and prolactin levels, with pituitary and abdominal imaging every 5 years from around 10 years of age. Visual field checks annually, with growth measurements in children.
Counseling issues
Cases of onset around 10 years of age have been reported, so screening and genetic testing should be initiated in childhood.
Multiple Endocrine Neoplasia Type IIA (also known as: MEN2A) MIM
171400
Clinical features
Virtually 100% of patients have medullary thyroid cancer, with 50% having pheochromocytoma, and 25% parathyroid hyperplasia or adenomas (see Figures 2–6).
Gene
RET (rearranged during transfection), a proto-oncogene with a tyrosine kinase domain.
Chromosomal location
10q11.2
Prevalence
1 in 30,000
Inheritance
Autosomal dominant, with 50% penetrance by 20 years of age and 95% by 35 years.
History
Sipple originally described medullary thyroid carcinoma in association with pheochromocytoma in 1961. Its hereditary thyroid nature was recognized by Cushman in 1962.
Age at onset
From 5 years of age onwards. In childhood, foci of medullary cancer may be found at thyroidectomy, so prophylactic thyroidectomy is advised before 10 years. This needs to be performed by an experienced thyroid surgeon to avoid problems with the recurrent laryngeal nerve and hypocalcemia.
Diagnosis
A combination of thyroid and pheochromocytomas in families with dominant inheritance. Medullary carcinoma is usually bilateral and multifocal. C-cell hyperplasia is also characteristic.
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Figure 2. Bilateral medullary thyroid cancer.
Figure 3. Medullary thyroid carcinoma of the neck.
Figure 4a. Adrenal pheochromocytoma. Figure 4b. Computed tomography scan of an adrenal pheochromocytoma.
Figure 5. Parathyroid adenoma.
Genetic testing
Systemic Cancers
Figure 6. Positive parathyroid subtraction scan (left lower).
Routinely available for RET. Common mutations found in codon 634 are associated with pheochromocytomas, while other mutations are associated with thyroid cancer only (the FMTC [familial medullary thyroid cancer] variant).
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Screening
Genetic testing from birth or early childhood. Regular stimulated calcitonin (intravenous pentagastrin) testing should be conducted from 5 years of age. Prophylactic total thyroidectomy is routine by 10 years. After 18 years of age, screening for pheochromocytomas should be by yearly 24-hour urine testing and regular adrenal imaging.
Counseling issues
A careful explanation of preventative surgery should be given and the possibility of genetic testing in childhood should be raised. Remember to test for adrenal symptoms in gene carriers over 18 years of age who have had preventative surgery.
Multiple Endocrine Neoplasia Type IIB (also known as: MEN2B; Wagenmann–Froboese syndrome) MIM
162300
Clinical features
All patients have medullary thyroid cancer (see Figure 7), around 50% have pheochromocytoma, and most have neuroendocrine features including mucosal neuromata, particularly involving the lips, tongue, and intestinal tract. Facial features include a long face with prominent “blubbery” lips (see Figure 8).
Gene
RET (rearranged during transfection), a proto-oncogene with a tyrosine kinase domain.
Chromosomal location
10q11.2
Prevalence
Rare
Inheritance
Autosomal dominant, with virtually 100% penetrance by 35 years of age.
History
Described by Wagenmann in 1922 and Froboese in 1923.
Age at onset
Early aggressive medullary carcinoma often begins as young as 1 year of age. Mucosal neuromas are noticeable in childhood.
Diagnosis
The facial appearance, in conjunction with a Marfanoid habitus, mucosal neuromas, and thyroid cancer, clinches the diagnosis. This is confirmed by genetic testing.
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Figure 7. Bilateral multifocal medullary Figure 8. Mucosal neuromas of the thyroid cancer of the neck. tongue and prominent “blubbery” lips.
Genetic testing
Routinely available to confirm the diagnosis. More than 95% of cases have a mutation in codon 918 of exon 16 of RET. Rare mutations, including codon 883 in exon 15, have also been reported.
Screening
Genetic testing from birth or infancy. Regular stimulated calcitonin (intravenous pentagastrin) testing should be conducted from 3 years of age. Prophylactic total thyroidectomy is routine by 5 years. After 18 years of age, screening for pheochromocytoma is by 24-hour urine testing and regular adrenal imaging.
Counseling issues
A careful explanation of preventative surgery should be given and the possibility of genetic testing in childhood should be raised. Remember to test for adrenal symptoms in gene carriers over 18 years of age who have had preventative surgery. The medullary thyroid cancers are very aggressive and should be treated by a specialist in endocrine surgery with total thyroidectomy and central node dissection (with careful preservation of the recurrent laryngeal nerves and parathyroids).
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Thyroid Cancer MIM
188550 (papillary) 188470 (follicular)
Clinical features
Familial non medullary thyroid cancers are usually pure thyroid cancer only. Multiple endocrine neoplasia type II (MEN2) is associated with pheochromocytoma, parathyroid hyperplasia or adenoma, and neuroendocrine features. See Figure 9.
Types
Around 60% of cases are papillary, 20% follicular, 15% anaplastic (see Figures 10 and 11), and 5% medullary. About 5%–8% of non medullary thyroid cancers have a family history, and around 25% of medullary cases are familial. See Figure 12.
Genes
Several are involved. Most medullary thyroid cancers are caused by the RET proto-oncogene (MEN2A, MEN2B, and familial medullary thyroid cancer [FMTC] variants).
Chromosomal location
FMTC and MEN2: 10q. Familial papillary thyroid cancer associated with familial adenomatous polyposis (FAP) and Cowden disease, and a pure mixed papillary/follicular presentation have both been described. Familial follicular thyroid cancer has been described in isolation.
Inheritance
All types identified to date are autosomal dominant, with variable penetrance.
Age at onset
Usually 10–15 years earlier than sporadic disease.
Diagnosis
Gene testing is widely available for the MEN2 syndromes, FAP, and Cowden disease.
Screening
Regular stimulated calcitonin (intravenous pentagastrin) testing from 5 years of age. Prophylactic total thyroidectomy is routine in childhood. In MEN2 syndromes, screening for pheochromocytoma is by 24-hour urine testing and regular adrenal imaging after 18 years of age. For papillary thyroid cancer, screening is with regular neck radiology by ultrasound or isotope imaging and, more recently, CT and magnetic resonance imaging. If a nodule is found, ultrasound-guided fine-needle aspiration is the recommended practice. See Figure 13.
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Figure 9. Hyperthyroid facies.
Figure 10. Anaplastic thyroid carcinoma.
Figure 11. Tracheostomy for anaplastic Figure 12. Medullary carcinoma of the thyroid. thyroid carcinoma.
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Figure 13. Retrosternal thyroid mass on computed tomography.
Mutational spectrum
Heterogeneity exists, so genetic investigation and counseling are important. Preventative surgery should be considered as in MEN2, although this can be carried out at a later stage, depending on age at onset in the family.
Cowden Disease MIM
158350
Clinical features
Multiple hamartomas and trichilemmomas (small warty dermal skin lesions) in association with thyroid disease (adenomas or goiter [see Figure 14] in 50% and papillary or follicular cancer in >5%), breast fibroadenomas or early malignant disease (70%), and lipomas (40%). Macrocephaly and pigmentation occur in some patients and endometrial cancer is common.
Gene
PTEN (phosphatase and tensin homolog)
Chromosomal location
10q23.3
Prevalence
1 in 200,000
Inheritance
Autosomal dominant, with variable penetrance.
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Figure 14. Diffuse benign thyroid goiter.
History
First described by Lloyd and Denis in 1963. They named the condition after their patient, Rachel Cowden, who died of bilateral breast cancer in her early thirties. A variety called Lhermitte Duclos disease, which involves cerebellar dysfunction, is also known, and Bannayan–Zonana, Riley-Smith, and Ruvalcaba syndromes are all part of the spectrum. These are rare, features include multiple lipomas, spotty pigmentation of the penis, and macrocephaly.
Age at onset
From birth onwards, with skin changes in the second decade and breast cancer in the third decade.
Diagnosis
Diagnostic criteria include the features listed above.
Genetic testing
Available for PTEN in specialist centers, but not widely available.
Screening
Ultrasound thyroid screening and endometrial screening from 30 years of age, plus mammography in women.
Counseling issues
Screening for thyroid, endometrial, and breast cancers is important. Melanoma may also occur.
von Hippel-Lindau Syndrome (also known as: VHL) MIM
193300
Clinical features
Characterized by renal cell carcinoma (see Figures 15–17), retinal angioma, and cerebellar hemangioblastoma.
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Figure 15. Renal cell carcinoma.
Figure 16. Renal cell carcinoma.
Figure 17. Renal cell carcinoma: resection specimen after embolization.
Gene
VHL (von Hippel-Lindau gene)
Chromosomal location
3p25
Prevalence
1 in 36,000
Inheritance
Autosomal dominant, with 50% penetrance by 25 years of age and 99% by 65 years (although rare mutations show complete non penetrance, see below).
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History
Described by Eugen von Hippel-Lindau, a German ophthalmologist, in a series of publications in 1895, 1904, 1911, and 1918 that detailed the retinal angioma. He recognized the cerebellar hemangioblastomas in 1926.
Age at onset
Usually during late childhood or adolescence.
Diagnosis
A clinical history of retinal, renal, or cerebellar abnormalities in family members, and finding retinal, renal, or cerebellar abnormalities on examination of the patient.
Genetic testing
Routinely available for VHL. Predictive testing is helpful in clarifying whether at-risk persons need screening.
Screening
Renal ultrasound, ophthalmic examination (with retinal fluorescein angiography in some cases), and 24-hour urine testing for catecholamines should be carried out annually. Magnetic resonance imaging of the head and spine should be carried out every 3 years from adult age onwards. Some families who are homozygous for the rare mutations 598C→T and 562C→G have recently been described with congenital polycythemia. It is interesting that none of the heterozygous parents who are obligate carriers for these mutations have an increased incidence of VHL-related tumors. Virtually all cases of presumed VHL are due to mutations in the VHL gene, and the link to polycythemia is interesting.
Counseling issues
Systemic Cancers
Refer to a clinical geneticist for specialist examination and to a team of neurosurgeons and renal specialists for brain and renal screening. Familial clear-cell renal carcinoma (very rare) does exist in an autosomal dominant form, and all patients with early-onset clear-cell renal cancer should have a detailed examination to exclude features of VHL and careful documentation of their renal histology.
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Familial Paraganglioma Syndrome (also known as: familial glomus tumor, carotid body tumor) MIM
168000
Clinical features
Swelling of parasympathetic paraganglia in the head and neck. The most common sites are the carotid body, glomus jugulare, and glomus vagale. Less than 5% of tumors metastasize. Around 50% of tumors are familial, usually bilateral, and multiple.
Genes
SDHC (succinate dehydrogenase complex, subunit C), SDHD (in paraganglioma type 1 [PGL1])
Chromosomal location
1q21 (SDHC), 11q23 (SDHD)
Prevalence
Rare
Inheritance
Autosomal dominant, but with genomic imprinting (the condition is dependent on methylation of genes). In this case, if passed from the father, the phenotype will affect children of either sex. If transmitted by the mother, however, the overall risk is low, despite carrying the gene.
Age at onset
10–50 years of age
Diagnosis
Magnetic resonance angiography of the neck and, occasionally, invasive angiography (see Figures 18–20).
Genetic testing
Available in regional centers for SDHC and SDHD. Common mutations arise in the SDHD (PGL1) gene.
Screening
Magnetic resonance imaging of the head and neck, and examination and assessment by a vascular surgeon every 3–4 years.
Mutational spectrum
Heterogeneity exists. Most cases are due to PGL1 and 20% of cases are due to mutations in SDHC. However, there may be other loci involved.
Counseling issues
The most difficult area, apart from the diagnosis, is the explanation of imprinting and genetic testing results.
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Figure 18. Angiogram of neck showing carotid stenosis.
Figure 19. Angiogram of carotid body tumor.
Figure 20. Angiogram of neck showing carotid body tumor.
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Familial Pheochromocytoma MIM
171300
Clinical features
Periodic rise in blood pressure. May cause sweating, tremors, and hypertensive crisis during anesthesia.
Genes
Various, including genes for neurofibromatosis type I (NF1), von Hippel-Lindau syndrome (VHL), multiple endocrine neoplasia type IIA (MEN2A), MEN2B, and pure familial pheochromocytoma. Also SDHB (succinate dehydrogenase complex, subunit B) and SDHD.
Chromosomal location
11q23, 1p
Prevalence
Rare
Inheritance
Autosomal dominant
Age at onset
Usually 10 years before the population onset, which is in early middle age.
Diagnosis
Clinical examination and 24-hour urine testing for catecholamines, with scanning of adrenals by computed tomography and magnetic resonance imaging. See Figure 21.
Genetic testing
Available for VHL, MEN2A, MEN2B, and SDHD. All isolated familial pheochromocytoma families should be screened in the first instance. In some families, the disease is not linked to these loci.
Screening
Annual 24-hour urine testing for catecholamines. Magnetic resonance imaging, metaiodobenzylguanidine (MIBG), or other appropriate imaging should be conducted every 3–5 years.
Counseling issues
More familial than sporadic cases are thought to exist. Around 25% of cases have a family history or a germline mutation in one of the genes listed above.
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Figure 21. The cut surface of a resected pheochromocytoma specimen.
Breast Cancer: Introduction Genetic screening and testing for familial breast cancer is now widely available in established genetic and oncology centers. It is one of the leading causes of death in western Europe and the USA: population risks of breast cancer are around 1 in 9–11 women. This risk mostly applies to older women, particularly those over 50 years of age. Apart from age, the next largest risk factor for breast cancer is family history. Guidelines exist for segregating breast cancer risk into high (greater than 1 in 4), medium (less than 1 in 4–7), and low risk (less than 1 in 7 – the population risk). Most cancer genetic screening programs offer a “triage” system of referrals, where patients fill in a detailed questionnaire to allow the presence of cancers in the family to be confirmed and an accurate family tree to be drawn. This enables the genetic team of a clinical geneticist and genetic counselors or associates to determine an accurate individual risk for the proband. Confirmation of cancers is important for two reasons. Firstly, some patients may not know the exact cancers that their relatives suffered from, or whether the cancer from which they died was primary or secondary. Secondly, some suspected cancers may actually be benign, and the risk to the family may be very low.
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Site-specific breast cancer One first-degree relative diagnosed at ≤ 40 years of age Two first-degree relatives diagnosed at ≤ 60 years of age (on the same side of the family) Three first- or second-degree relatives diagnosed at any age (on the same side of the family) One first-degree male relative with breast cancer One first-degree relative with bilateral breast cancer (NB. Breast cancer can be inherited through the paternal side of the family. Other cancers, including ovary and early prostate and pancreatic cancers [35–50 years], may be suggestive – particularly for BRCA1 for breast and ovary cancers, and BRCA2 for prostate, pancreas, melanoma, and gall bladder cancers) If in doubt, contact a family-history specialist clinic for advice
Breast and ovarian cancer At least one case of breast cancer and one of ovarian cancer in first-degree relatives (if only one of each cancer, the breast cancer must have occurred in a relative <50 years of age) A first-degree relative who has both breast and ovarian cancer Table 1. Typical referral criteria for high-risk (>1 in 4 lifetime risk) patients.
Rarely, some patients fabricate a family history, as they may be suffering from other problems of a nonphysical nature or to seek attention, and these patients require special help in dealing with their problems. We have had some such cases in our own practice and surgeons should be aware of this possibility, even if it is rare. If patients are in the low-risk category after preliminary risk estimation, management is usually by telephone and written contact to the patient, with copies to their primary-care physician, detailing that the patient is at low risk and giving reassurance and an offer of further risk evaluation if the family history changes (eg, if another relative becomes affected). Patients often find this very helpful, especially as they do not need to attend a hospital clinic. Mediumrisk patients are offered screening at an appropriate secondary
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level clinic with mammography and breast examination at defined intervals (see Table 1). High-risk patients are offered a consultation with a geneticist for consideration of genetic testing and a range of screening and preventative measures, including prophylactic surgery.
Breast Cancer (BRCA1) MIM
113705
Clinical features
Early-onset breast cancer (typically in the third and fifth decades in association with ovarian cancer. See Figures 22 and 23.
Gene
BRCA1 (breast cancer 1)
Chromosomal location
17q21
Incidence
1 in 900 (1 in 100 in Ashkenazi Jewish populations). The normal risk of breast cancer is 1 in 9–11.
Inheritance
Autosomal dominant, with 40%–80% penetrance.
History
BRCA1 was the first breast cancer gene to be localized, and was isolated in 1994. The patent for this gene has controversially been filed by Myriad Genetics. In the USA, testing for both BRCA1 and BRCA2 requires permission from a laboratory accredited by Myriad Genetics. A similar patent application has been filed in the EU and is being contested by some EU member states.
Age at onset
Breast cancer from 30 years of age onwards, ovarian cancer from around 45 years onwards. The risk of breast cancer tends to fall after the menopause in gene carriers, but the risk of ovarian cancer continues into old age.
Diagnosis
A strong history of early breast and ovarian cancer in the family (eg, three affected first-degree relatives with onset in their thirties or early forties) or in the same person is suggestive. Breast tumors may be estrogen negative. Note that 50% of hereditary breast cancer cases have a paternal family history (eg, a male with two affected sisters and an affected mother). The referring physician or patient may not realize this, as an assumption is often made that breast cancer is a female disease inherited from the mother’s side.
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Figure 22. A clinical photograph of cancer of the right breast.
Figure 23. Resection specimen of breast cancer.
Genetic testing is routinely available for BRCA1 and is fast in laboratories controlled by Myriad Genetics (turnaround within 3 months for BRCA1 and BRCA2 screen), but is very slow in the UK due to under-resourcing of National Health Service laboratories; samples may take several months to process and the actual testing varies – some laboratories will have a faster protein truncation test or other rapid test for exon 11 (and sometimes exons 2 and 20) of the gene. Definitive testing requires full sequencing of all exons and a search for duplications and deletions. These may account for up to 5% of mutations and are not picked up by sequencing.
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Once a mutation is found in a family, presymptomatic gene testing for a known mutation within family members is very rapid (within a few days). Few common mutations exist, although each population may have some founder or common mutations; these rarely exceed 20% of the possible mutations and can occasionally be run as a rapid test. Two common mutations (185delAG and 5382insC) are found in Ashkenazi Jewish populations. A test for these can be combined with that for a common BRCA2 mutation (6174delT) to form an “Ashkenazi screen”. If a patient tests negative for these mutations, their risk of breast cancer is significantly reduced. Screening
For high-risk women (those with greater than 1 in 4 lifetime risk) and gene carriers, annual mammography (from either 35 years of age or 5 years before the earliest onset of breast disease in the family) should be offered, along with breast self-examination and a specialist breast examination every 6–12 months by a surgeon or clinician used to examining younger women. The use of magnetic resonance scanning of the breast as a screening procedure is under trial. It is particularly effective in younger women with dense breast tissue. Initial data from the USA on magnetic resonance screening in young women are encouraging. Prophylactic surgery is the single most effective mode of prevention, reducing the risk by up to 95% (see Figure 24). However, long-term data are limited and women need to go through a prophylactic mastectomy protocol in a specialist center. This protocol includes advice on genetics, risk, and all screening options, detailed explanation of the surgical and reconstruction options, and psychological assessment. Chemoprevention options, such as tamoxifen, are under trial. Tamoxifen is increasingly being prescribed in the USA, along with more recently developed alternatives. In the UK, however, tamoxifen is generally not prescribed outside of a clinical trial (awaiting firm evidence about efficacy with specific BRCA1 or BRCA2 genotype). This is because of significant side-effects of cancer of the endometrium and pulmonary emboli.
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Figure 24. A 30-year-old woman who is a BCRA1 carrier and who opted for a prophylatic bilateral mastectomy with implant reconstruction.
Other surveillance includes ovarian screening – usually by transvaginal ultrasound and CA125 tumor marker testing annually from 35 to 40 years of age onwards – and discussion of prophylactic surgery, which should include bilateral salpingo-oophorectomy (BSO). Hysterectomy is not necessary unless surgically indicated. Preventive BSO will reduce the risk of ovarian tumors by more than 99%, but a residual risk of peritoneal tumor remains. Counseling issues
The lifetime risk of breast cancer in gene carriers is 50%–80%. Risk of ovarian cancer varies from 20% to 40%. Risk of bowel cancer is also increased, but is not thought to be significant enough to merit any screening, other than an awareness of the symptoms. It is important to discuss the 30%–50% risk of a new contralateral breast cancer before 60 years of age; prevention of a further tumor is one of the most common reasons for taking up prophylactic mastectomy. The risk of male breast or prostate cancer in BRCA1 carriers is very small and additional screening is not recommended. The situation is different for male BRCA2 carriers (see next entry).
Breast Cancer (BRCA2) MIM
600185
Clinical features
Early-onset breast cancer (typically fourth to fifth decades), sometimes in association with ovarian cancer. See Figure 25.
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Figure 25. Cancer of the breast.
Gene
BRCA2 (breast cancer 2)
Chromosomal location
13q12
Incidence
1 in 1,000 (1 in 100 in Ashkenazi Jewish population). The normal risk of breast cancer is 1 in 9–11.
Inheritance
Autosomal dominant, with 20%–60% penetrance.
History
BRCA2 was the second major breast cancer gene to be localized, and was isolated in 1995. The patent for this gene (like BRCA1) has controversially been filed by Myriad Genetics. In the USA, testing for both BRCA1 and BRCA2 requires permission from a laboratory accredited by Myriad Genetics. A similar patent application has been filed in the EU and is being contested by some EU member states
Age at onset
Breast cancer from 35 to 40 years of age onwards, ovarian cancer from around 45 years onwards. The risk of breast cancer tends to plateau after the menopause in gene carriers, but the risk of ovarian cancer may continue into old age.
Diagnosis
A strong history of breast cancer (often with perimenopausal onset) and other cancers in the family (including ovarian, pancreatic, and prostate cancer) is suggestive. Breast tumors tend to be estrogen positive, unlike BRCA1 tumors, which are mainly estrogen negative. A paternal history occurs in 50% of cases, and may include male breast cancer and prostate cancer.
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Genetic testing is routinely available for BRCA2 and is fast in laboratories controlled by Myriad Genetics (turnaround within 3 months for BRCA1 and BRCA2 screen), but is very slow in the UK due to under-resourcing of National Health Service laboratories; BRCA2 testing may be limited to some laboratories, samples can take several months to process, and the actual testing varies – some laboratories will have a faster protein truncation test or other rapid test for exons 10 and 11 of the gene. Definitive testing requires full sequencing of all exons and a search for duplications and deletions. These may account for up to 5% of mutations and are not picked up by sequencing. Once a mutation is found in a family, presymptomatic gene testing for a known mutation within family members is very rapid. Few common mutations exist, although each population may have some founder or common mutations; these rarely exceed 15%–20% of the possible mutations and can occasionally be run as a rapid test. The 6174delT mutation is commonly found in Ashkenazi Jewish populations. A test for this mutation can be combined with two BRCA1 mutations (185delAG and 5382insC) to form an “Ashkenazi screen”. If a patient tests negative for these mutations, their risk of breast cancer is significantly reduced. Screening
For high-risk women (those with greater than 1 in 4 lifetime risk) and gene carriers, annual mammography (from 35 years of age or 5 years before the earliest onset of breast disease in the family should be offered) (see Figure 26), along with breast self-examination and a specialist breast examination every 6–12 months by a surgeon or clinician used to examining younger women. Screening by magnetic resonance imaging is under trial and should be considered in some women, particularly younger women who usually have dense breast tissue. Prophylactic surgery is the single most effective mode of prevention, reducing the risk by up to 98%. However, long-term data are limited and women need to go through a prophylactic mastectomy protocol in a specialist center. This protocol includes advice on genetics, risk, and all screening options, detailed explanation of the surgery and reconstruction options, and psychological assessment.
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Figure 26. Cancer of the breast shown by density on a mammogram.
Chemoprevention options, such as tamoxifen, are under trial. Other surveillance includes ovarian screening – usually by transvaginal ultrasound and CA125 tumor marker testing annually from 35 to 40 years of age onwards – and discussion of prophylactic surgery, which should include bilateral salpingo-oophorectomy (BSO). Hysterectomy is not necessary unless surgically indicated. Preventive BSO will reduce the risk of ovarian tumors by more than 99%, but a residual risk of peritoneal tumor remains. Preventative surgery will also reduce the risk of breast cancer, but the exact risk reduction is not clear. The risks of pancreatic, gall bladder, and laryngeal malignancies are not increased enough to merit screening, but there should be awareness of the possibility that these cancers may occur. Any suggestive symptoms should trigger prompt referral to a surgeon for screening. In male BRCA2 carriers, the risk of prostate cancer (around 10%) merits yearly digital rectal examination and prostate-specific antigen screening from around 40 years of age. Awareness that 1 in 20 male BRCA2 carriers may develop breast cancer should encourage regular examination of the chest for lumps, and prompt referral or a regular annual physical examination at the same time as the prostatic screening is prudent.
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The lifetime risk of breast cancer in gene carriers is 25%–60%. Risk of ovarian cancer varies from 10% to 30%, with a higher proportion of cases of ovarian cancer due to mutations in an ovarian cancer control region, but the overall genotype–phenotype correlation is debated. It is important to discuss the 20%–40% risk of a new contralateral breast cancer (before 60 years of age); prevention of a further tumor is one of the most common reasons for prophylactic mastectomy.
Breast Cancer (BRCA3 and BRCA4) Of the 10% of breast cancer cases that have a familial basis, around 40%–50% are due to mutations in BRCA1 and BRCA2 . Around 1% of cases are caused by mutations in TP53 (tumor protein p53) (Li–Fraumeni syndrome, characterized by early-onset breast cancer [around 15–25 years of age], childhood leukemias, and sarcomas). A further 1% of cases occur in Cowden disease (characterized by benign and malignant thyroid and endometrial tumors with skin lesions). Figure 27 shows neurofibromatosis of the breast and other unusual tumor patterns may be seen. An unknown proportion of breast cancer cases occur in heterozygote carriers of the ataxia–telangiectasia gene (characterized by radiationinduced tumors and possible family history of ataxia, conjunctival telangiectasia, and developmental delay in an affected child).
Figure 27. Neurofibromatosis of the breast.
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The cause of the remainder of hereditary breast cancers in the population is currently unknown, but several families not linked to either BRCA1 or BRCA2 exist. At least two other genes, BRCA3 and BRCA4, are suspected but not isolated at present. The phenotype of these families varies, but includes ductal carcinoma in situ and later onset breast cancers (similar to BRCA2) with lower penetrance and a smaller family history (eg, two affected aunts rather than at least three cases). No other particular associations with other cancers have been recognized to date.
Ataxia–Telangiectasia (also known as: Louis-Bar syndrome) MIM
208900
Clinical features
Truncal ataxia, dysarthria, athetosis, and dystonia. On average, patients lose the ability to walk at 10 years of age. Children are short, prone to chest infections, and have telangiectasia in the conjunctivae (see Figure 28), ear, face, and neck. Eye movements are jerky and ocular motor apraxia is common. Malignancies such as lymphoma, leukemia, and lymphocytopenia occur.
Gene
ATM1 (ataxia–telangiectasia mutated gene 1)
Chromosomal location
11q22.3
Prevalence
1 in 300,000
Inheritance
Autosomal recessive
Figure 28. Conjunctival telangiectasia.
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History
Described by Denise Louis-Bar, a Belgian neuropathologist, in 1941.
Age at onset
Childhood onset. Telangiectasia occurs from around 3 years of age. Walking may be delayed and progressively worsens. The mean age of loss of walking is 10 years.
Diagnosis
Serum α-fetoprotein is raised, serum immunoglobulin A (IgA), IgG, and IgM are reduced. On chromosome analysis, cells have increased sensitivity to irradiation, with increased chromosome breakage. Genetic testing is available for ATM1 in supraregional centers.
Screening
It is important to check and confirm the diagnosis, as female carriers may be at risk of breast cancer (although this is debated).
Mutational spectrum
Heterogeneity exists. Some patients have ataxia without telangiectasia, caused by the hMRE11 (human meiotic recombination 11, S. cerevisiae, homolog of) gene, while others have the Aicardi ataxia variant (ocular motor apraxia, but normal serum immunoglobulins and no telangiectasia), caused by the APTX (aprataxin) gene.
Counseling issues
It is important for surgeons to understand the genetics of this disorder. There needs to be a careful explanation of the possible breast cancer risk to heterozygote females. This may be around 6-fold higher, with early onset and bilateral disease. Ultrasound and careful clinical examination are recommended because of radiosensitivity and the possibility of inducing breast cancer in the radiation field with mammography. The role of magnetic resonance imaging is unclear.
Li–Fraumeni Syndrome (also known as: LFS) MIM
151623
Clinical features
Early-onset malignant sarcoma of bone (see Figures 29 and 30) and muscle, with childhood leukemia, early-onset breast cancer (typically in the early twenties), and adrenocortical tumors. Other associated tumors include pancreas, brain, melanoma, gastric, and lung tumors.
Gene
TP53 (tumor protein p53)
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Figure 29. Osteosarcoma of the femur
Figure 30. Osteosarcoma of the femur. shown on X-ray.
Chromosomal location
17p13.1
Prevalence
Rare
Inheritance
Autosomal dominant, with 50% penetrance by 30 years of age and 90% by 70 years.
History
Described by Joseph Li and Fred Fraumeni Jr in 1969.
Age at onset
Childhood or early adulthood.
Diagnosis
Classic families have a proband with muscle or bone sarcoma, a first-degree relative with any cancer, and another first- or seconddegree relative with any cancer or sarcoma before 45 years of age. A Li–Fraumeni-like (LFL) syndrome exists in which the proband has a childhood tumor or sarcoma, a brain tumor, or adrenocortical tumor, and is under 45 years of age with a first-degree relative with any typical LFS cancer at any age, and a first- or second-degree relative with any cancer in a patient under 60 years.
Genetic testing
Available for TP53 in supraregional centers. Mutations are found in 70% of families that fit LFS criteria and 20% of those that fit LFL criteria. Presymptomatic gene testing is available, but uptake is low because of the poor prognosis and lack of screening.
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Screening
Difficult, as there is wide variation in the range of tumors. Radiationinduced tumors are a risk, so the use of computed tomography and mammography is not recommended for screening. Screening should instead be by clinical examination annually from childhood, with abdominal ultrasound from late childhood and annual specialist breast examination and magnetic resonance breast imaging in females from about 25 years of age.
Mutational spectrum
Heterogeneity exists – some LFS families may have mutations in BRCA2 (breast cancer 2), and mutations in CHEK2 (checkpoint kinase 2, S. pombe, homolog of; 22q12.1) have been found in a small number of cases of LFL and LFS, although leukemias are more common with CHEK2 mutations.
Counseling issues
This is difficult as testing in childhood is controversial and no screening or prevention has proven to be effective. An overall poor prognosis makes this a depressing condition for patients to handle. Awareness of family history is important, and a check for BRCA2 or CHECK2 mutations or leukemia predominance should be considered in LFL families.
Hereditary Non Polyposis Colon Cancer (also known as: HNPCC, Lynch 1 and 2 syndromes) MIM
120436 (MLH1) 120435 (MSH2) 600678 (MSH6)
Clinical features
100
Synchronous and metachronous colon cancers (see Figures 31 and 32), often arising as polyps in the colon (hence the possibility of screening and early prevention by colonoscopy). Extracolonic features include stomach, ovary and endometrium, renal, ureteric, and biliary tract cancers. In the Muir–Torre variant, associated skin lesions include keratoacanthoma, sebaceous adenoma, epithelioma, and basal cell carcinoma. This type is allelic to the MSH2 gene. In the Turcot syndrome variant (a heterogeneous disorder associated with colonic polyps and brain tumors, which may also be due to familial adenomatous polyposis in some cases), gliomas may occur with colon cancers (with the onset of the gliomas from 20 years of age). Genetics for Surgeons
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Figure 31. Colonic cancer.
Figure 32. A resected specimen of a rectal cancer.
Genes
Several mismatch repair genes. A total of 80% of cases are caused by MLH1 (mutL, E. coli, homolog of, 1) and MSH2 (mutS, E. coli, homolog of, 2), and around 5% by MSH6 and mixture of others, including MSH3, MLH3, PMS1 (postmeiotic segregation increased, S. cerevisiae, 1) and PMS2.
Chromosomal location
3p21 (MLH1), 2p22 (MSH2), 2p16 (MSH6). Others are also involved, but are rare.
Prevalence
1 in 3,139
Inheritance
Autosomal dominant
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History
First described by Henry Lynch, an American oncologist, in the 1960s. He described a family with pure colon cancer (Lynch type 1) and a family with colon cancer with extracolonic features, including stomach, ovary and endometrium, and urogenital cancer (Lynch type 2). The Lynch naming is now not so widely used, but type 1 generally refers to colon-only families and type 2 to a mixture of cancers.
Age at onset
Often 30–50 years of age – the general population onset of colon cancer is in older age (55–75 years). Lynch syndromes account for around 5% of colon cancers in the population.
Diagnosis
Families fitting the Amsterdam (“1, 2, 3”) criteria (one affected relative under 40 years of age, two generations affected [eg, father and daughter], and at least three affected relatives) have mutations in MLH1, MSH2, and MSH6 in 85% of cases. Modified Amsterdam criteria (Amsterdam II) include affected relatives with other extracolonic cancers. The more recent, less restrictive Bethesda criteria allow a wider mixture of extracolonic cancers. Familial adenomatous polyposis should be excluded, and the cancer histology and pathology should be checked.
Genetic testing
Available for MSH2 in most regional centers and for MLH1 in several laboratories, but this is usually carried out with full sequencing and will take several months outside of commercial laboratories. MSH6 is difficult to access, but may be done on a research basis or as a clinical service in some laboratories.
Screening
Gene carriers or at-risk Amsterdam-positive families should have colonoscopy every 2 years from 35 years of age or 5 years before the earliest tumor in the family. If gastric cancer is present in the family, screening should be by gastroscopy every 3 years from 50 years of age. Ovarian and endometrial screening by ultrasound and CA125 tumor marker tests with hysteroscopy should be carried out annually. If the patient has a history of renal or ureteric cancers, renal ultrasound and urinalysis should be conducted at 2-yearly intervals.
Mutational spectrum
Heterogeneity exists. Around 15% of families who fit the Amsterdam criteria will not have a mutation.
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Advice should be given on diet, exercise, and other lifestyle features that will reduce risk. Trials have shown that aspirin and starch reduce the risk of polyp formation. Recently, mutations within the AXIN2 (axis inhibitor 2) gene have been identified – these cause a combination of colon cancer and tooth agenesis. Patients with missing teeth and a family history of colon cancers should be screened for this interesting and rare gene.
Familial Adenomatous Polyposis (also known as: FAP. Includes: Turcot syndrome, Gardner syndrome) MIM
175100
Clinical features
Florid polyposis, usually with over 100 polyps in the colon and often several thousand (see Figure 33), associated with dental cysts and congenital hypertrophy of the retinal pigment epithelium (see Figure 34). Papillary thyroid, hepatoblastoma, and medulloblastomas are rarely associated.
Gene
APC (adenomatous polyposis coli)
Chromosomal location
5q21
Prevalence
1 in 10,000
Inheritance
Autosomal dominant, with 50% penetrance by 15 years of age and 95% by 35 years.
History
Some eponymous variants exist, which have all now been shown to be part of the FAP syndrome: Turcot syndrome is a heterogeneous disorder associated with colonic polyposis and brain tumors (and may also be due to hereditary non polyposis colon cancer in some cases); Gardner syndrome is the association of jaw cysts with polyposis.
Age at onset
Variable, but most cases start in late childhood and there is usually evidence of polyposis by 25 years of age.
Diagnosis
Flexible sigmoidoscopy and biopsy confirming multiple colonic polyps is virtually diagnostic.
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Figure 33. Multiple colon polyps.
Figure 34. Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis.
Genetic testing
Widely available for APC. Testing can commence at around 10 years of age because of the early onset of polyps. Rapid testing is cheap and allows mutations to be identified in a few weeks. Rare mutations are identified by full gene sequencing, which may take several months in routine hospital laboratories.
Screening
Annual colonoscopy from 10 years, with elective surgery when polyps are found in the late teenage years or early twenties. Surgery may include colectomy with ileorectal anastomosis or
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panproctocolectomy, with or without a pouch. A pouch is now preferred for most patients. Screening for extra colonic features should include upper gastrointestinal endoscopy at 20 years and repeated every 3 years to exclude gastric, duodenal, and periampullary carcinoma, which occur in up to 12% of cases. Mandibular osteomas occur in 90% of cases. Counseling issues
Diagnosis of over 100 polyps confirms the common type of FAP. An attenuated form exists (AFAP) in which less than 100 polyps occur in patients over 40 years of age. In AFAP, the polyps are often more flat than in other forms of the syndrome. Predictive testing is widely available in genetic centers. Non carriers can be reassured, but gene carriers will have to cope with the inexorable progression of the disease and will require colonic surgery at some stage of their life, usually by their early twenties. The psychological difficulties of genetic testing in adolescence, when the need for prevention is greatest, should not be underestimated.
Peutz–Jeghers Syndrome MIM
175200
Clinical features
Pigmentation of the skin and gastrointestinal polyposis. Skin features:brown–black or blue–black freckles on the lips (see Figures 35 and 36), perioral region, face, and neck, and smudgy pigmentation of the fingers. Gastrointestinal features: jejunal hamartomas are classic, but hamartomas or polyps occur in other gastrointestinal regions, including the ileum, stomach, pancreas, and colon. There is a 10%–20% risk of adenocarcinoma of the colon and small bowel. Extra-gastrointestinal features: tumors, including benign and malignant thyroid tumors, ovarian sex cord tumors with annular tubules, and carcinoma of the cervix, pancreas, breast (usually ductal), and testis (particularly Sertoli cell tumors, which are estrogen secreting and will cause gynecomastia in prepubertal males).
Gene
Systemic Cancers
STK11 (serine/threonine protein kinase 11; also known as LKB1)
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Figure 35. Mild pigmentation of the lips, which has faded with age.
Figure 36a. Peutz–Jeghers pigmentation of the lips.
Figure 36b. A close-up showing vertical pigmentation of the lips.
Chromosomal location
19q13
Prevalence
1 in 50,000
Inheritance
Autosomal dominant
History
Described by Peutz in 1921, with later descriptions amplified by Jeghers in 1949. Before Peutz, in 1896, Hutchinson had described pigmentary changes in an individual who later died of intussusception.
Diagnosis
Colicky abdominal pain (60%), gastrointestinal bleeding (25%). May present with intussusception.
Genetic testing
Available through the specialist clinical genetics service, and may often be available on a research basis. Clinical examination is
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virtually diagnostic if the signs are present. However, incomplete penetrance does occur, so genetic testing in families is useful to determine screening. Screening
Screening should consist of testicular examination around puberty, colonoscopy every 3 years from 18 years of age, and mammography and specialist breast examination in females every year from their early thirties. Intervention should visualize the whole colon (ie, colonoscopy and small bowel series). Enteroscopy, in which the patient swallows a mini camera in order to visualize the entire gastrointestinal tract, looks to be a promising development.
Mutational spectrum
Heterogeneity exists. Cases that are not linked to STK11 are known, but no other gene has been identified. Non-STK11 cases have a higher incidence of biliary adenocarcinoma.
Autosomal Recessive Colon Cancer MIM
604933
Clinical features
Fewer than 100 polyps, with little in the way of extra colonic features and normal parents. The number of polyps is variable; there may be up to 1,000 adenomas.
Gene
MYH (mutY, E. coli, homolog of)
Chromosomal location
1p34.3–p32.1
Prevalence
Rare: represents less than 0.5% of cases of colon cancer, or around 1 in 10,000 cases.
Inheritance
Autosomal recessive
Age at onset
30–70 years of age
Diagnosis
Abnormal colonoscopy with multiple polyps (usually 10–100, and not florid polyposis as in familial adenomatous polyposis) in a person with early onset and no family history suggestive of autosomal dominant inheritance.
Genetic testing
Available for MYH on a research basis.
Screening
Regular colonoscopy
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Genetic testing confirms the diagnosis. Heterozygous gene carriers are not known to be at increased risk, but mutations were only first described in 2002 and characterized in 2003, so details may change with further clinical evidence. Some gene carriers may have incomplete penetrance, even in their sixth or seventh decades.
Juvenile Polyposis Syndromes (also known as: JPS) MIM
174900 and others
Clinical features
Multiple hamartomatous polyps (predominantly in the large bowel) in childhood and adolescence. Patients often present with intussusception, bleeding, and failure to thrive.
Gene
SMAD4 (SMA- and MAD-related protein 4), BMPR1A (bone morphogenetic protein receptor, type IA)
Chromosomal location
18q21.1 (SMAD4), 10q22–q23 (BMP1A)
Prevalence
Rare
Inheritance
Autosomal dominant
Age at onset
Usually 10–20 years of age, but may be older.
Diagnosis
Colonoscopy is suggestive if polyps are present in young children.
Genetic testing
Available for BMPR1A and SMAD4 on a research basis.
Screening
Regular colonoscopy from 10 years of age and polyp removal by colonoscopy (or elective surgery if multiple large polyps appear). Upper gastrointestinal endoscopy should be considered from about 20 years of age, as there is an increased risk of pancreatic, duodenal, and stomach malignancies.
Mutational spectrum
Heterogeneity exists. SMAD4 accounts for 15%–25% of JPS cases, and other cases exist that are not linked to SMAD4 or BMPR1A.
Counseling issues
Consider colonoscopy screening of unaffected parents who are gene carriers. Malignancy usually begins in the third decade.
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Gastric Cancer MIM
192090 (CHD1) and others
Clinical features
Diffuse gastric malignancy, often resulting in linitis plastica. See Figure 37 .
Gene
CHD1 (E-cadherin)
Chromosomal location
16q22.1
Prevalence
Rare. Around 10% of gastric cancer cases have a familial basis.
Inheritance
Autosomal dominant
History
Napoleon was thought to have had familial gastric cancer, and his family tree has been well documented.
Age at onset
Starting in third decade – the general population onset is in the fifth decade or later.
Diagnosis
CDH1 gene analysis confirms the diagnosis. Genetic testing is not routinely available and may only be available on a research basis.
Screening
Upper gastrointestinal endoscopy every 3–5 years from 35 years of age or from 5 years before the earliest onset recorded in the family. Prophylactic gastrectomy has been used in some cases, but is not popular as complications occur. However, even in the 21st century, there is still significant morbidity and some mortality.
Figure 37. Gastric cancer.
Systemic Cancers
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Mutational spectrum
Heterogeneity exists. CHD1 accounts for familial diffuse gastric cancer, but variants exist, including familial intestinal gastric cancer, and no genes have yet been isolated. Other conditions in which gastric cancer is common include familial polyposis coli, hereditary non polyposis colon cancer, Peutz–Jeghers syndrome, Cowden disease, Li–Fraumeni syndrome, and familial breast cancer due to BRCA2.
Counseling issues
Pathological verification is important. The prevalence of gastric cancer increases with age due to diet, smoking, alcohol consumption, and Helicobacter pylori infection, all of which may be familial tendencies, but rarely impact at an early age. An H. pylori breath test should be part of the screening and upper gastrointestinal endoscopy should be carried out, as appropriate. DNA testing for mutations in family members is useful. If it is not available, firstdegree relatives should be offered screening by endoscopy.
Pancreatic Cancer MIM
260350
Clinical features
Affected individuals may have little in the way of symptoms, which include upper abdominal pain, weight loss, and jaundice (see Figure 38).
Genes
PRSS1 (protease serine-1), TP53 (tumor protein p53), CDKN2 (cyclin-dependent kinase inhibitor 2), BRCA2 (breast cancer 2)
Chromosomal location
Various
Prevalence
Rare. Around 2% of cases of pancreatic cancer have a familial basis.
Inheritance
Autosomal dominant
Age at onset
Variable – generally 10 years earlier than the population onset.
Diagnosis
Patients should be tested for several conditions, including Li–Fraumeni syndrome (childhood leukemias, osteosarcomas, and rhabdomyosarcomas in association with early breast cancer). Pancreatic cancer is more common in BRCA2 carriers, familial mole melanoma syndrome patients, and hereditary pancreatitis patients due to PRSS1 on chromosome 7q35 (around 40% of hereditary pancreatitis patients develop pancreatic cancer).
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Figure 38. A patient with deep jaundice caused by pancreatic cancer.
Figure 39. Pancreatic cancer relieved by a duodenal stent.
Genetic testing
Routinely available for BRCA2 and TP53. Screening for familial pancreatic cancer genes is undertaken on a research basis in some centers, but it is not otherwise available.
Screening
Difficult. Endoscopic retrograde cannulation of the pancreatic duct has been the tool of choice, but this is controversial as the benefits are outweighed by the invasive nature of the procedure, the possible complications, and the lack of sensitivity. Abdominal ultrasound has little role, and magnetic resonance scanning is probably the best current investigation, but is still relatively insensitive for early pancreatic cancer.
Mutational spectrum
Heterogeneity exists; see the list of genes above.
Systemic Cancers
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This is a difficult condition on which to adequately counsel, as a reliable diagnosis is needed and often no living affected relative is available for genetic testing (due to the late diagnosis of patients and short survival time). Prophylactic surgery carries significant mortality, in advanced cancer, duodenal stenting may relieve vomiting due to duodenal obstruction, thus avoiding open bypass (see Figure 39).
Tylosis and Esophageal Cancer MIM
148500, 133239
Clinical features
Association of esophageal cancer (see Figure 40) with non epidermolytic palmoplantar keratoderma (see Figure 41), resulting in hyperkeratosis of the soles of the feet and palms of the hands (95%). Oral leukoplakia is a feature.
Gene
TOC (tylosis esophageal cancer) is a candidate.
Chromosomal location
17q25
Prevalence
Very rare
Inheritance
Autosomal dominant, with 95% penetrance of esophageal cancer by 60 years of age. Pure esophageal-only autosomal recessive genes exist.
Age at onset
Around 40 years of age.
Diagnosis
Clinical examination and endoscopy with a dermatology opinion to confirm skin changes.
Genetic testing
Not available, although linkage analysis is possible in large families.
Screening
Upper gastrointestinal endoscopy with biopsies checking for dysplastic change. Prophylactic esophagectomy may be considered because of the poor outcome without surgery, but this is a major operation with significant mortality and frequent morbidity. Laser treatment may be suitable for early tumors.
Mutational spectrum
Heterogeneity occurs, in that esophageal cancers exist without tylosis. Barrett’s metaplasia proceeds to cancer in around 5%–10% of cases. Further research is needed to delineate genes in this area.
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Figure 40. Esophageal cancer.
Counseling issues
Figure 41. Palmoplantar keratoderma.
The childhood-onset tylosis variant is not associated with esophageal cancer. Autosomal recessive genes may exist in the Chinese population.
Papillary Renal Cancer MIM
164860
Clinical features
MET (see below) is associated with papillary renal cell carcinoma.
Genes
MET (proto-oncogene with tyrosine kinase binding domain). Others include genes for tuberose sclerosis, Birt–Hogg–Dubé syndrome, and cutaneous leiomyomas.
Chromosomal location
7q31 (MET)
Prevalence
Rare. Around 2% of renal cancers have a familial basis.
Inheritance
Autosomal dominant, with around 50% penetrance by 50 years of age.
Age at onset
Often between the third and fifth decades – the general population onset is in the sixth to seventh decades.
Diagnosis
Ultrasound scan with biopsy and histology confirming papillary type.
Genetic testing
Testing for MET can be performed on a research basis, but is not routinely available.
Screening
Regular renal ultrasound with further delineation by computed tomography or magnetic resonance imaging from around 20 years of age on an annual basis. Cancers are often bilateral.
Systemic Cancers
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Mutational spectrum
Heterogeneity exists. Clear-cell renal cancers are predominantly caused by von Hippel-Lindau syndrome. Familial clear-cell renal carcinoma (rare) does exist in an autosomal dominant form. A rare mixed papillary cancer occurs in the familial leiomyoma syndrome.
Counseling issues
Careful documentation of family history and pathology. Wood’s lamp and skin examination should be used to exclude tuberose sclerosis and Birt–Hogg–Dubé syndrome.
Birt–Hogg–Dubé Syndrome MIM
135150
Clinical features
Skin fibrofolliculomas (see Figure 42) and trichodiscomas. The lesions comprise dome-shaped papules on the head, neck, chest, back, and arms associated with a central hair. Acrochordons (skin tags) are also associated, as are lipomas and oral fibromas, and a tendency to pneumothorax. Rarely, thyroid cancers and parathyroid adenomas have been described. The characteristic renal lesions are type 1 papillary cancers and oncocytomas (benign renal tumors).
Gene
BHD (Birt-Hogg-Dubé syndrome gene; also known as folliculin)
Chromosomal location
17p11.2
Prevalence
Rare
Inheritance
Autosomal dominant
History
First described by AR Birt, GR Hogg, and WJ Dubé in 1977 in a paper entitled “Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons”, which described the rare characteristic skin changes.
Age at onset
Skin lesions in childhood, renal cancers from 45 to 50 years of age.
Diagnosis
Careful skin examination for the fibrofolliculomas.
Genetic testing
Available on a research basis for BHD.
Screening
Renal ultrasound from 40 years of age on an annual basis, with clinical examination of the thyroid and skin.
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Figure 42. Skin fibrofolliculomas in Birt–Hogg–Dubé syndrome.
Counseling issues
Skin problems can be irritating. Presymptomatic testing of family members is available on a research basis and is useful in targeting renal ultrasound screening.
Cutaneous Leiomyoma Syndrome MIM
150800
Clinical features
Cutaneous leiomyomata (see Figure 43) in association with uterine fibroids. Papillary renal cell carcinoma is occasionally associated. Fibroids or leiomyoma may run in families or be associated with skin fibroids and renal cancer as part of the fumarate hydratase gene.
Gene
FH (fumarate hydratase; also known as MCUL1 [multiple cutaneous and uterine leiomyomata 1])
Chromosomal location
1q42.3
Prevalence
Rare
Age at onset
Skin changes typically present in adolescence; fibroids present from 20 years of age.
Diagnosis
Combination of skin and uterine leiomyomata.
Genetic testing
Sometimes available on a research basis for FH.
Inheritance
Autosomal dominant
Screening
Dermatological examinations, although skin changes rarely require intervention. Uterine ultrasound yearly from 40 years of age. Renal ultrasound is useful on an annual basis to check for renal cancer (albeit rare).
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Figure 43. Cutaneous leiomyoma.
Counseling issues
Renal cancer is rare, but it is prudent to check for it with an annual renal ultrasound. Uterine fibroids may necessitate a hysterectomy because of bleeding.
Ovarian and other Gynecological Cancers MIM
604370
Clinical features
Presentation is often late as symptoms vary and are vague. Symptoms include irregular bleeding, fluid retention and abdominal bloating. These often occur after 40 years of age. As this coincides with the menopause, symptoms may be ignored or confused with menopausal symptoms. See Figures 44 and 45.
Genes
BRCA1 (breast cancer 1), BRCA2 – see familial breast cancer, p. 89 MLH1 (mutL, E. coli, homolog of, 1), MSH2 (mutS, E. coli, homolog of, 2), MSH6 – see hereditary non polyposis colorectal cancer (HNPCC), p. 100 STK11 (serine/threonine protein kinase 11) – see Peutz–Jeghers syndrome (PJS), p. 105.
Chromosomal location
Various
Prevalence
1 in 70 in the UK. Around 10% of ovarian cancer cases have a familial basis.
Inheritance
Autosomal dominant.
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Figure 44. Ovarian cystadenocarcinoma. Figure 45. An ovarian cyst.
Age at onset
Typically 40–70 years of age – the population onset is usually 60–70 years.
Diagnosis
Ultrasound, computed tomography, laparoscopy, or laparotomy.
Genetic testing
Available for BRCA1, BRCA2, and the HNPCC and PJS genes.
Screening
There is insufficient evidence to determine whether screening is any more effective in higher risk women than in the general population. Screening in higher risk women is currently being investigated as part of Familial Ovarian Cancer Screening trials in the UK and USA. The current practice throughout Europe for women at high risk of developing ovarian cancer involves surveillance of the ovaries on an at least annual basis. This includes clinical examination, measurement of serum CA125 levels, and transvaginal ultrasound scanning with color Doppler imaging. Surveillance usually starts either when patients are 35 years of age or 5 years before the earliest onset of ovarian cancer in the family. Ovarian cancer is curable if found at an early stage (eg, stage Ia). Presentation is usually at stage III or stage IV – survival at these stages is <20%.
Mutational spectrum
Heterogeneity exists – several genes may cause ovarian cancer (see Table 2), although the largest proportion of ovarian-only cancers are caused by mutations in BRCA1 and BRCA2.
Counseling issues
If only one relative is affected, the risk increases to 1 in 23, but this is still not high enough to justify regular screening (the usual threshold is over 1 in 10 risk). Two or more affected relatives in the family will give a risk of at least 1 in 5. The presence of breast and ovarian cancer either in the family or in the same person is significant and suggestive of BRCA1 or BRCA2.
Systemic Cancers
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Tumor type
Genetic disorder
Ovarian epithelial carcinoma
Breast/ovarian cancer (BRCA1) Breast/ovarian cancer (BRCA2) HNPCC
Ovarian granulosa cell tumors
Peutz–Jeghers syndrome Ollier disease Maffucci syndrome
Ovarian fibroma
Gorlin’s syndrome Autosomal dominant
Ovarian teratomas and dermoid cysts
Familial cases reported
Gonadoblastoma
Intersex states (usually 46XY)
Table 2. Genetic disorders associated with ovarian tumors. HNPCC: hereditary non polyposis colon cancer.
Female carriers of a BRCA1 mutation are thought to have up to 50% lifetime risk for developing ovarian cancer, and mutations in BRCA2 may confer a lifetime risk of up to 35%. The risk of breast cancer in BRCA1 and BRCA2 carriers is around twice the risk of ovarian cancer, so gene carriers should also be screened for this. Prophylactic salpingo-oophorectomy should be discussed. This will reduce the risk by >99%, although a residual risk of peritoneal cancer exists. Some surgeons may offer a hysterectomy at the same time, depending on other gynecological history.
Endometrial Cancer Familial site-specific endometrial cancer is rare and occasionally occurs as part of the HNPCC spectrum or in Cowden syndrome. Ovarian and endometrial cancer risks are increased in these conditions with changes in MLH1 and MSH2. Mutations in MSH6 will cause a predominance of endometrial cancer and occurs without colon cancer in some families.
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Cervical and Vulval Cancer Cervical and vulval cancers have no major hereditary component, although there is a slightly higher incidence in families with BRCA1 or BRCA2 mutations. The main causes are environmental or lifestyle factors – having multiple sexual partners and smoking being the main risk factors. Smoking may, via nicotine action, decrease DNA repair in the cervix.
Prostate Cancer MIM
176807
Clinical features
History of difficulty in passing urine, blood in the urine, or passing small volumes regularly with incomplete emptying. There may be a family history. May present with bony secondaries (see Figure 46).
Gene
HPC1 (hereditary prostate cancer-1), HPC2, HPC20, HPCX (hereditary prostate cancer, X-linked), MSR1 (macrophage scavenger receptor), PCAP (predisposing for prostate cancer), BRCA2 (breast cancer 2; see familial breast cancer, p. 92)
Chromosomal location
1q24–q25 (HPC1), 17p11 (HPC2), 20q13 (HPC20), Xq27–q28 (HCPX), 8p22–p23 (MSR1), 1q42.2–q43 (PCAP)
Prevalence
Rare. Around 2%–4% of prostate cancer cases have a familial basis.
Inheritance
Autosomal dominant and X-linked inheritance have been described.
Age at onset
Often 40–50 years of age. The usual sporadic onset (seen in around 5%–9% of the normal male population) is age-related, with onset generally over 60 years.
Diagnosis
Test serum prostate-specific antigen (PSA) levels followed by ultrasound-guided fine-needle or core biopsy (transrectal). Genetic testing is available in some centers on a research basis for HPC1 and other rare genes, but is not available in service laboratories.
Screening
PSA is useful as a screening tool in familial cases, but is not 100% sensitive or specific. Early diagnosis appears to help treatment, but trials are needed and this is a controversial area. Currently, laparoscopic radical prostatectomy for established disease is becoming more common, but there is a long learning curve.
Systemic Cancers
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Figure 46. Prostatic cancer-positive bone scan.
Mutational spectrum
Heterogeneity exists, with several unlinked families known.
Counseling issues
Screening is difficult and, in the sex-linked type, there may not be a good family history. Any family with three or more cases of prostate cancer or two cases at an early age (<50 years) should be investigated. There is a higher risk of prostate cancer in male BRCA2 carriers. In these patients, screening by annual digital rectal examination and testing of PSA levels is recommended from 40 years of age.
Testicular Cancer MIM
273300
Clinical features
Check for associated syndromic features, such as oral pigmentation in Peutz–Jeghers syndrome (PJS), and a family history of breast cancer.
Gene
None isolated
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Figure 47. Teratoma testis.
Figure 48. Seminoma testis.
Chromosomal location
12q22, 4q12
Prevalence
Rare
Inheritance
Autosomal dominant and sex-linked inheritance have been described.
Age at onset
Possibly earlier than population onset, but this is not well defined.
Diagnosis
Ultrasound of testicular swelling. Genetic testing for PJS if indicated in young boys with pigmentation; otherwise, the diagnosis depends on family history.
Genetic testing
Not generally available, other than for PJS.
Screening
Regular testicular examination, awareness of the risk, and ultrasound. The frequency of ultrasound is not clear, but should initially be annual. Families may be linked to hereditary undescended testes, and there is a risk of testicular cancer in patients with a family history of testicular maldescent.
Mutational spectrum
Heterogeneity exists, and several genes are still to be isolated or linked. Testicular teratomas (see Figure 47), seminomas (see Figure 48), and germ cell tumors may all have a familial element. Klinefelter syndrome should be considered if testicular teratomas occur.
Counseling issues
No clear genetic test. Onset around puberty is suggestive of PJS, if there is pigmentation. Check for the possibility of sex-linked inheritance.
Systemic Cancers
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Gorlin’s Syndrome (also known as: basal cell carcinoma syndrome) MIM
109400
Clinical features
Multiple basal cell carcinomas of the skin (see Figure 49) with jaw cysts. Other features include macrocephaly, missing or fused ribs, abnormal vertebrae segmentation, cleft palate (seen in 5% of cases), and eye abnormalities (25%). Rare findings include ovarian calcification or fibromas (25%), cardiac fibromas (3%), and medulloblastomas (5%). Spina bifida occulta occurs in around 60% of cases.
Gene
PTCH (patched, Drosophila, homolog of)
Chromosomal location
9q22.3
Prevalence
1 in 57,000
Inheritance
Autosomal dominant, with around 90% penetrance.
History
First described by Robert Gorlin, an American dentist and geneticist, in 1960.
Age at onset
Three quarters of patients develop problems by 20 years of age; almost 90% do so by 40 years.
Diagnosis
Thorough clinical examination will reveal most cases. Genetic testing is available in some supraregional service laboratories and it is useful in predictive testing, but is time consuming and not routinely available.
Screening
Annual skin examination – palmar and plantar pits are characteristic. Dental panorthograms on a regular basis to detect dental cysts and other jaw and dental anomalies. Basal cell cancers often develop around puberty and, rarely, medulloblastomas develop between 1 and 2 years of age (compared with 7–8 years in the general population).
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Figure 49. Basal cell carcinoma of skin in Gorlin syndrome.
Counseling issues
Basal cell carcinomas occur in sun-exposed areas of skin, so patients should minimize sun exposure and use extensive protection. There is an adverse response to radiation, so radiotherapy and mammography should be used with extreme caution. Basal cell carcinomas may also occur in other genetic disorders, including the following:
Site-specific Familial Basal Cell Carcinoma Truncal predominance with clustering occurs in younger patients. Cytochrome P450, CYP2D6 (cytochrome P450, subfamily IId 6), and GSTT1 (glutathione S-transferase, τ-1) are associated with both the clustering phenotype in younger patients and a multiple scattered presentation in older patients.
Xeroderma Pigmentosum An autosomal recessive disorder of excess sensitivity to UV light, skin atrophy, hyperpigmentation, and telangiectasia.
Oculocutaneous Albinism Types 1 and 2, autosomal recessive, characterized by lack of pigment in hair, skin, and eyes.
Rhombo Syndrome (Autosomal Dominant) With cyanotic redness of the lips and hands and follicular atrophy of the skin.
Systemic Cancers
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Familial Atypical Mole Melanoma Syndrome (also known as: FAMM) MIM
155600, 600160
Clinical features
Melanoma (see Figures 50 and 51), pancreatic, and breast cancers.
Genes
CDKN2 (cyclin-dependent kinase inhibitor 2A; also known as p16), CMM1 (melanoma, cutaneous malignant 1), CMM3
Chromosomal location
9p21 (CDKN2), 1p36 (CMM1), 6p (CMM3)
Prevalence
Rare. Around 1%–4% of melanoma cases have a familial basis.
Inheritance
Autosomal dominant, with between 50% and 100% penetrance, depending on the mutation.
Age at onset
Usually >10 years before the population onset and by the end of the third decade – around 10% of cases develop before 20 years of age.
Diagnosis
A clinical history of breast or pancreatic cancer in association with melanoma. There are often several melanomas either in a family or in the same person.
Genetic testing
Available in service laboratories for families with several melanomas, with selection based on family history and age at onset of melanoma. Predictive (presymptomatic) testing may be used to guide prevention and surveillance in families where mutations have been identified; however, the exact utility of the test is unclear.
Screening
Examination by a dermatologist every 6 months, use of high protection factor sunscreens, and protective clothing. Any suspicious lesions should be removed or biopsied. Self-examination should be taught. Beware of sunburn in at-risk children.
Mutational spectrum
Heterogeneity exists. The main gene is CDKN2 (p16) on 9p21. Other predisposing diseases include BRCA2 mutation carriers, who are at risk from breast, pancreas, and skin cancers, and Li–Fraumeni syndrome (TP53 [tumor protein p53]) gene carriers, who are at risk from early-onset breast and skin cancers, with muscle and bone sarcomas in childhood. In Cowden syndrome (PTEN [phosphatase and tensin homolog]), thyroid, breast, endometrial, and melanoma cancers occur.
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Figure 50. Cutaneous melanoma.
Counseling issues
Figure 51. Subungal melanoma.
Breast examination and mammogram should be offered from 30 years of age, along with screening advice as described above.
Squamous Cell Carcinoma (also known as: SCC) MIM
601400
Clinical features
A raised skin ulcer with a bleeding and sometimes infected surface (see Figures 52–54). SCC may be isolated, autosomal dominant, or part of a number of associated syndromes, including the following.
Oculocutaneous Albinism (Autosomal Recessive) Lack of pigment in hair, skin, and eyes.
Rothmund–Thomson Syndrome (Autosomal Recessive) Sun-sensitive skin rash with cataracts, osteosarcoma, and hypogonadism.
Flegel Disease (also known as Hyperkeratosis Lenticularis Perstans) (Autosomal Dominant) Hyperkeratosis on the dorsum of the foot and leg.
Xeroderma Pigmentosum (Autosomal Recessive) Sensitivity to ultraviolet light, skin atrophy and hyperpigmentation, and telangiectasia. Systemic Cancers
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Figure 52. Squamous cell carcinoma of skin of the hand.
Figure 53. Squamous cell carcinoma of the tongue.
Figure 54. Squamous cell carcinoma of the lip.
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Epidermolysis Bullosa (Autosomal Recessive) Multiple skin bullae with scarring predisposing to SCC. Genes
Several possible genes are responsible for pure SCC (and as part of syndromes), including: TNFRSF10B (tumor necrosis factor receptor superfamily, member 10B), ING (inhibitor of growth 1), and PTEN (phosphatase and tensin homolog).
Prevalence
Syndromic types (ie, SCC in association with other features such as listed above) are rare. Around 5%–10% of SCC cases have a familial basis.
Age at onset
Often around the third decade. Generally earlier than the population onset of SCC.
Screening
Regular clinical examination by a dermatologist, with prompt biopsy or removal of lesions.
Mutational spectrum
Heterogeneity exists and several genes probably exist for the pure form.
Counseling issues
Apart from the rare syndromes, risk factors commonly include fair skin, alcohol, and smoking. A second primary tumor occurs in 10%–30% of cases. There is a 4-fold risk in relatives of an index case; this is further increased by alcohol and tobacco intake. Abnormalities of metabolism of the GSTT1 (glutathione S-transferase, τ-1) enzyme may also increase the risk.
Gliomas MIM
137800
Clinical features
Gliomas as a group include astrocytomas, ependymomas, oligodendrogliomas (see Figure 55), and glioblastomas. Syndromic causes include neurofibromatosis (NF) types I and II, tuberose sclerosis (particularly subependymal giant cell astrocytoma [SEGA]), Gorlin’s syndrome (familial basal cell nevus), Li–Fraumeni syndrome (childhood leukemia and sarcoma in which astrocytomas are the third most common tumor), and the Turcot variants.
Genes
Several, including those for familial adenomatous polyposis (FAP), hereditary non polyposis colon cancer (HNPCC), NF1, and NF2,
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Figure 55. The autopsy appearance of an oligodendroglioma.
PTCH (patched, Drosophila, homolog of), TP53 (tumor protein p53), and INK4. Chromosomal location
Various. Autosomal dominant gliomas have been linked to 15q23 and 9p.
Prevalence
Around 2%–5% of all gliomas have a familial basis.
Inheritance
Predominantly autosomal dominant
History
In 1959, Turcot described two siblings with brain tumors and colon cancer. It is now clear that this description of what appeared to be an autosomal recessive gene was incorrect. Follow-up of the original family has confirmed mutations in mismatch repair genes as part of the HNPCC spectrum. It is perhaps more likely that two variants of “Turcot” syndrome exist: HNPCC (in which gliomas may occur as part of the extended Lynch type 2 variant) and a form found in gene carriers of mismatch-repair gene mutations (who tend to have glioblastoma multiforme tumors). In contrast, the combination of colonic polyposis and brain tumors caused by mutations in the APC gene in FAP also includes central nervous system tumors, mainly medulloblastomas.
Age at onset
From childhood to middle age – usually earlier than sporadic cases.
Diagnosis
Symptoms including a persistent headache and neurologic dysfunction, confirmed on brain imaging (eg, computed tomography or magnetic resonance imaging). Biopsy (where possible) is useful
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to confirm the exact histologic type and to tailor chemotherapy and radiotherapy. Genetic testing
Routinely available for syndromic causes, including FAP, HNPCC, Li–Fraumeni syndrome, and NF2. Detailed skin examination should be performed to exclude Gorlin’s syndrome, tuberose sclerosis, and NF1. At present, testing is not available in rare “glioma-only” families.
Screening
Regular neurologic examination and magnetic resonance imaging in site-specific types. Site-specific familial glioblastoma occurs, but is rare.
Counseling issues
Little information is available on hereditary site-specific gliomas. NF1 and NF2 should always be excluded.
Meningiomas MIM
156100
Clinical features
These include cerebral and anaplastic meningiomas. Syndromic causes include neurofibromatosis type II (NF2).
Genes
Various, including those for site-specific meningioma and NF2.
Chromosomal location
22q11 (NF2), 1q34–q36 (anaplastic meningioma)
Prevalence
Around 15% of all brain tumors
Inheritance
Predominantly autosomal dominant
Age at onset
Between childhood and middle age – usually earlier than in sporadic cases.
Diagnosis
Symptoms including persistent headache and neurologic dysfunction, confirmed on brain imaging (eg, computed tomography or magnetic resonance imaging). Biopsy is useful to confirm the exact histologic type. Treatment is by surgical removal.
Genetic testing
Routinely available for NF2. A detailed skin examination should be performed to exclude Gorlin’s syndrome, tuberose sclerosis, and NF1. A locus at 1q34–q36 has been described in rare atypical and anaplastic meningiomas.
Screening
Regular neurologic examination and magnetic resonance imaging may be life-long in at-risk patients.
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Little information is available on hereditary site-specific meningioma. Families have been described who are not linked to the NF2 locus. NF1 and NF2 should always be excluded.
Primitive Neural Ectodermal Tumors (also known as: PNET) MIM
260500 (choroid plexus tumors) 601607 (others)
Clinical features
Classification includes choroid plexus carcinomas, malignant rhabdoid tumors, pineoblastomas, and medulloblastomas.
Genes
Various, including site-specific and hSNF5.
Chromosomal location
22q11 (hSNF5)
Prevalence
Around 15% of all brain tumors
Inheritance
Predominantly autosomal dominant
Age at onset
Generally in childhood – PNET accounts for the majority of all childhood brain tumors. Medulloblastomas alone account for around 25%.
Diagnosis
Symptoms including persistent headache and neurologic dysfunction, confirmed on brain imaging (computed tomography or magnetic resonance imaging). Biopsy is useful to confirm the exact histologic type and to guide decisions about the most appropriate mode of treatment.
Genetic testing
Routinely available for syndromic tumors, but not for site-specific tumors. A full physical examination should be performed to exclude Gorlin’s syndrome (the association of familial basal cell nevi and medulloblastoma due to PTCH [patched, Drosophila, homolog of] mutations), familial polyposis coli, Li–Fraumeni syndrome (childhood leukemias and sarcoma), and ataxia–telangiectasia syndrome. Some medulloblastomas have mutations in the SUFU (suppressor of fused, Drosophila, homolog of) gene.
Screening
Regular neurologic examination and magnetic resonance imaging. Such screening may be life-long, depending on age at onset in families. If PNET in the family is at younger onset, then screening
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may stop in middle age, but specialist advice is necessary to determine screening length. Counseling issues
Little information is available on hereditary site-specific PNET subtypes. Familial malignant rhabdoid tumors due to hSNF5 have been described. Choroid plexus papillomas are seen in Aicardi syndrome, which is an X-linked dominant disorder, characterized by infantile spasms, chorioretinopathy, and agenesis of the corpus callosum. Familial neuroepithelial (colloid) cysts may occur as an autosomal dominant entity. Familial germinomas occur in childhood and are predominantly midline tumors involving the pineal gland, basal ganglia, and thalamus. Symptomatology is related to the site of involvement. No genes have been isolated. Retinoblastoma gene carriers may rarely develop pineal gland tumors in adulthood.
Pituitary Tumors MIM
131100 (MEN1) 102200 (acromegaly) 174800 (McCune–Albright) Site specific
Clinical features
Compression of optic nerves causes visual field defects. Hormone-secreting tumors may cause lactation or other endocrine dysfunction syndromes.
Genes
MEN1 (menin), GNAS1 (guanine nucleotide-binding protein, a-stimulating activity polypeptide 1; McCune–Albright syndrome)
Chromosomal location
11q13
Prevalence
Rare
Inheritance
Autosomal dominant
Age at onset
20–50 years of age, on average
Genetic testing
Available for syndromic forms, including MEN1. Testing is currently unavailable for rare forms, although testing for GNAS1 is possible in some centers on a research basis.
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Screening
Visual field assessment and computed tomography or magnetic resonance imaging of the sella turcica at regular intervals, usually 1–2 yearly (depending on the syndrome and family history).
Mutational spectrum
Heterogeneity exists. Further genes will be delineated in the future.
Counseling issues
Surgery is relatively straightforward, although presymptomatic surgery is usually not practical because of endocrine dysfunction.
Retinoblastoma MIM
180200
Clinical features
Loss of the red reflex of the eye or other visual problems in the neonatal period or early childhood.
Gene
RB1 (retinoblastoma)
Chromosomal location
13q14.1–q14.2
Prevalence
1 in 20,000. Around 10% of cases have a familial basis.
Inheritance
Autosomal dominant, with incomplete penetrance in around 50% of cases.
History
In 1971, Alfred Knudson put forward his “two-hit” hypothesis using retinoblastoma as a model. He observed that inherited retinoblastoma patients were more likely to have bilateral, earlier onset disease. This led him to postulate that the malignant change followed mutations in two alleles at the same locus and that there was a two-step process. This would mean that, in familial cases in which one mutation had already occurred, only one further event was necessary to cause cancer. However, in sporadic cases, two separate events were necessary to initiate malignant change, causing cancer to appear at a later age (as multiple mutations in sporadic cases take longer to occur than in familial cases).
Age at onset
Birth to mid-childhood. Later onset can occasionally occur, but is rare.
Diagnosis
Ophthalmic examination reveals characteristic retinal change.
Genetic testing
Available in regional centers for RB1. Mutation analysis can be used to determine if changes are germline or sporadic.
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Screening
Retinal examination every month from birth until 3 months, and then every 3 months until 2 years of age. A general anesthetic may be required unless the child is extremely co-operative. After 2 years, the frequency of screening is reduced until 5 years of age, and is then annual until adolescence. Screening can be avoided completely if presymptomatic gene testing shows the baby is not a gene carrier.
Counseling issues
Tumors are often bilateral (30%). Later tumors, such as osteogenic sarcoma and pinealoma, may occur in adulthood.
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4 4. Topics Surgeons and Anesthetists Should Both Know
Pheochromocytomas 136 Malignant Hyperthermia 137 Muscle Diseases 138 Chloride Ion Channel Disease 139 Sodium Ion Channel Disease 140 Inherited C1 Esterase Inhibitor Deficiency 141
Topics Surgeons and Anesthetists Should Both Know
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Topics Surgeons and Anesthetists Should Both Know Anesthetics usually run smoothly for surgeons, thanks principally to the skill of the anesthetist! Some hereditary conditions, however, have an effect on anesthetic uptake or metabolism and can affect the response to respiration, cardiac function, and muscle contraction, occasionally – unless the anesthetist is prepared – in a catastrophic way. The gender and size (height and weight) of the patient will affect the quantity of anesthetic agent needed to metabolize drugs (pharmacokinetics). The rate of metabolism of anesthetic agents will also be determined by the genetic make-up of the individual. The degree to which different genetic polymorphisms metabolize genes in the body varies considerably, but these are too numerous to list here. A number of conditions are described below because of their importance – either because surgery for the disease is not uncommon (eg, pheochromocytoma) or because there are possible serious consequences for a patient with certain rare genetic conditions undergoing anesthesia.
Pheochromocytomas Clinical features
Periodic rise in blood pressure – may cause hypertensive crisis during anesthetic, sweating, and a rapid fall in blood pressure without evidence of hemorrhage. May lead to death if not diagnosed and treated quickly.
Genes
Various, including genes for neurofibromatosis type I (NF1), von Hippel-Lindau syndrome (VHL), multiple endocrine neoplasia type IIA (MEN2A), MEN2B, and isolated familial pheochromocytoma, and SDHD (succinate dehydrogenase complex, subunit D).
Chromosomal location
Various
Prevalence
Rare, but important
Inheritance
Autosomal dominant in most cases. Some cases may be the result of new mutations and therefore have no family history.
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Age at onset
Usually 10 years before population onset.
Genetic testing
Commonly available for VHL, MEN2A, MEN2B, and SDHD. All isolated familial pheochromocytoma families should be screened for these initially. Some families exist that are not linked to these loci.
Screening
Clinical examination and annual 24-hour urine testing for catecholamines. Magnetic resonance imaging or metiodobenzylguanidine (MIBG) adrenal imaging.
Management
Preoperative α-blockade (such as phenoxybenzamine or other agents).
Malignant Hyperthermia MIM
180901, 145600
Clinical features
This condition may be triggered by many commonly used anesthetics, especially halothane, and by succinylcholine. During anesthesia, temperature rises at a rate of 2°C per hour and may exceed 43°C. This is accompanied by accelerated muscle metabolism with metabolic acidosis. Central core disease and other muscle diseases are common causes. A serum creatine phosphokinase test is useful prior to anesthetic in all male patients with a suggestive family history.
Gene
RYR1 (ryanodine receptor 1) mutations account for 30%–40% of malignant hyperpyrexia.
Chromosome
19q12–q13
Prevalence
Rare
Inheritance
Autosomal dominant
Genetic testing
A common mutation in RYR1 is found in 10% of Caucasians.
Screening
Susceptibility can be tested by looking at the magnitude of contractions of a biopsied muscle stimulated by caffeine or halothane in vitro. However, this test is not 100% accurate.
Management
Withdraw all anesthetic agents and abandon surgery if feasible. Monitor core temperature, blood gases, and blood chemistry and apply surface cooling, whilst avoiding vasoconstriction. Serious arrhythmias should be controlled with β-blockers and hyperkalemia
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and metabolic acidosis should be treated. Intravenous dantrolene can be given. Follow-up should include a clotting screen and monitoring of urine output for renal failure, with serum creatine kinase testing. Refer to an anesthetic manual for intensive care specialists for further details and advice. The patient should carry a warning card or alert bracelet in the future.
Muscle Diseases (include: Duchenne muscular dystrophy [DMD], central core disease) MIM
310200 (DMD) 117000 (central core) Various others
Clinical features
As in malignant hyperpyrexia, anesthetic reactions in these conditions may be triggered by many commonly used anesthetics, especially halothane, and by succinylcholine. During anesthesia, temperature rises at a rate of 2°C per hour and may exceed 43°C. This is accompanied by accelerated muscle metabolism with metabolic acidosis. A serum creatine phosphokinase test is useful prior to anesthetic in all male patients with a suggestive family history, as this is markedly elevated in DMD and Becker muscular dystrophy (BMD).
Genes
RYR1 (ryanodine receptor gene; central core disease), DMD (dystrophin; DMD and BMD)
Chromosome
19q12–q13 (RYR1), Xp21 (DMD)
Prevalence
DMD: 1 in 3,000 males Central core: rare
Inheritance
X-linked recessive (DMD), Autosomal dominant (central core)
Genetic testing
Dystrophin gene testing in DMD and BMD is widely available. RYR1 causes central core disease, but testing is difficult to access and often only available in interested research centers.
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Screening
Most patients should have a warning from their neurologist about the potential risks during anesthesia, and also know to alert the anesthetist preoperatively.
Management
Careful monitoring of the patient during anesthetic and the use of agents known to not cause reactions.
Chloride Ion Channel Disease (includes: myotonia congenita, Thomsen’s disease) MIM
160800
Clinical features
Congenital, cardinal features include myotonia and muscle hypertrophy. This may be so prominent that males look Herculean. Anesthetic problems can occur if patients are left immobile and myotonia is induced.
Gene
CLCN1 (chloride channel 1, skeletal muscle – a chloride channel disorder)
Chromosome
7q35
Prevalence
Rare
Inheritance
Autosomal dominant
History
Described by Dr Julius Thomsen, a Danish physician who was himself affected, in a five-generation family.
Screening
Genetic testing for mutations in CLCN1 is available in specialist neurogenetic centers, or on a research basis. A rare Becker type (possibly autosomal recessive and caused by a mutation with in the same gene) is found in the Finnish population.
Management
None needed, other than to maintain a stable body temperature and move myotonic parts of the body slowly.
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Sodium Ion Channel Disease (includes: paramyotonia congenita, hyperkalemic periodic paralysis [HPP]) MIM
603967
Clinical features
Congenital, cardinal features include paramyotonia (inability to relax the muscle with repetitive movement), prolonged myotonia on exposure to cold (which may fix the facial expression or the hands when washing, or the tongue on eating ice cream), and muscle hypertrophy. This may be so prominent that males look Herculean. Anesthetic problems may occur if patients get cold and paramyotonia is induced. The conditions paramyotonia congenita and HPP are due to allelic mutations at the same locus. HPP can cause rapid hyperkalemia induced by inactivity or cold – serum potassium should be monitored during anesthesia.
Gene
SCN4A (sodium channel, voltage-gated, type IV, α-subunit – a sodium channel gene disorder)
Chromosome
17q23
Prevalence
Rare
Inheritance
Autosomal dominant
Screening
Genetic testing for mutations in SCN4A is available in specialist neurogenetic centers, or on a research basis.
Management
None needed, other than warming slowly.
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Inherited C1 Esterase Inhibitor Deficiency (includes: hereditary angioneurotic edema) MIM
106100
Clinical features
Episodic edema involving upper respiratory and gastrointestinal systems with mucosal involvement, which may make intubation difficult due to the swelling.
Gene
C1NH (C1 esterase inhibitor)
Chromosome
11q11–q13
Prevalence
Rare
Inheritance
Autosomal dominant, but some recessive families may exist.
Screening
Genetic testing for mutations in C1NH is available in specialist centers, or on a research basis. Serum C1 esterase inhibitor levels are diagnostic if reduced, although they may rarely be normal with dysfunctional protein.
Management
Steroids are helpful.
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5 5. Further reading
The following are useful resources for hereditary cancer information: 1. Gene Reviews: www.geneclinics.org 2. Hodgson SV, Maher E. A Practical Guide to Human Cancer Genetics, 2nd edition. Cambridge: Cambridge University Press, 1999. 3. Kingston H. ABC of Clinical Genetics, 3rd edition. London: BMJ Publishing Group, 2002. 4. Morrison PJ, Hodgson SV, Haites NE (Editors). Familial Breast and Ovarian Cancer: Genetics, Screening and Management. Cambridge: Cambridge University Press, 2002. 5. Online Mendelian Inheritance in man (OMIM): www.ncbi.nlm.nih.gov/omim 6. Pagon RA, Pinsky L, Beahler CC. Online medical genetics resources: a US perspective. Br Med J 2001;322:1035–7. 7. Stewart A, Haites N, Rose P. Online medical genetics resources: a UK perspective. Br Med J 2001;322:1037–9. 8. Harper. PS. Practical Genetic Counselling, 6th edition. London: Arnold, 2004.
Further Reading
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6 6. Glossary
Glossary
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A Adenine (A)
One of the bases making up DNA and RNA (pairs with thymine in DNA and uracil in RNA).
Agarose gel electrophoresis
See electrophoresis.
Allele
One of two or more alternative forms of a gene at a given location (locus). A single allele for each locus is inherited separately from each parent. In normal human beings there are two alleles for each locus (diploidy). If the two alleles are identical, the individual is said to be homozygous for that allele; if different, the individual is heterozygous. For example, the normal DNA sequence at codon 6 in the beta-globin gene is GAG (coding for glutamic acid), whereas in sickle cell disease the sequence is GTG (coding for valine). An individual is said to be heterozygous for the glutamic acid → valine mutation if he/she possesses one normal (GAG) and one mutated (GTG) allele. Such individuals are carriers of the sickle cell gene and do not manifest classical sickle cell disease (which is autosomal recessive).
Allelic heterogeneity Similar/identical phenotypes caused by different mutations within a gene. For example, many different mutations in the same gene are now known to be associated with Marfan’s syndrome (FBN1 gene at 15q21.1). Amniocentesis
Withdrawal of amniotic fluid, usually carried out during the second trimester, for the purpose of prenatal diagnosis.
Amplification
The production of increased numbers of a DNA sequence. 1. In vitro In the early days of recombinant DNA techniques, the only way to amplify a sequence of interest (so that large amounts were available for detailed study) was to clone the fragment in a vector (plasmid or phage) and transform bacteria with the recombinant vector. The transformation technique generally results in the “acceptance” of a single vector molecule by each bacterial cell. The vector is able to exist autonomously within the bacterial cell, sometimes at very high copy numbers (eg, 500 vector copies per cell). Growth of the bacteria containing the vector, coupled
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with a method to recover the vector sequence from the bacterial culture, allows for almost unlimited production of a sequence of interest. Cloning and bacterial propagation are still used for applications requiring either large quantities of material or else exceptionally pure material. However, the advent of the polymerase chain reaction (PCR) has meant that amplification of desired DNA sequences can now be performed more rapidly than was the case with cloning (a few hours cf. days), and it is now routine to amplify DNA sequences 10 million-fold. 2. In vivo Amplification may also refer to an increase in the number of DNA sequences within the genome. For example, the genomes of many tumors are now known to contain regions that have been amplified many fold compared to their nontumor counterparts (ie, a sequence or region of DNA that normally occurs once at a particular chromosomal location may be present in hundreds of copies in some tumors). It is believed that many such regions harbor oncogenes, which, when present in high copy number, predispose to development of the malignant phenotype. Aneuploid
Possessing an incorrect number (abnormal complement) of chromosomes. The normal human complement is 46 chromosomes, any cell that deviates from this number is said to be aneuploid.
Aneuploidy
The chromosomal condition of a cell or organism with an incorrect number of chromosomes. Individuals with Down’s syndrome are described as having aneuploidy, because they possess an extra copy of chromosome 21 (trisomy 21), making a total of 47 chromosomes.
Anticipation
A general phenomenon that refers to the observation of an increase in severity, and/or decrease in age of onset, of a condition in successive generations of a family (see Figure 1). Anticipation is now known, in many cases, to result directly from the presence of a dynamic mutation in a family. In the absence of a dynamic mutation, anticipation may be explained by “ascertainment bias”. Thus, before the first dynamic mutations were described (in Fragile X and myotonic dystrophy), it was believed that ascertainment bias was the complete explanation for anticipation. There are two main reasons for ascertainment bias: 1. Identical mutations in different individuals often result in variable expressions of the associated phenotype. Thus, individuals within a
Glossary
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Figure 1. Autosomal dominant inheritance with anticipation. In many disorders that exhibit anticipation, the age of onset decreases in subsequent generations. It may happen that the transmitting parent (grandparent in this case) is unaffected at the time of presentation of the proband (see arrow). A good example is Huntington’s disease, caused by the expansion of a CAG repeat in the coding region of the huntingtin gene. Note that this pedigree would also be consistent with either gonadal mosaicism or reduced penetrance (in the carrier grandparent).
family, all of whom harbor an identical mutation, may have variation in the severity of their condition. 2. Individuals with a severe phenotype are more likely to present to the medical profession. Moreover, such individuals are more likely to fail to reproduce (ie, they are genetic lethals), often for social, rather than direct physical reasons. For both reasons, it is much more likely that a mildly affected parent will be ascertained with a severely affected child, than the reverse. Therefore, the severity of a condition appears to increase through generations. Anticodon
The 3-base sequence on a transfer RNA (tRNA) molecule that is complementary to the 3-base codon of a messenger RNA (mRNA) molecule.
Ascertainment bias
See anticipation.
Autosomal disorder
A disorder associated with a mutation in an autosomal gene.
Autosomal dominant An autosomal disorder in which the phenotype is expressed in (AD) inheritance the heterozygous state. These disorders are not sex-specific. Fifty percent of offspring (when only one parent is affected) will usually manifest the disorder (see Figure 2). Marfan syndrome is a good example of an AD disorder; affected individuals possess one wild-type (normal) and one mutated allele at the FBN1 gene.
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Figure 2. Autosomal dominant (AD) inheritance.
Autosomal recessive An autosomal disorder in which the phenotype is manifest in the (AR) inheritance homozygous state. This pattern of inheritance is not sex-specific and is difficult to trace through generations because both parents must contribute the abnormal gene, but may not necessarily display the disorder. The children of two heterozygous AR parents have a 25% chance of manifesting the disorder (see Figure 3). Cystic fibrosis (CF) is a good example of an AR disorder; affected individuals possess two mutations, one at each allele.
Figure 3. Autosomal recessive (AR) inheritance.
Autosome
Any chromosome, other than the sex chromosomes (X or Y), that occurs in pairs in diploid cells.
B Barr body
An inactive X chromosome, visible in the somatic cells of individuals with more than one X chromosome (ie, all normal females and all males with Klinefelter’s syndrome). For individuals with nX chromosomes, n–1 Barr bodies are seen. The presence of a Barr body in cells obtained by amniocentesis or chorionic villus sampling was formerly used as an indication of the sex of a baby before birth.
Base pair (bp)
Two nucleotides held together by hydrogen bonds. In DNA, guanine always pairs with cytosine, and thymine with adenine. A base pair is also the basic unit for measuring DNA length.
Glossary
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C Carrier
An individual who is heterozygous for a mutant allele (ie, carries one wild-type [normal copy] and one mutated copy of the gene under consideration).
CentiMorgan (cM)
Unit of genetic distance. If the chance of recombination between two loci is 1%, the loci are said to be 1 cM apart. On average, 1 cM implies a physical distance of 1 Mb (1,000,000 base pairs) but significant deviations from this rule of thumb occur because recombination frequencies vary throughout the genome. Thus if recombination in a certain region is less likely than average, 1 cM may be equivalent to 5 Mb (5,000,000 base pairs) in that region.
Centromere
Central constriction of the chromosome where daughter chromatids are joined together, separating the short (p) from the long (q) arms (see Figure 4).
Chorionic villus sampling (CVS)
Prenatal diagnostic procedure for obtaining fetal tissue at an earlier stage of gestation than amniocentesis. Generally performed after 10 weeks, ultrasound is used to guide aspiration of tissue from the villus area of the chorion.
Chromatid
One of the two parallel identical strands of a chromosome, connected at the centromere during mitosis and meiosis (see Figure 4). Before replication, each chromosome consists of only one chromatid. After replication, two identical sister chromatids are present. At the end of mitosis or meiosis, the two sisters separate and move to opposite poles before the cell splits.
Chromatin
A readily stained substance in the nucleus of a cell consisting of DNA and proteins. During cell division it coils and folds to form the metaphase chromosomes.
Chromosome
One of the threadlike “packages” of genes and other DNA in the nucleus of a cell (see Figure 4). Humans have 23 pairs of chromosomes, 46 in total: 44 autosomes and two sex chromosomes. Each parent contributes one chromosome to each pair.
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Chromosome p arm Centromere q arm DNA Double helix
Nucleus Chromatid Telomere
AT A T T
Figure 4. Chromosome structure.
A G A
C T
Chromosomal
A disorder that results from gross changes in chromosome dose.
disorder
May result from addition or loss of entire chromosomes or just portions of chromosomes.
Clone
A group of genetically identical cells with a common ancestor.
Codon
A 3-base coding unit of DNA that specifies the function of a corresponding unit (anticodon) of transfer RNA (tRNA).
Complementary DNA (cDNA)
DNA synthesized from messenger RNA (mRNA) using reverse transcriptase. Differs from genomic DNA because it lacks introns.
Complementation
The wild-type allele of a gene compensates for a mutant allele of the same gene so that the heterozygote’s phenotype is wild-type.
Complementation analysis
A genetic test (usually performed in vitro) that determines whether or not two mutations that produce the same phenotype are allelic. It enables the geneticist to determine how many distinct genes are involved when confronted with a number of mutations that have similar phenotypes.
Glossary
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Occasionally it can be observed clinically. Two parents who both suffer from recessive deafness (ie, both are homozygous for a mutation resulting in deafness) may have offspring that have normal hearing. If A and B refer to the wild-type (normal) forms of the genes, and a and b the mutated forms, one parent could be aa,BB and the other AA,bb. If alleles A and B are distinct, each child will have the genotype aA,bB and will have normal hearing. If A and B are allelic, the child will be homozygous at this locus and will also suffer from deafness. Compound heterozygote
An individual with two different mutant alleles at the same locus.
Concordant Consanguinity
A pair of twins who manifest the same phenotype as each other. Sharing a common ancestor, and thus genetically related. Recessive disorders are seen with increased frequency in consanguineous families.
Consultand
An individual seeking genetic advice.
Contiguous gene syndrome
A syndrome resulting from the simultaneous functional imbalance of a group of genes (see Figure 5). The nomenclature for this group of disorders is somewhat confused, largely as a result of the history of their elucidation. The terms submicroscopic rearrangement/deletion/ duplication and microrearrangement/deletion/duplication are often used interchangeably. Micro or submicroscopic refer to the fact that such lesions are not detectable with standard cytogenetic approaches (where the limit of resolution is usually 10 Mb, and 5 Mb in only the most fortuitous of circumstances). A newer, and perhaps more comprehensive, term that is currently applied to this group of disorders is segmental aneusomy syndromes (SASs). This term embraces the possibility not only of loss or gain of a chromosomal region that harbors many genes (leading to imbalance of all those genes), but also of functional imbalance in a group of genes, as a result of an abnormality of the machinery involved in their silencing/transcription (ie, methylationbased mechanisms that depend on a master control gene). In practice, most contiguous gene syndromes result from the heterozygous deletion of a segment of DNA that is large in molecular terms but not detectable cytogenetically. The size of such deletions is usually 1.5–3.0 Mb. It is common for one to two dozen genes to be involved in such deletions, and the resultant phenotypes are often
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22
21
15.3 15.2 15.1 14
p
13 12
7
11.2 11.1 11.1 11.21 11.22
11.23
Williams’ syndrome region: 1.5–2.5 Mb in size.
21.1 21.2 21.3
22.1
q
31.1 31.2
31.3
32 33 34 35
36
Figure 5. Schematic demonstrating the common deletion found in Williams’ syndrome, at 7q11.23. The common deletion is not detectable using standard cytogenetic analysis (even high resolution), despite the fact that the deletion is at least 1.5 Mb in size. In practice, only genomic rearrangements that affect at least 5–10 Mb are detectable, either by standard cytogenetic analysis or, in fact, any technique whose endpoint involves analysis at the chromosomal level. Such deletions are termed microdeletions or submicroscopic deletions. Approximately 20 genes are known to be involved in the 7q11.23 microdeletion, and work is underway to determine which genes contribute to which aspects of the Williams’ syndrome phenotype.
complex, involving multiple organ systems and, almost invariably, learning difficulties. A good example of a contiguous gene syndrome is Williams’ syndrome, a sporadic disorder that is due to a heterozygous deletion at chromosome 7q11.23. Affected individuals have characteristic phenotypes, including recognizable facial appearance and typical behavioral traits (including moderate learning difficulties). Velocardiofacial syndrome is currently the most common microdeletion known, and is caused by deletions of 3 Mb at chromosome 22q11. Crossing over
Reciprocal exchange of genetic material between homologous chromosomes at meiosis (see Figure 6).
Cytogenetics
The study of the structure of chromosomes.
Cytosine (C)
One of the bases making up DNA and RNA (pairs with guanine).
Cytotrophoblast
Cells obtained from fetal chorionic villi by chorionic villus sampling (CVS). Used for DNA and chromosome analysis.
Glossary
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A
A´
A
A´
B C
B´ C´
B´ C´
B C
Figure 6. Schematic demonstrating the principle of recombination (crossing over). On average, 50 recombinations occur per meiotic division (1–2 per chromosome). Loci that are far apart on the chromosome are more likely to be separated during recombination than those that are physically close to each other (they are said to be linked, see linkage), ie, A and B are less likely to cosegregate than B and C. Note that the two homologues of a sequence have been differentially labeled according to their chromosome of origin.
D Deletion
154
A particular kind of mutation that involves the loss of a segment of DNA from a chromosome with subsequent re-joining of the two extant ends. It can refer to the removal of one or more bases within a gene or to a much larger aberration involving millions of bases. The term deletion is not totally specific, and differentiation must be made between heterozygous and homozygous deletions. Large heterozygous deletions are a common cause of complex phenotypes (see contiguous gene syndrome); large germ-line homozygous deletions are extremely rare, but have been described. Homozygous deletions are frequently described in somatic cells, in association with the manifestation of the malignant phenotype. The two deletions in a homozygous deletion need not be identical, but must result in the complete absence of DNA sequences that occupy the “overlap” region.
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Broadly used to describe two general phenomena: 1. The “melting” or separation of double-stranded DNA (dsDNA) into its constituent single strands, which may be achieved using heat or chemical approaches. 2. The denaturation of proteins. The specificity of proteins is a result of their 3-dimensional conformation, which is a function of their (linear) amino acid sequence. Heat and/or chemical approaches may result in denaturation of a protein – the protein loses its 3-dimensional conformation (usually irreversibly) and, with it, its specific activity.
Diploid
Having two sets of chromosomes. The number of chromosomes in most human somatic cells is 46. This is double the number found in gametes (23, the haploid number).
Discordant
A pair of twins who differ in their manifestation of a phenotype.
Dizygotic
The fertilization of two separate eggs by two separate sperm resulting in a pair of genetically nonidentical twins.
DNA (deoxyribonucleic acid)
The molecule of heredity. DNA normally exists as a double-stranded (ds) molecule; one strand is the complement (in sequence) of the other. The two strands are joined together by hydrogen bonding, a noncovalent mechanism that is easily reversible using heat or chemical means. DNA consists of four distinct bases: guanine (G), cytosine (C), thymine (T), and adenine (A). The convention is that DNA sequences are written in a 5´ to 3´ direction, where 5´ and 3´ refer to the numbering of carbons on the deoxyribose ring. A guanine on one strand will always pair with a cytosine on the other strand, while thymine pairs with adenine. Thus, given the sequence of bases on one strand, the sequence on the other is immediately determined: 5´–AGTGTGACTGATCTTGGTG–3´ 3´–TCACACTGACTAGAACCAC–5´ The complexity (informational content) of a DNA molecule resides almost completely in the particular sequence of its bases. For a sequence of length “n” base pairs, there are 4n possible sequences. Even for relatively small n, this number is astronomic (4n = 1.6 x 1060 for n = 100).
Glossary
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The complementarity of the two strands of a dsDNA molecule is a very important feature and one that is exploited in almost all molecular genetic techniques. If dsDNA is denatured, either by heat or by chemical means, the two strands become separated from each other. If the conditions are subsequently altered (eg, by reducing heat), the two strands eventually “find” each other in solution and re-anneal to form dsDNA once again. The specificity of this reaction is quite high, under the right circumstances – strands that are not highly complementary are much less likely to re-anneal compared to perfect or near perfect matches. The process by which the two strands “find” each other depends on random molecular collisions, and a “zippering” mechanism, which is initiated from a short stretch of complementarity. This property of DNA is vital for the polymerase chain reaction (PCR), Southern blotting, and any method that relies on the use of a DNA/RNA probe to detect its counterpart in a complex mix of molecules. DNA chip
A “chip” or microarray of multiple DNA sequences immobilized on a solid surface (see Figure 7). The term chip refers more often to semiconductor-based DNA arrays, in which short DNA sequences (oligos) are synthesized in situ, using a photolithographic process akin to that used in the manufacture of semiconductor devices for the electronics industry. The term microarray is much more general and includes any collection of DNA sequences immobilized onto a solid surface, whether by a photolithographic process, or by simple “spotting” of DNA sequences onto glass slides. The power of DNA microarrays is based on the parallel analysis that they allow for. In conventional hybridization analysis (ie, Southern blotting), a single DNA sequence is usually used to interrogate a small number of different individuals. In DNA microarray analysis, this approach is reversed – an individual’s DNA is hybridized to an array that may contain 30,000 distinct spots. This allows for direct information to be obtained about all DNA sequences on the array in one experiment. DNA microarrays have been used successfully to directly uncover point mutations in single genes, as well as detect alterations in gene expression associated with certain disease states/cellular differentiation. It is likely that certain types of array will be useful in the determination of subtle copy number alterations, as occurs in microdeletion/microduplication syndromes.
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Figure 7. DNA chip. DNA arrays (or “chips”) are composed of thousands of “spots” of DNA, attached to a solid surface (normally glass). Each spot contains a different DNA sequence. The arrays allow for massively parallel experiments to be performed on samples. In practice, two samples are applied to the array. One sample is a control (from a “normal” sample) and one is the test sample. Each sample is labeled with fluorescent tags, control with green and test with red. The two labeled samples are cohybridized to the array and the results read by a laser scanner. Spots on the array whose DNA content is equally represented in the test and control samples yield equal intensities in the red and green channels, resulting in a yellow signal. Spots appearing as red represent DNA sequences that are present at higher concentration in the test sample compared to the control sample and vice versa.
DNA methylation
Addition of a methyl group (–CH3) to DNA nucleotides (often cytosine). Methylation is often associated with reduced levels of expression of a given gene and is important in imprinting.
DNA replication
Use of existing DNA as a template for the synthesis of new DNA strands. In humans and other eukaryotes, replication takes place in the cell nucleus. DNA replication is semiconservative – each new doublestranded molecule is composed of a newly synthesized strand and a pre-existing strand.
Glossary
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Dominant (traits/diseases)
Manifesting a phenotype in the heterozygous state. Individuals with Huntington’s disease, a dominant condition, are affected even though they possess one normal copy of the gene.
Dynamic/ nonstable mutation
The vast majority of mutations known to be associated with human genetic disease are intergenerationally stable (no alteration in the mutation is observed when transmitted from parent to child). However, a recently described and growing class of disorders result from the presence of mutations that are unstable intergenerationally. These disorders result from the presence of tandem repeats of short DNA sequences (eg, the sequence CAG may be repeated many times in tandem), see Table 1. For reasons that are not completely clear, the copy number of such repeats may vary from parent to child (usually resulting in a copy number increase) and within the somatic cells of a given individual. Abnormal phenotypes result when the number of repeats reaches a given threshold. Furthermore, when this threshold has been reached, the risk of even greater expansion of copy number in subsequent generations increases.
E Electrophoresis
The separation of molecules according to size and ionic charge by an electrical current. Agarose gel electrophoresis Separation, based on size, of DNA/RNA molecules through agarose. Conventional agarose gel electrophoresis generally refers to electrophoresis carried out under standard conditions, allowing the resolution of molecules that vary in size from a few hundred to a few thousand base pairs. Polyacrylamide gel electrophoresis Allows resolution of proteins or DNA molecules differing in size by only 1 base pair. Pulsed field gel electrophoresis (Also performed using agarose) refers to a specialist technique that allows resolution of much larger DNA molecules, in some cases up to a few Mb in size.
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Disorder
Protein/location
Repeat
Repeat location
Normal range
Pre-mutation
Full mutation
Type
MIM
Progressive myoclonus epilepsy of UnverrichtLundborg type (EPM1)
cystatin B 21q22.3
C4GC4G CG
Promoter
2–3
12–17
30–75
AR
254800
Fragile X type A (FRAXA)
FMR1 Xq27.3
CGG
5’UTR
6–52
~60–200
~200–>2,000
XLR
309550
Fragile X type E (FRAXE)
FMR2 Xq28
CGG 5
C’UTR
6–25
–
>200
XLR
309548
Friedreich’s ataxia (FRDA)
frataxin 9q13
GAA
intron
1 7–22
–
200–>900
AR
229300
Huntington’s disease (HD)
huntingtin 4p16.3
CAG
ORF
6–34
–
36–180
AD
143100
Dentatorubal-pallidoluysian atrophy (DRPLA)
atrophin 12p12
CAG
ORF
7–25
–
49–88
AD
125370
Spinal and bulbar muscular atrophy (SBMA – Kennedy syndrome)
androgen receptor CAG Xq11-12
ORF
11–24
–
40–62
XLR
313200
Spinocerebellar ataxia type 1 (SCA1)
ataxin-1 6p23
CAG
ORF
6–39
–
39–83
AD
164400
Spinocerebellar ataxia type 2 (SCA2)
ataxin-2 12q24
CAG
ORF
15–29
–
34–59
AD
183090
Spinocerebellar ataxia type 3 (SCA3)
ataxin-3 14q24.3-q31
CAG
ORF
13–36
–
55–84
AD
109150
Spinocerebellar ataxia type 6 (SCA6)
PQ calcium channel 19p13
CAG
ORF
4–16
–
21–30
AD
183086
Spinocerebellar ataxia type 7 (SCA7)
ataxin-7 3p21.1-p12
CAG
ORF
4–35
28–35
34–>300
AD
164500
Spinocerebellar ataxia type 8 (SCA8)
SCA8 13q21
CTG
3’UTR
6–37
–
~107–2501
AD
603680
Spinocerebellar ataxia type 10 (SCA10)
SCA10 22q13-qter
ATTCT
intron 9
10–22
–
500–4,500
AD
603516
Spinocerebellar ataxia type 12 (SCA12)
PP2R2B 5q31-33
CAG
5’UTR
7–28
–
66–78
AD
604326
Myotonic dystrophy (DM)
DMPK 19q13.3
CTG
3’UTR
5–37
~50–180
~200–>2,000
AD
160900
Table 1. “Classical” repeat expansion disorders. 1Longer alleles exist but are not associated with disease. AD: autosomal dominant; AR: autosomal recessive; ORF: open reading frame (coding region); 3´ UTR: 3´ untranslated region (downstream of gene); 5´ UTR: 5´ untranslated region (upstream of gene); XLR: X-linked recessive.
Empirical Based on observation, rather than detailed knowledge of, eg, modes recurrence of inheritance or environmental factors. risk – recurrence risk Endonuclease
An enzyme that cleaves DNA at an internal site (see also restriction enzyme).
Euchromatin
Chromatin that stains lightly with trypsin G banding and contains active/potentially active genes.
Euploidy
Having a normal chromosome complement.
Glossary
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Exon
Coding part of a gene. Historically, it was believed that all of a DNA sequence is mirrored exactly on the messenger RNA (mRNA) molecule (except for the presence of uracil in mRNA compared to thymine in DNA). It was a surprise to discover that this is generally not the case. The genomic sequence of a gene has two components: exons and introns. The exons are found in both the genomic sequence and the mRNA, whereas the introns are found only in the genomic sequence. The mRNA for dystrophin, an X-linked gene associated with Duchenne muscular dystrophy (DMD), is 14,000 base pairs long but the genomic sequence is spread over a distance of 1.5 million base pairs, because of the presence of very long intronic sequences. After the genomic sequence is initially transcribed to RNA, a complex system ensures specific removal of introns. This system is known as splicing.
Expressivity
Degree of expression of a disease. In some disorders, individuals carrying the same mutation may manifest wide variability in severity of the disorder. Autosomal dominant disorders are often associated with variable expressivity, a good example being Marfan’s syndrome. Variable expressivity is to be differentiated from incomplete penetrance, an all or none phenomenon that refers to the complete absence of a phenotype in some obligate carriers.
F Familial
Any trait that has a higher frequency in relatives of an affected individual than the general population.
FISH
Fluorescence in situ hybridization (see In situ hybridization).
Founder effect
The high frequency of a mutant allele in a population as a result of its presence in a founder (ancestor). Founder effects are particularly noticeable in relative genetic isolates, such as the Finnish or Amish.
Frame-shift mutation
Deletion/insertion of a DNA sequence that is not an exact multiple of 3 base pairs. The result is an alteration of the reading frame of the gene such that all sequence that lies beyond the mutation is missence (ie, codes for the wrong amino acids) (see Figure 8). A premature stop codon is usually encountered shortly after the frame shift.
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T
G
T
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T
T
T
C
C
C
C
C
A
C
C
C
A
PITX2 sequence
Mutant (protein)
ATG Met
TTT Phe
TCC Ser
CCC Pro
ACC Thr
CAA Gln
Normal (protein)
ATG Met
TTT Phe
TCC Ser
CCA Pro
CCC Pro
AAC Asn
Figure 8. Frame-shift mutation. This example shows a sequence of PITX2 in a patient with Rieger’s syndrome, an autosomal dominant condition. The sequence graph shows only the abnormal sequence. The arrow indicates the insertion of a single cytosine (C) residue. When translated, the triplet code is now out of frame by 1 base pair. This totally alters the translated protein’s amino acid sequence. This leads to a premature stop codon later in the protein and results in Rieger’s syndrome.
G Gamete (germ cell)
The mature male or female reproductive cells, which contain a haploid set of chromosomes.
Gene
An ordered, specific sequence of nucleotides that controls the transmission and expression of one or more traits by specifying the sequence and structure of a particular protein or RNA molecule. Mendel defined a gene as the basic physical and functional unit of all heredity.
Gene expression
The process of converting a gene’s coded information into the existing, operating structures in the cell.
Gene mapping
Determines the relative positions of genes on a DNA molecule and plots the genetic distance in linkage units (centiMorgans) or physical distance (base pairs) between them.
Genetic code
Relationship between the sequence of bases in a nucleic acid and the order of amino acids in the polypeptide synthesized from it
Glossary
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1st
1st
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2nd
2nd
2nd
2nd
T
C
A
G
TTT Phe [F]
TCT Ser [S]
TAT Tyr [Y]
TGT Cys [C]
T
TTC Phe [F]
TCC Ser [S]
TAC Tyr [Y]
TGC Cys [C]
C
TTA Leu [L]
TCA Ser [S]
TAA Ter [end]
TGA Ter [end]
A
TTG Leu [L]
TCG Ser [S]
TAG Ter [end]
TGG Trp [W]
G
CTT Leu [L]
CCT Pro [P]
CAT His [H]
CGT Arg [R]
T
CTC Leu [L]
CCC Pro [P]
CAC His [H]
CGC Arg [R]
C
CTA Leu [L]
CCA Pro [P]
CAA Gln [Q]
CGA Arg [R]
A
CTG Leu [L]
CCG Pro [P]
CAG Gln [Q]
CGG Arg [R]
G
ATT Ile [I]
ACT Thr [T]
AAT Asn [N]
AGT Ser [S]
T
ATC Ile [I]
ACC Thr [T]
AAC Asn [N]
AGC Ser [S]
C A
ATA Ile [I]
ACA Thr [T]
AAA Lys [K]
AGA Arg [R]
ATG Met [M]
ACG Thr [T]
AAG Lys [K]
AGG Arg [R]
G
GTT Val [V]
GCT Ala [A]
GAT Asp [D]
GGT Gly [G]
T
GTC Val [V]
GCC Ala [A]
GAC Asp [D]
GGC Gly [G]
C
GTA Val [V]
GCA Ala [A]
GAA Glu [E]
GGA Gly [G]
A
GTG Val [V]
GCG Ala [A]
GAG Glu [E]
GGG Gly [G]
G
3rd
3rd
3rd
3rd
Table 2. The genetic code. To locate a particular codon (eg, TAG, marked in bold) locate the first base (T) in the left hand column, then the second base (A) by looking at the top row, and finally the third (G) in the right hand column (TAG is a stop codon). Note the redundancy of the genetic code – for example, three different codons specify a stop signal, and threonine (Thr) is specified by any of ACT, ACC, ACA, and ACG.
(see Table 2). A sequence of three nucleic acid bases (a triplet) acts as a codeword (codon) for one amino acid or instruction (start/stop). Genetic counseling
Information/advice given to families with, or at risk of, genetic disease. Genetic counseling is a complex discipline that requires accurate diagnostic approaches, up-to-date knowledge of the genetics of the condition, an insight into the beliefs/anxieties/wishes of the individual seeking advice, intelligent risk estimation, and, above all, skill in communicating relevant information to individuals from a wide variety of educational backgrounds. Genetic counseling is most often carried out by trained medical geneticists or, in some countries, specialist genetic counselors or nurses.
Genetic heterogeneity
Association of a specific phenotype with mutations at different loci. The broader the phenotypic criteria, the greater the heterogeneity (eg, mental retardation). However, even very specific phenotypes may be genetically heterogeneous. Isolated central hypothyroidism is a good example: this autosomal recessive condition is now known to be associated (in different individuals) with mutations in the TSH β
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chain at 1p13, the TRH receptor at 8q23, or TRH itself at 3q13.3–q21. There is no obvious distinction between the clinical phenotypes associated with these two genes. Genetic heterogeneity should not be confused with allelic heterogeneity, which refers to the presence of different mutations at the same locus. Genetic locus
A specific location on a chromosome.
Genetic map
A map of genetic landmarks deduced from linkage (recombination) analysis. Aims to determine the linear order of a set of genetic markers along a chromosome. Genetic maps differ significantly from physical maps, in that recombination frequencies are not identical across different genomic regions, resulting occasionally in large discrepancies.
Genetic marker
A gene that has an easily identifiable phenotype so that one can distinguish between those cells or individuals that do or do not have the gene. Such a gene can also be used as a probe to mark cell nuclei or chromosomes, so that they can be isolated easily or identified from other nuclei or chromosomes later.
Genetic screening
Population analysis designed to ascertain individuals at risk of either suffering or transmitting a genetic disease.
Genetically lethal
Preventing reproduction of the individual, either by causing death prior to reproductive age, or as a result of social factors making it highly unlikely (although not impossible) that the individual concerned will reproduce.
Genome
The complete DNA sequence of an individual, including the sex chromosomes and mitochondrial DNA (mtDNA). The genome of humans is estimated to have a complexity of 3.3 x 109 base pairs (per haploid genome).
Genomic
Pertaining to the genome. Genomic DNA differs from complementary DNA (cDNA) in that it contains noncoding as well as coding DNA.
Genotype
Genetic constitution of an individual, distinct from expressed features (phenotype).
Germ line
Germ cells (those cells that produce haploid gametes) and the cells from which they arise. The germ line is formed very early in embryonic development. Germ line mutations are those present constitutionally
Glossary
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in an individual (ie, in all cells of the body) as opposed to somatic mutations, which affect only a proportion of cells. Giemsa banding
Light/dark bar code obtained by staining chromosomes with Giemsa stain. Results in a unique bar code for each chromosome.
Guanine (G)
One of the bases making up DNA and RNA (pairs with cytosine).
H Haploid
The chromosome number of a normal gamete, containing one each of every individual chromosome (23 in humans).
Haploinsufficiency
The presence of one active copy of a gene/region is insufficient to compensate for the absence of the other copy. Most genes are not “haploinsufficient” – 50% reduction of gene activity does not lead to an abnormal phenotype. However, for some genes, most often those involved in early development, reduction to 50% often correlates with an abnormal phenotype. Haploinsufficiency is an important component of most contiguous gene disorders (eg, in Williams’ syndrome, heterozygous deletion of a number of genes results in the mutant phenotype, despite the presence of normal copies of all affected genes).
Hemizygous
Having only one copy of a gene or DNA sequence in diploid cells. Males are hemizygous for most genes on the sex chromosomes, as they possess only one X chromosome and one Y chromosome (the exceptions being those genes with counterparts on both sex chromosomes). Deletions on autosomes produce hemizygosity in both males and females.
Heterochromatin
Contains few active genes, but is rich in highly repeated simple sequence DNA, sometimes known as satellite DNA. Heterochromatin refers to inactive regions of the genome, as opposed to euchromatin, which refers to active, gene expressing regions. Heterochromatin stains darkly with Giemsa.
Heterozygous
Presence of two different alleles at a given locus.
Histones
Simple proteins bound to DNA in chromosomes. They help to maintain chromatin structure and play an important role in regulating gene expression.
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Holandric
Pattern of inheritance displayed by mutations in genes located only on the Y chromosome. Such mutations are transmitted only from father to son.
Homolog or homologous gene
Two or more genes whose sequences manifest significant similarity because of a close evolutionary relationship. May be between species (ortholog) or within a species (paralog).
Homologous chromosomes
Chromosomes that pair during meiosis. These chromosomes contain the same linear gene sequences as one another and derive from one parent.
Homology
Similarity in DNA or protein sequences between individuals of the same species or among different species.
Homozygous
Presence of identical alleles at a given locus.
Human gene therapy The study of approaches to treatment of human genetic disease, using the methods of modern molecular genetics. Many trials are under way studying a variety of disorders, including cystic fibrosis. Some disorders are likely to be more treatable than others – it is probably going to be easier to replace defective or absent gene sequences rather than deal with genes whose aberrant expression results in an actively toxic effect. Human genome project
Worldwide collaboration aimed at obtaining a complete sequence of the human genome. Most sequencing has been carried out in the USA, although the Sanger Centre in Cambridge, UK has sequenced one third of the genome, and centers in Japan and Europe have also contributed significantly. The first draft of the human genome was released in the summer of 2000 to much acclaim. Celera, a privately funded venture, headed by Dr Craig Ventner, also published its first draft at the same time.
Hybridization
Pairing of complementary strands of nucleic acid. Also known as re-annealing. May refer to re-annealing of DNA in solution, on a membrane (Southern blotting) or on a DNA microarray. May also be used to refer to fusion of two somatic cells, resulting in a hybrid that contains genetic information from both donors.
Glossary
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I Imprinting
A general term used to describe the phenomenon whereby a DNA sequence (coding or otherwise) carries a signal or imprint that indicates its parent of origin. For most DNA sequences, no distinction can be made between those arising paternally and those arising maternally (apart from subtle sequence variations); for imprinted sequences this is not the case. The mechanistic basis of imprinting is almost always methylation – for certain genes, the copy that has been inherited from the father is methylated, while the maternal copy is not. The situation may be reversed for other imprinted genes. Note that imprinting of a gene refers to the general phenomenon, not which parental copy is methylated (and, therefore, usually inactive). Thus, formally speaking, it is incorrect to say that a gene undergoes paternal imprinting. It is correct to say that the gene undergoes imprinting and that the inactive (methylated) copy is always the paternal one. However, in common genetics parlance, paternal imprinting is usually understood to mean the same thing.
In situ hybridization Annealing of DNA sequences to immobilized chromosomes/cells/ (ISH) tissues. Historically done using radioactively labeled probes, this is currently most often performed with fluorescently tagged molecules (fluorescent in situ hybridization – FISH, see Figure 9). ISH/FISH allows for the rapid detection of a DNA sequence within the genome. Incomplete penetrance
Complete absence of expression of the abnormal phenotype in a proportion of individuals known to be obligate carriers. To be distinguished from variable expressivity, in which the phenotype always manifests in obligate carriers, but with widely varying degrees of severity.
Index case – proband The individual through which a family medically comes to light. For example, the index case may be a baby with Down’s syndrome. Can be termed propositus (if male) or proposita (if female). Insertion
166
Interruption of a chromosomal sequence as a result of insertion of material from elsewhere in the genome (either a different chromosome, or elsewhere from the same chromosome). Such insertions may result in abnormal phenotypes either because of direct interruption of a gene (uncommon), or because of the resulting imbalance (ie, increased dosage) when the chromosomes that contain the normal counterparts of the inserted sequence are also present. Genetics for Surgeons
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Figure 9. Fluorescence in situ hybridization. FISH analysis of a patient with a complex syndrome, using a clone containing DNA from the region 8q24.3. In addition to that clone, a control from 8pter was used. The 8pter clone has yielded a signal on both homologues of chromosome 8, while the “test” clone from 8q24.3 has yielded a signal on only one homologue, demonstrating a (heterozygous) deletion in that region.
Intron
A noncoding DNA sequence that “interrupts” the protein-coding sequences of a gene; intron sequences are transcribed into messenger RNA (mRNA), but are cut out before the mRNA is translated into a protein (this process is known as splicing). Introns may contain sequences involved in regulating expression of a gene. Unlike the exon, the intron is the nucleotide sequence in a gene that is not represented in the amino acid sequence of the final gene product.
Inversion
A structural abnormality of a chromosome in which a segment is reversed, as compared to the normal orientation of the segment. An inversion may result in the reversal of a segment that lies entirely on one chromosome arm (paracentric) or one that spans (ie, contains) the centromere (pericentric). While individuals who possess an inversion are likely to be genetically balanced (and therefore usually phenotypically normal), they are at increased risk of producing unbalanced offspring because of problems at meiosis with pairing of the inversion chromosome with its normal homolog. Both deletions and duplications may result, with concomitant congenital abnormalities related to genomic imbalance, or miscarriage if the imbalance is lethal.
Glossary
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K Karyotype
A photomicrograph of an individual’s chromosomes arranged in a standard format showing the number, size, and shape of each chromosome type, and any abnormalities of chromosome number or morphology (see Figure 10).
Kilobase (kb)
1000 base pairs of DNA.
Knudson hypothesis See tumor suppressor gene
L Linkage
Coinheritance of DNA sequences/phenotypes as a result of physical proximity on a chromosome. Before the advent of molecular genetics, linkage was often studied with regard to proteins, enzymes, or cellular characteristics. An early study demonstrated linkage between the Duffy blood group and a form of autosomal dominant congenital cataract (both are now known to reside at 1q21.1). Phenotypes may also be linked in this manner (ie, families manifesting two distinct Mendelian disorders). During the recombination phase of meiosis, genetic material is exchanged (equally) between two homologous chromosomes. Genes/ DNA sequences that are located physically close to each other are unlikely to be separated during recombination. Sequences that lie far apart on the same chromosome are more likely to be separated. For sequences that reside on different chromosomes, segregation will always be random, so that there will be a 50% chance of two markers being coinherited.
Linkage analysis
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An algorithm designed to map (ie, physically locate) an unknown gene (associated with the phenotype of interest) to a chromosomal region. Linkage analysis has been the mainstay of disease-associated gene identification for some years. The general availability of large numbers of DNA markers that are variable in the population (polymorphisms), and which therefore permit allele discrimination, has made linkage analysis a relatively rapid and dependable approach (see Figure 11). However, the method relies on the ascertainment of large families manifesting Mendelian disorders. Relatively little phenotypic Genetics for Surgeons
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Figure 10. Schematic of a normal human (male) karyotype. (ISCN 550 ideogram produced by the MRC Human Genetics Unit, Edinburgh, reproduced with permission.)
heterogeneity is tolerated, as a single misassigned individual (believed to be unaffected despite being a gene carrier) in a pedigree may completely invalidate the results. Genetic heterogeneity is another problem, not within families (usually) but between families. Thus, conditions that result in identical phenotypes despite being associated with mutations within different genes (eg, tuberous sclerosis) are often hard to study. Linkage analysis typically follows a standard algorithm: 1. Large families with a given disorder are ascertained. Detailed clinical evaluation results in assignment of affected vs. unaffected individuals. 2. Large numbers of polymorphic DNA markers that span the genome are analyzed in all individuals (affected and unaffected). 3. The results are analyzed statistically, in the hope that one of the markers used will have demonstrably been coinherited with the phenotype in question more often than would be predicted by chance.
Glossary
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5kb 2kb
2kb
5kb 2kb
5kb 2kb
5kb 2kb
2kb
5kb 2kb
2kb
2kb
2kb
In the example above, note that the (affected) mother has a 5-kb band in addition to a 2-kb band. All the unaffected individuals have the small band only, all those who are affected have the large band. The unaffected individuals must have the mother’s 2-kb fragment rather than her 5-kb fragment, and the affected individuals must have inherited the 5-kb band from the mother (as the father does not have one) – note that those individuals who only show the 2-kb band still have two alleles (one from each parent), they are just the same size and so cannot be differentiated. Thus, it appears that the 5-kb band is segregating with the disorder. The results in a family such as this are suggestive but further similar results in other families would be required for a sufficiently high LOD score.
X
2kb
X
3kb
X
Probe
The probe recognizes a DNA sequence adjacent to a restriction site (see arrow) that is polymorphic (present on some chromosomes but not others). When such a site is present, the DNA is cleaved at that point and the probe detects a 2-kb fragment. When absent, the DNA is not cleaved and the probe detects a fragment of size (2 + 3) kb = 5 kb. X refers to the points at which the restriction enzyme will cleave the DNA. The recognition sequence for most restriction enzymes is very stringent – change in just one nucleotide will result in failure of cleavage. Most RFLPs result from the presence of a single nucleotide polymorphism that has altered the restriction site. Figure 11. Schematic demonstrating the use of restriction fragment length polymorphisms (RFLPs) in linkage analysis.
The LOD score (logarithm of the odds) gives an indication of the likelihood of the result being significant (and not having occurred simply as a result of chance coinheritance of the given marker with the condition). Linkage disequilibrium
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Association of particular DNA sequences with each other, more often than is likely by chance alone (see Figure 12). Of particular relevance to inbred populations (eg, Finland), where specific disease mutations are found to reside in close proximity to specific variants of DNA markers, as a result of the founder effect. Genetics for Surgeons
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Marker A
Marker B
–
+
–
–
+
+
+
–
Mutant allele
Many generations
+
–
–
–
Mutant allele
Mutant allele
Figure 12. Schematic demonstrating the concept of linkage disequilibrium. A gene is physically very close to marker B and further from marker A. Markers A and B, both on the same chromosome, can exist in one of two forms : +/–. Thus there are four possible haplotypes, as shown. If the founder mutation in the gene occurred as shown, then it is likely that even after many generations the mutant allele will segregate with the – form of marker B, as recombination is unlikely to have occurred between the two. However, since marker A is further away, the gene will now often segregate with the – form of marker A, which was not present on the original chromosome. The likelihood of recombination between the gene and marker A will depend on the physical distance between them, and on rates of recombination. It is possible that the gene would show a lesser but still significant degree of linkage disequilibrium with marker A.
Linkage map
A map of genetic markers as determined by genetic analysis (ie, recombination analysis). May differ markedly from a map determined by actual physical relationships of genetic markers, because of the variability of recombination.
Locus
The position of a gene/DNA sequence on the genetic map. Allelic genes/sequences are situated at identical loci in homologous chromosomes.
Locus heterogeneity Mutations at different loci cause similar phenotypes.
Glossary
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LOD (Logarithm of the Odds) score
A statistical test of linkage. Used to determine whether a result is likely to have occurred by chance or to truly reflect linkage. The LOD score is the logarithm (base 10) of the likelihood that the linkage is meaningful. A LOD score of 3 implies that there is only a 1:1,000 chance that the results have occurred by chance (ie, the result would be likely to occur once by chance in 1,000 simultaneous studies addressing the same question). This is taken as proof of linkage (see Figure 11).
Lyonization
The inactivation of n–1 X chromosomes on a random basis in an individual with n X chromosomes. Named after Mary Lyon, this mechanism ensures dosage compensation of genes encoded by the X chromosome. X chromosome inactivation does not occur in normal males who possess only one X chromosome, but does occur in one of the two X chromosomes of normal females. In males who possess more than one X chromosome (ie, XXY, XXXY, etc.), the rule is the same and only one X chromosome remains active. X-inactivation occurs in early embryonic development and is random in each cell. The inactivation pattern in each cell is faithfully maintained in all daughter cells. Therefore, females are genetic mosaics, in that they possess two populations of cells with respect to the X chromosome: one population has one X active, while in the other population the other X is active. This is relevant to the expression of X-linked disease in females.
M Meiosis
The process of cell division by which male and female gametes (germ cells) are produced. Meiosis has two main roles. The first is recombination (during meiosis I). The second is reduction division. Human beings have 46 chromosomes, and each is conceived as a result of the union of two germ cells; therefore, it is reasonable to suppose that each germ cell will contain only 23 chromosomes (ie, the haploid number). If not, then the first generation would have 92 chromosomes, the second 184, etc. Thus, at meiosis I, the number of chromosomes is reduced from 46 to 23.
Mendelian inheritance
Refers to a particular pattern of inheritance, obeying simple rules: each somatic cell contains two genes for every characteristic and each pair of genes divides independently of all other pairs at meiosis.
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A catalogue of human Mendelian disorders, initiated in book form by Dr Victor McKusick of Johns Hopkins Hospital in Baltimore, USA. The original catalogue (produced in the mid-1960s) listed approximately 1500 conditions. By December 1998, this number had risen to 10,000 and by November 2003 the figure had reached 14,897. With the advent of the Internet, MIM is now available as an online resource, free of charge (OMIM – Online Mendelian Inheritance in Man). The URL for this site is: http://www.ncbi.nlm.nih.gov/omim/. The online version is updated frequently, far faster than is possible for the print version; therefore, new gene discoveries are quickly assimilated into the database. OMIM lists disorders according to their mode of inheritance: 1 - - - - (100000– ) Autosomal dominant (entries created before May 15, 1994) 2 - - - - (200000– ) Autosomal recessive (entries created before May 15, 1994) 3 - - - - (300000– ) X-linked loci or phenotypes 4 - - - - (400000– ) Y-linked loci or phenotypes 5 - - - - (500000– ) Mitochondrial loci or phenotypes 6 - - - - (600000– ) Autosomal loci/phenotypes (entries created after May 15, 1994). Full explanations of the best way to search the catalogue are available at the home page for OMIM.
Messenger RNA (mRNA)
The template for protein synthesis, carries genetic information from the nucleus to the ribosomes where the code is translated into protein. Genetic information flows: DNA → RNA → protein.
Methylation
See DNA methylation.
Microdeletion
Structural chromosome abnormality involving the loss of a segment that is not detectable using conventional (even high resolution) cytogenetic analysis. Microdeletions usually involve 1–3 Mb of sequence (the resolution of cytogenetic analysis rarely is better than 10 Mb). Most microdeletions are heterozygous, although some individuals/families have been described with homozygous microdeletions. See also contiguous gene syndrome.
Glossary
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Microduplication
Structural chromosome abnormality involving the gain of a segment that may involve long sequences (commonly 1–3 Mb), which are, nevertheless, undetectable using conventional cytogenetic analysis. Patients with microduplications have three copies of all sequences within the duplicated segment, as compared to two copies in normal individuals. See also contiguous gene syndrome.
Microsatellites
DNA sequences composed of short tandem repeats (STRs), such as di- and trinucleotide repeats, distributed widely throughout the genome with varying numbers of copies of the repeating units. Microsatellites are very valuable as genetic markers for mapping human genes.
Missense mutation
Single base substitution resulting in a codon that specifies a different amino acid than the wild-type.
Mitochondrial disease/disorder
Ambiguous term referring to disorders resulting from abnormalities of mitochondrial function. Two separate possibilities should be considered. 1. Mutations in the mitochondrial genome (see Figure 13). Such disorders will manifest an inheritance pattern that mirrors the manner in which mitochondria are inherited. Therefore, a mother will transmit a mitochondrial mutation to all her offspring (all of whom will be affected, albeit to a variable degree). A father will not transmit the disorder to any of his offspring. 2. Mutations in nuclear encoded genes that adversely affect mitochondrial function. The mitochondrial genome does not code for all the genes required for its maintenance; many are encoded in the nuclear genome. However, the inheritance patterns will differ markedly from the category described in the first option, and will be indistinguishable from standard Mendelian disorders. Each mitochondrion possesses between 2–10 copies of its genome, and there are approximately 100 mitochondria in each cell. Therefore, each cell possesses 200–1,000 copies of the mitochondrial genome. Heteroplasmy refers to the variability in sequence of this large number of genomes – even individuals with mitochondrial genome mutations are likely to have wild-type alleles. Variability in the proportion of molecules that are wild-type may have some bearing on the clinical variability often seen in such disorders.
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Figure 13. Mitochondrial inheritance. This pedigree relates to mutations in the mitochondrial genome.
Mitochondrial DNA
The DNA in the circular chromosome of mitochondria. Mitochondrial DNA is present in multiple copies per cell and mutates more rapidly than genomic (nuclear) DNA.
Mitosis
Cell division occurring in somatic cells, resulting in two daughter cells that are genetically identical to the parent cell.
Monogenic trait
Causally associated with a single gene.
Monosomy
Absence of one of a pair of chromosomes.
Monozygotic
Arising from a single zygote or fertilized egg. Monozygotic twins are genetically identical.
Mosaicism or mosaic Refers to the presence of two or more distinct cell lines, all derived from the same zygote. Such cell lines differ from each other as a result of DNA content/sequence. Mosaicism arises when the genetic alteration occurs postfertilization (postzygotic). The important features that need to be considered in mosaicism are: The proportion of cells that are “abnormal”. In general, the greater the proportion of cells that are abnormal, the greater the severity of the associated phenotype. The specific tissues that contain high levels of the abnormal cell line(s). This variable will clearly also be relevant to the manifestation of any phenotype. An individual may have a mutation bearing cell line in a tissue where the mutation is largely irrelevant to the normal functioning of that tissue, with a concomitant reduction in phenotypic sequelae. Mosaicism may be functional, as in normal females who are mosaic for activity of the two X chromosomes (see Lyonization).
Glossary
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Mosaicism may occasionally be observed directly. X-linked skin disorders, such as incontinentia pigmenti, often manifest mosaic changes in the skin of a female, such that abnormal skin is observed alternately with normal skin, often in streaks (Blaschko’s lines), which delineate developmental histories of cells. Multifactorial inheritance
A type of hereditary pattern resulting from a complex interplay of genetic and environmental factors.
Mutation
Any heritable change in DNA sequence.
N Nondisjunction
Failure of two homologous chromosomes to pull apart during meiosis I, or two chromatids of a chromosome to separate in meiosis II or mitosis. The result is that both are transmitted to one daughter cell, while the other daughter cell receives neither.
Nondynamic (stable) mutations
Stably inherited mutations, in contradistinction to dynamic mutations, which display variability from generation to generation. Includes all types of stable mutation (single base substitution, small deletions/ insertions, microduplications, and microdeletions).
Nonpenetrance
Failure of expression of a phenotype in the presence of the relevant genotype.
Nonsense mutation
A single base substitution resulting in the creation of a stop codon (see Figure 14).
Northern blot
Hybridization of a radiolabeled RNA/DNA probe to an immobilized RNA sequence. So called in order to differentiate it from Southern blotting, which was described first. Neither has any relationship to points on the compass. Southern blotting was named after its inventor Ed Southern.
Nucleotide
A basic unit of DNA or RNA consisting of a nitrogenous base – adenine, guanine, thymine, or cytosine in DNA, and adenine, guanine, uracil, or cytosine in RNA. A nucleotide is composed of a phosphate molecule and a sugar molecule – deoxyribose in DNA and ribose in RNA. Many thousands or millions of nucleotides link to form a DNA or RNA molecule.
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A C T
G T C
C T C
T G A
G
Collagen IIα1 sequence
Mutant (protein)
ACT Thr
GTC Val
CTC Leu
TGA STOP
Normal (protein)
ACT Thr
GTC Val
CTC Leu
TGC Cys
Figure 14. Nonsense mutation. This example shows a sequence graph of collagen II (α1) in a patient with Stickler syndrome, an autosomal dominant condition. The sequence is of genomic DNA and shows both normal and abnormal sequences (the patient is heterozygous for the mutation). The base marked with an arrow has been changed from C to A. When translated the codon is changed from TGC (cysteine) to TGA (stop). The premature stop codon in the collagen gene results in Stickler syndrome.
O Obligate carrier
See obligate heterozygote.
Obligate heterozygote (obligate carrier)
An individual who, on the basis of pedigree analysis, must carry the mutant allele.
Oncogene
A gene that, when over expressed, causes neoplasia. This contrasts with tumor suppressor genes, which result in tumorigenesis when their activity is reduced.
P p
Glossary
Short arm of a chromosome (from the French petit) (see Figure 4).
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Palindromic sequence
A DNA sequence that contains the same 5´ to 3´ sequence on both strands. Most restriction enzymes recognize palindromic sequences. An example is 5´–AGATCT–3´, which would read 3´–TCTAGA–5´ on the complementary strand. This is the recognition site of BglII.
Pedigree
A schematic for a family indicating relationships to the proband and how a particular disease or trait has been inherited (see Figure 15).
Penetrance
An all-or-none phenomenon related to the proportion of individuals with the relevant genotype for a disease who actually manifest the phenotype. Note the difference between penetrance and variable expressivity.
Phenotype
Observed disease/abnormality/trait. An all-embracing term that does not necessarily imply pathology. A particular phenotype may be the result of genotype, the environment or both.
Physical map
A map of the locations of identifiable landmarks on DNA, such as specific DNA sequences or genes, where distance is measured in base pairs. For any genome, the highest resolution map is the complete nucleotide sequence of the chromosomes. A physical map should be distinguished from a genetic map, which depends on recombination frequencies.
Plasmid
Found largely in bacterial and protozoan cells, plasmids are autonomously replicating, extrachromosomal, circular DNA molecules that are distinct from the normal bacterial genome and are often used as vectors in recombinant DNA technologies. They are not essential for cell survival under nonselective conditions, but can be incorporated into the genome and are transferred between cells if they encode a protein that would enhance survival under selective conditions (eg, an enzyme that breaks down a specific antibiotic).
Pleiotropy
Diverse effects of a single gene on many organ systems (eg, the mutation in Marfan’s syndrome results in lens dislocation, aortic root dilatation, and other pathologies).
Ploidy
The number of sets of chromosomes in a cell. Human cells may be haploid (23 chromosomes, as in mature sperm or ova), diploid (46 chromosomes, seen in normal somatic cells), or triploid (69 chromosomes, seen in abnormal somatic cells, which results in severe congenital abnormalities).
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Male, female - unaffected
Abortion/stillbirth
Sex not known
Twins
Male, female – affected
Monozygotic twins
4 unaffected females
Heterozygote (AR)
Deceased, affected female
Heterozygote (X-linked)
Consanguineous marriage
Propositus/proband
Figure 15. Symbols commonly used in pedigree drawing.
Point mutation
Single base substitution.
Polygenic disease
Disease (or trait) that results from the simultaneous interaction of multiple gene mutations, each of which contributes to the eventual phenotype. Generally, each mutation in isolation is likely to have a relatively minor effect on the phenotype. Such disorders are not inherited in a Mendelian fashion. Examples include hypertension, obesity, and diabetes.
Polymerase chain reaction (PCR)
A molecular technique for amplifying DNA sequences in vitro (see Figure 16). The DNA to be copied is denatured to its single strand form and two synthetic oligonucleotide primers are annealed to complementary regions of the target DNA in the presence of excess deoxynucleotides and a heat-stable DNA polymerase. The power of PCR lies in the exponential nature of amplification, which results from repeated cycling of the “copying” process. Thus, a single molecule will be copied in the first cycle, resulting in two molecules. In the second cycle, each of these will also be copied, resulting in four copies. In theory, after n cycles, there will be 2n molecules for each starting molecule. In practice, this theoretical limit is rarely reached, mainly for technical reasons. PCR has become a standard technique in molecular biology research as well as routine diagnostics.
Glossary
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Polymorphism
May be applied to phenotype or genotype. The presence in a population of two or more distinct variants, such that the frequency of the rarest is at least 1% (more than can be explained by recurrent mutation alone). A genetic locus is polymorphic if its sequence exists in at least two forms in the population.
Premutation
Any DNA mutation that has little, if any, phenotypic consequence but predisposes future generations to the development of full mutations with phenotypic sequelae. Particularly relevant in the analysis of diseases associated with dynamic mutations.
Proband (propositus) The first individual to present with a disorder through which a pedigree – index case can be ascertained. Probe
General term for a molecule used to make a measurement. In molecular genetics, a probe is a piece of DNA or RNA that is labeled and used to detect its complementary sequence (eg, Southern blotting).
Promoter region
The noncoding sequence upstream (5´) of a gene where RNA polymerase binds. Gene expression is controlled by the promoter region both in terms of level and tissue specificity.
Protease
An enzyme that digests other proteins by cleaving them into small fragments. Proteases may have broad specificity or only cleave a particular site on a protein or set of proteins.
Protease inhibitor
A chemical that can inhibit the activity of a protease. Most proteases have a corresponding specific protease inhibitor.
Proto-oncogene
A misleading term that refers to genes that are usually involved in signaling and cell development, and are often expressed in actively dividing cells. Certain mutations in such genes may result in malignant transformation, with the mutated genes being described as oncogenes. The term proto-oncogene is misleading because it implies that such genes were selected for by evolution in order that, upon mutation, cancers would result because of oncogenic activation. A similar problem arises with the term tumor suppressor gene.
Pseudogene
Near copies of true genes. Pseudogenes share sequence homology with true genes, but are inactive as a result of multiple mutations over a long period of time.
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3'
5'
5'
3' 95°C
DENATURATION
3'
5' P1
P2
1st Cycle
5'
3'
3'
5'
5'
3'
3'
5'
5'
3'
2nd Cycle
Genomic doublestranded DNA
P2
P1
Temperature is lowered to ~50°C to permit annealing of primers to their complementary DNA sequence Temperature is elevated to the optimal heat (~72°C) for the thermophilic polymerase, resulting in primer extension
Denaturation and annealing of primers
3'
Figure 16. Schematic illustrating the technique of polymerase chain reaction (PCR).
Purine
A nitrogen-containing, double-ring, basic compound occurring in nucleic acids. The purines in DNA and RNA are adenine and guanine.
Pyrimidine
A nitrogen-containing, single-ring, basic compound that occurs in nucleic acids. The pyrimidines in DNA are cytosine and thymine, and cytosine and uracil in RNA.
Q q
Long arm of a chromosome (see Figure 4).
R Re-annealing
See hybridization
Recessive (traits, diseases)
Manifest only in homozygotes. For the X chromosome, recessivity applies to males who carry only one (mutant) allele. Females who carry X-linked mutations are generally heterozygotes and, barring unfortunate X-inactivation, do not manifest X-linked recessive phenotypes.
Glossary
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Reciprocal translocation
The exchange of material between two non-homologous chromosomes.
Recombination
The creation of new combinations of linked genes as a result of crossing over at meiosis (see Figure 6).
Recurrence risk
The chance that a genetic disease, already present in a member of a family, will recur in that family and affect another individual.
Restriction enzyme
Endonuclease that cleaves double-stranded (ds)DNA at specific sequences. For example, the enzyme BglII recognizes the sequence AGATCT, and cleaves after the first A on both strands. Most restriction endonucleases recognize sequences that are palindromic – the complementary sequence to AGATCT, read in the same orientation, is also AGATCT. The term “restriction” refers to the function of these enzymes in nature. The organism that synthesizes a given restriction enzyme (eg, BglII) does so in order to “kill” foreign DNA – ”restricting” the potential of foreign DNA that has become integrated to adversely affect the cell. The organism protects its own DNA from the restriction enzyme by simultaneously synthesizing a specific methylase that recognizes the same sequence and modifies one of the bases, such that the restriction enzyme is no longer able to cleave. Thus, for every restriction enzyme, it is likely that a corresponding methylase exists, although in practice only a relatively small number of these have been isolated.
Restriction fragment A restriction fragment is the length of DNA generated when DNA is length polymorphism cleaved by a restriction enzyme. Restriction fragment length varies (RFLP) when a mutation occurs within a restriction enzyme sequence. Most commonly the polymorphism is a single base substitution, but it may also be a variation in length of a DNA sequence due to variable number tandem repeats (VNTRs). The analysis of the fragment lengths after DNA is cut by restriction enzymes is a valuable tool for establishing familial relationships and is often used in forensic analysis of blood, hair, or semen (see Figure 11). Restriction map
A DNA sequence map, indicating the position of restriction sites.
Reverse genetics
Identification of the causative gene for a disorder, based purely on molecular genetic techniques, when no knowledge of the function of the gene exists (the case for most genetic disorders).
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Reverse transcriptase Catalyzes the synthesis of DNA from a single-stranded RNA template. Contradicted the central dogma of genetics (DNA → RNA → protein) and earned its discoverers the Nobel Prize in 1975. RNA (ribonucleic acid)
RNA molecules differ from DNA molecules in that they contain a ribose sugar instead of deoxyribose. There are a variety of types of RNA (including messenger RNA, transfer RNA, and ribosomal RNA) and they work together to transfer information from DNA to the protein-forming units of the cell.
Robertsonian translocation
A translocation between two acrocentric chromosomes, resulting from centric fusion. The short arms and satellites (chromosome segments separated from the main body of the chromosome by a constriction and containing highly repetitive DNA) are lost.
S Second hit hypothesisSee tumor suppressor gene Segmental aneusomy A general term designed to encompass microdeletion/microduplication syndrome (SAS) syndrome, contiguous gene syndrome, and any situation that results in loss of function of a group of genes at a particular chromosome location, irrespective of genomic copy number (ie, loss of function may be related to mutations in master control regions, which affect the expression of many genes). See also contiguous gene syndrome. Sex chromosomes
Refers to the X and Y chromosomes. All normal individuals possess 46 chromosomes, of which 44 are autosomes and two are sex chromosomes. An individual’s sex is determined by his/her complement of sex chromosomes. Essentially, the presence of a Y chromosome results in the male phenotype. Males have an X and a Y chromosome, while females possess two X chromosomes. The Y chromosome is small and contains relatively few genes, concerned almost exclusively with sex determination and/or sperm formation. By contrast, the X chromosome is a large chromosome that possesses many hundreds of genes.
Sex-limited trait
A trait/disorder that is almost exclusively limited to one sex and often results from mutations in autosomal genes. A good example of a sex-limited trait is breast cancer. While males are affected by breast cancer, it is much less common (~1%) than in women. Females
Glossary
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are more prone to breast cancer than males, not only because they possess significantly more breast tissue, but also because their hormonal milieu is significantly different. In many cases, early onset bilateral breast cancer is associated with mutations either in BRCA1 or BRCA2, both autosomal genes. An example of a sex-limited trait in males is male pattern baldness, which is extremely rare in premenopausal women. The inheritance of male pattern baldness is consistent with autosomal dominant, not sex-linked dominant, inheritance. Sex-linked dominant See X-linked dominant Sex-linked recessive See X-linked recessive Sibship
The relationship between the siblings in a family.
Silent mutation
One that has no (apparent) phenotypic effect.
Single gene disorder A disorder resulting from a mutation on one gene. Somatic cell
Any cell of a multicellular organism not involved in the production of gametes.
Southern blot
Hybridization with a radiolabeled RNA/DNA probe to an immobilized DNA sequence (see Figure 17). Named after Ed Southern (currently Professor of Biochemistry at Oxford University, UK), the technique has spawned the nomenclature for other types of blot (Northern blots for RNA and Western blots for proteins).
Splicing
Removal of introns from precursor RNA to produce messenger RNA (mRNA). The process involves recognition of intron–exon junctions and specific removal of intronic sequences, coupled with reconnection of the two strands of DNA that formerly flanked the intron.
Start codon
The AUG codon of messenger RNA recognized by the ribosome to begin protein production.
Stop codon
The codons UAA, UGA, or UAG on messenger RNA (mRNA) (see Table 2). Since no transfer RNA (tRNA) molecules exist that possess anticodons to these sequences, they cannot be translated. When they occur in frame on an mRNA molecule, protein synthesis stops and the ribosome releases the mRNA and the protein.
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A
B
Figure 17. Southern blotting.
Synergistic heterozygosity
This refers to the phenomenon whereby the manifestation of a phenotype normally associated with complete loss of function of a single gene (ie, that gene has two mutations) may be associated with heterozygous mutations in two distinct genes that inhabit the same or related pathways.
T Telomere
End of a chromosome. The telomere is a specialized structure involved in replicating and stabilizing linear DNA molecules.
Teratogen
Any external agent/factor that increases the probability of congenital malformations. A teratogen may be a drug, whether prescribed or illicit, or an environmental effect, such as high temperature. The classical example is thalidomide, a drug originally prescribed for morning sickness, which resulted in very high rates of congenital malformation in exposed fetuses (especially limb defects).
Termination codon
See stop codon.
Glossary
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RNA polymerase
CTC
Sense strand
DNA 3' CUC GAG
Antisense strand
5' RNA
Figure 18. Schematic demonstrating the process of transcription. The sense strand has the sequence CTC (coding for leucine). RNA is generated by pairing with the antisense strand, which has the sequence GAG (the complement of CTC). The RNA produced is the complement of GAG, CUC (essentially the same as CTC, uracil replaces thymine in RNA).
Thymine (T)
One of the bases making up DNA and RNA (pairs with adenine).
Transcription
Synthesis of single-stranded RNA from a double-stranded DNA template (see Figure 18).
Transfer RNA (tRNA)
An RNA molecule that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which that codon specifies. When the ribosome “reads” the mRNA codon, the tRNA with the corresponding anticodon and amino acid is recruited for protein synthesis. The tRNA “gives up” its amino acid to the production of the protein.
Translation
Protein synthesis directed by a specific messenger RNA (mRNA), (see Figure 19). The information in mature mRNA is converted at the ribosome into the linear arrangement of amino acids that constitutes a protein. The mRNA consists of a series of trinucleotide sequences, known as codons. The start codon is AUG, which specifies that methionine should be inserted. For each codon, except for the stop codons that specify the end of translation, a transfer RNA (tRNA) molecule exists that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which that codon specifies. The process of translation results in the sequential addition of amino acids to the growing polypeptide chain. When translation is complete, the protein is released from the ribosome/mRNA complex and may
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Growing polypeptide chain
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LEU tRNA with anticodon GAG, charged with Leucine
Amino (NH2) terminus of protein
GAG CUCGUC 5'
3' mRNA
Ribosome
Ribosome moves to next codon
Figure 19. Schematic of the process of translation. Messenger RNA (mRNA) is translated at the ribosome into a growing polypeptide chain. For each codon, there is a transfer RNA (tRNA) molecule with the anticodon and the appropriate amino acid. Here, the amino acid leucine is shown being added to the polypeptide. The next codon is GUC, specifying valine. Translation happens in a 5´ to 3´ direction along the mRNA molecule. When the stop codon is reached, the polypeptide chain is released from the ribosome.
then undergo posttranslational modification, in addition to folding into its final, active, conformational shape. Translocation
Glossary
Exchange of chromosomal material between two or more nonhomologous chromosomes. Translocations may be balanced or unbalanced. Unbalanced translocations are those that are observed in association with either a loss of genetic material, a gain, or both. As with other causes of genomic imbalance, there are usually phenotypic consequences, in particular mental retardation. Balanced translocations are usually associated with a normal phenotype, but increase the risk of genomic imbalance in offspring, with expected consequences (either severe phenotypes or lethality). Translocations are described by incorporating information about the chromosomes involved (usually but not always two) and the positions on the chromosomes at which the breaks have occurred. Thus t(11;X)(p13;q27.3) refers to an apparently balanced translocation involving chromosome 11 and X, in which the break on 11 is at 11p13 and the break on the X is at Xq27.3
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Triallelic inheritance The association of a phenotype with three mutations. The classical example is Bardet–Biedl syndrome, in which some individuals only manifest the phenotype when three independent mutations are present (two on one gene and another on one of several genes implicated in this disorder). Triallelic inheritance has been trumpeted as providing an insight into the no-man’s land that lies between Mendelian and polygenic disorders. Triplet repeats
Tandem repeats in DNA that comprise many copies of a basic trinucleotide sequence. Of particular relevance to disorders associated with dynamic mutations, such as Huntington’s chorea (HC). HC is associated with a pathological expansion of a CAG repeat within the coding region of the huntingtin gene. This repeat codes for a tract of polyglutamines in the resultant protein, and it is believed that the increase in length of the polyglutamine tract in affected individuals is toxic to cells, resulting in specific neuronal damage.
Trisomy
Possessing three copies of a particular chromosome instead of two.
Tumor suppressor genes
Genes that act to inhibit/control unrestrained growth as part of normal development. The terminology is misleading, implying that these genes function to inhibit tumor formation. The classical tumor suppressor gene is the Rb gene, which is inactivated in retinoblastoma. Unlike oncogenes, where a mutation at one allele is sufficient for malignant transformation in a cell (since mutations in oncogenes result in increased activity, which is unmitigated by the normal allele), both copies of a tumor suppressor gene must be inactivated in a cell for malignant transformation to proceed. Therefore, at the cellular level, tumor suppressor genes behave recessively. However, at the organismal level they behave as dominants, and an individual who possesses a mutation in only one Rb allele still has an extremely high probability of developing bilateral retinoblastomas. The explanation for this phenomenon was first put forward by Knudson and has come to be known as the Knudson hypothesis (also known as the second hit hypothesis). An individual who has a germ-line mutation in one Rb allele (and the same argument may be applied to any tumor suppressor gene) will have the mutation in every cell in his/her body. It is believed that the rate of spontaneous somatic mutation (defined functionally, in terms of loss of function of that gene by whatever mechanism) is of the order of one in a million per gene per cell division.
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Given that there are many more than one million retinal cells in each eye, and many cell divisions involved in retinal development, the chance that the second (wild-type) Rb allele will suffer a somatic mutation is extremely high. In a cell that has acquired a “second hit”, there will now be no functional copies of the Rb gene, as the other allele is already mutated (germ-line mutation). Such a cell will have completely lost its ability to control cell growth and will eventually manifest as a retinoblastoma. The same mechanism occurs in many other tumors, the tissue affected being related to the tissue specificity of expression of the relevant tumor suppressor gene.
U Unequal crossing over
Occurs between similar sequences on chromosomes that are not properly aligned. It is common where specific repeats are found and is the basis of many microdeletion/microduplication syndromes (see Figure 20).
Uniparental disomy (UPD)
In the vast majority of individuals, each chromosome of a pair is derived from a different parent. However, UPD occurs when an offspring receives both copies of a particular chromosome from only one of its parents. UPD of some chromosomes results in recognizable phenotypes whereas for other chromosomes there do not appear to be any phenotypic sequelae. One example of UPD is Prader–Willi syndrome (PWS), which can occur if an individual inherits both copies of chromosome 15 from their mother.
Uniparental heterodisomy
Uniparental disomy in which the two homologues inherited from the same parent are not identical. If the parent has chromosomes A,B the child will also have A,B.
Uniparental isodisomy
Uniparental disomy in which the two homologues inherited from the same parent are identical (ie, duplicates). So, if the parent has chromosomes A,B then the child will have either A,A or B,B.
Uracil (U)
A nitrogenous base found in RNA but not in DNA, uracil is capable of forming a base pair with adenine.
Glossary
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B1
A2
B2
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C1
Repeats 1 and 2 represent identical repeated sequences in different positions on the chromosome. These are likely to have no function.
C2 Equal (normal) recombination at meiosis
B1
A1 A2
A1 A2
B1
B2
C2
Product 1 Duplication of region B and all genes within it A2
C2
B2 C1 Meiotic exchange (crossing over)
C1 Unequal (abnormal) recombination at meiosis B2
B1
C1
Product 2 Deletion of region B and all genes within it A1
C2
Figure 20. Schematic demonstrating (i) normal homologous recombination and (ii) homologous unequal recombination, resulting in a deletion and a duplication chromosome.
V Variable expressivity Variable expression of a phenotype: not all-or-none (as is the case with penetrance). Individuals with identical mutations may manifest variable severity of symptoms, or symptoms that appear in one organ and not in another. Variable number of tandem repeats (VNTR)
Certain DNA sequences possess tandem arrays of repeated sequences. Generally, the longer the array (ie, the greater the number of copies of a given repeat), the more unstable the sequence, with a consequent wide variability between alleles (both within an individual and between individuals). Because of their variability, VNTRs are extremely useful for genetic studies as they allow for different alleles to be distinguished.
W Western blot
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Like a Southern or Northern blot but for proteins, using a labeled antibody as a probe.
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X X-autosome translocation
Translocation between the X chromosome and an autosome.
X chromosome
See sex chromosomes.
X-chromosome inactivation
See lyonization.
X-linked
Relating to the X chromosome/associated with genes on the X chromosome.
X-linked recessive (XLR)
X-linked disorder in which the phenotype is manifest in homozygous/hemizygous individuals (see Figure 21). In practice, it is hemizygous males that are affected by X-linked recessive disorders, such as Duchenne’s muscular dystrophy (DMD). Females are rarely affected by XLR disorders, although a number of mechanisms have been described that predispose females to being affected, despite being heterozygous.
X-linked dominant (XLD)
X-linked disorder that manifests in the heterozygote. XLD disorders result in manifestation of the phenotype in females and males (see Figure 22). However, because males are hemizygous, they are more severely affected as a rule. In some cases, the XLD disorder results in male lethality.
Y Y chromosome
See sex chromosomes.
Z Zippering
Glossary
A process by which complementary DNA (cDNA) strands that have annealed over a short length undergo rapid full annealing along their whole length. DNA annealing is believed to occur in two main stages. A chance encounter of two strands that are complementary results in a short region of double-stranded DNA (dsDNA), which if perfectly matched, stabilizes the two single strands so that further re-annealing
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Figure 21a. X-linked recessive inheritance – A. Most X-linked disorders manifest recessively, in that heterozygous females (carriers) are unaffected and males, who are hemizygous (possess only one X chromosome) are affected. In this example, a carrier mother has transmitted the disorder to three of her sons. One of her daughters is also a carrier. On average, 50% of the male offspring of a carrier mother will be affected (having inherited the mutated X chromosome), and 50% will be unaffected. Similarly, 50% of daughters will be carriers and 50% will not be carriers. None of the female offspring will be affected but the carriers will carry the same risks to their offspring as their mother. The classical example of this type of inheritance is Duchenne muscular dystrophy.
Figure 21b. X-linked recessive inheritance – B. In this example the father is affected. Because all his sons must have inherited their Y chromosome from him and their X chromosome from their normal mother, none will be affected. Since all his daughters must have inherited his X chromosome, all will be carriers but none affected. For this type of inheritance, it is clearly necessary that males reach reproductive age and are fertile – this is not the case with Duchenne’s muscular dystrophy, which is usually fatal by the teenage years in boys. Emery-Dreifuss muscular dystrophy is a good example of this form of inheritance, as males are likely to live long enough to reproduce.
Figure 22. X-linked dominant inheritance. In X-linked dominant inheritance, the heterozygous female and hemizygous male are affected, however, the males are usually more severely affected than the females. In many cases, X-linked dominant disorders are lethal in males, resulting either in miscarriage or neonatal/infantile death. On average, 50% of all males of an affected mother will inherit the gene and be severely affected; 50% of males will be completely normal. Fifty percent of female offspring will have the same phenotype as their affected mother and the other 50% will be normal and carry no extra risk for their offspring. An example of this type of inheritance is incontinentia pigmenti, a disorder that is almost always lethal in males (males are usually lost during pregnancy).
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of their specific sequences proceeds extremely rapidly. The initial stage is known as nucleation, while the second stage is called zippering. Zygote
Glossary
Diploid cell resulting from the union of male and female haploid gametes.
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7 7. Abbreviations AFAP ASD BMD BSO BWS CALS CARD15 CDH CF CLL CML CMT CMTX CNC DMD EDS FAMM FAP FISH FMTC FSHD GAP GJB1 GSTT1 HNPCC HPP Ig IBD JPS Abbreviations
attenuated form of familial adenomatous polyposis atrial septal defect Becker muscular dystrophy bilateral salpingo-oophorectomy Beckwith–Wiedemann syndrome café-au-lait spots caspase-recruitment domain-containing protein 15 congenital dislocation of the hip cystic fibrosis chronic lymphocytic leukemia chronic myeloid leukemia Charcot–Marie–Tooth Charcot–Marie–Tooth X-linked Carney complex Duchenne muscular dystrophy Ehlers–Danlos syndrome familial atypical mole melanoma syndrome familial adenomatous polyposis fluorescence in situ hybridization familial medullary thyroid cancer facioscapulohumeral muscular dystrophy guanosine 5'-triphosphatase-activating protein GAP junction protein, b-1 glutathione S-transferase, t-1 hereditary nonpolyposis colon cancer hyperkalemic periodic paralysis immunoglobulin inflammatory bowel disease juvenile polyposis syndrome 195
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LAMB LFL LFS MEN MIBG MIM MMPV NAME NF NOD2 OMIM Ph PGL PJS PNET PSA SCC SEGA TSC VHL
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lentigines, atrial myxoma, myxoid tumors, blue nevi Li–Fraumeni-like syndrome Li–Fraumeni syndrome multiple endocrine neoplasia metaiodobenzylguanidine Mendelian Inheritance in Man myxomatous mitral valve prolapse nevi, atrial myxoma, myxoid neurofibromata, ephelides neurofibromatosis nucleotide-binding oligomerization domain 2 Online Mendelian Inheritance in man Philadelphia paraganglioma Peutz–Jeghers syndrome primitive neural ectodermal tumors prostate-specific antigen squamous cell carcinoma subependymal giant cell astrocytoma tuberose sclerosis complex Von Hippel–Lindau syndrome
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8 8. Index Page numbers in italics indicate tables. Page numbers in bold indicate figures. vs indicates a comparison or differential diagnosis. A AAT gene, 47 abdominal wall defects, 24 acromegaly, 131–2 acute myeloid leukemia (AML), 53–4 adenine, 146, 155 adenomatous polyposis, familial see familial adenomatous polyposis (FAP) adiposis dolorosa (Dercum’s disease), 34 agarose gel electrophoresis, 158 Aicardi ataxia variant, 98 Aicardi syndrome, primitive neuroectodermal tumors, 130 Alagille syndrome, biliary atresia, 27 albinism, oculocutaneous, 123, 125 alcohol consumption, gastric cancer, 110 alleles, 146 allelic heterogeneity, 146 α-1 antitrypsin deficiency, 47 amniocentesis, 146 amplification, 146–7 Amsterdam criteria, hereditary non polyposis colon cancer, 102 anal atresia, 27 anesthesia problems, 136–41 aneuploidy, 147 angiofibromas, facial, 27, 28, 29 angiography, familial paraganglioma syndrome, 84, 85 angiomas, retinal, 81 angiomyolipomas, renal, 28 annealing, DNA, 156 anticipation, 147–8, 148 anticodons, 148 aortic valve defects, 42
Index
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aortic valve stenosis, William’s syndrome, 42 APC gene familial adenomatous polyposis, 103 gliomas, 127 APTX gene, 98 ascertainment bias, 147 Ashkenazi Jewish populations BRCA1 gene, 91 BRCA2 gene, 94 asplenia, 25–6 astrocytomas see gliomas ataxia, spinocerebellar, 159 ataxia–telangiectasia, 97, 97–8 primitive neuroectodermal tumors vs, 130 ATM gene ataxia–telangiectasia, 97 breast cancer, 96 chronic lymphocytic leukemia, 55 atresia duodenal, 27 intestinal, 26–7 laryngeal see laryngeal atresia atrial septal defects (ASD), 43 audiologic testing, neurofibromatosis type II, 33 autosomal disorders, 148 dominant inheritance, 148, 148, 149 recessive inheritance, 149 see also specific diseases/disorders autosomal recessive colon cancer, 107–8 autosomes, 149 AXIN2 gene gliomas, 127 hereditary non polyposis colon cancer, 103 B Bannayan–Zonana syndrome, 81 Barr bodies, 149 Barrett’s metaplasia, esophageal cancer, 112 basal cell carcinoma syndrome see Gorlin’s syndrome base pairs, 149 BCL2 gene, chronic lymphocytic leukemia, 55 BCR–ABL fusion, 54 Beal’s syndrome, Marfan’s syndrome vs, 38 Beckwith–Wiedemann syndrome, 24
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behavioral therapy, tuberose sclerosis, 28 BHD gene, 114 bilateral salpingo-oophorectomy (BSO), 92 bile duct cancers, Peutz–Jeghers syndrome, 18 biliary atresia, 27 Birt–Hogg–Dubé syndrome, 114–15 papillary renal cancer vs, 113, 114 BMPR1A gene, 108 bone morphogenetic protein receptor type IA, 108 bone sarcoma, Li–Fraumeni syndrome, 98, 99 BRCA1 gene, 88–92, 89–92, 90 Ashkenazi Jewish populations, 91 CA125 tumor marker testing, 92 chemoprevention, 91 familial history, 89 genetic testing, 90–1 gynecological cancers, 116, 117, 119 magnetic resonance imaging, 91 mammography, 91 ovarian epithelial carcinoma, 118 presymptomatic genetic testing, 91 prophylactic surgery, 91, 92, 92 prostate cancer, 92 tamoxifen, 91 BRCA2 gene, 92–6, 93 Ashkenazi Jewish populations, 94 CA125 tumor marker testing, 95 chemoprevention, 95 cholangiocarcinoma, 18 familial atypical mole melanoma syndrome, 124 familial pancreatitis association, 16 gall bladder cancer, 95 gastric cancer, 110 genetic testing, 94 gynecological cancers, 116, 117, 119 laryngeal tumors, 95 Li–Fraumeni syndrome, 100 mammography screening, 94 ovarian epithelial carcinoma, 118 pancreatic cancer, 95, 110 presymptomatic genetic testing, 94 prophylactic surgery, 94 prostate cancer, 95, 119 tamoxifen, 95
Index
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BRCA3 gene, 96–7 BRCA4 gene, 96–7 breast cancer, 87–100 BRCA3 gene, 96–7 BRCA4 gene, 96–7 Cowden disease, 96 familial history, 85 genetic testing, 85 Li–Fraumeni syndrome, 96 pedigree construction, 2–3 referral criteria, 86 risk factors, 85 screening, 8, 85 see also BRCA1 gene; BRCA2 gene C C1NH gene, 141 CA125 tumor marker testing BRCA1 gene, 92 BRCA2 gene, 95 E-cadherin, gastric cancer, 109 café-au-lait spots, neurofibromatosis type I, 30, 31 CARD15 gene, 20 cardiac defects, structural, 42–3 see also specific types cardiac myxoma, 41–2 Carney complex type I, 41–2 Carney complex type II, 41–2 carotid body tumors, 83–4 carriers, 150 caspase-recruitment domain-containing protein 13, 20 cataracts, 68–9 cationic trypsinogen, 16 CDKN1C gene, 24 CDKN2 gene familial atypical mole melanoma syndrome, 124 pancreatic cancer, 110 celiac disease, 23 centimorgan, 150 central core disease, 138–9 central nervous system tumors, 127–33 see also specific types centromeres, 150 cerebellar hemangioblastomas, von Hippel–Lindau syndrome, 81
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cervical cancer, 119 CFTR gene, 43 Charcot–Marie–Tooth (CMT) disease, 60–1 CHD1 gene, 109 CHEK2 gene, 100 chemoprevention BRCA1 gene carriers, 91 BRCA2 gene carriers, 95 chest X-rays, lung cancer, 48 children, genetic testing, 7 chloride ion channel disease, 139 cholangiocarcinoma, 18 cholecystitis, 17–18 chorionic villus sampling (CVS), 150 Christmas disease, 52 chromatid, 150 chromatin, 150 chromosome(s), 150 see also specific chromosomes chromosome 1 autosomal recessive colon cancer, 107 Charcot–Marie–Tooth, 61 cutaneous leiomyosarcoma syndrome, 115 familial atypical mole melanoma syndrome, 124 familial paraganglioma syndrome, 84 meningiomas, 129 prostate cancer, 119 chromosome 2 Carney complex type II, 41 hereditary non polyposis colon cancer, 101 Hodgkin’s lymphoma, 57 non-Hodgkin’s lymphoma, 56 chromosome 3 hereditary non polyposis colon cancer, 101 von Hippel–Lindau syndrome, 82 chromosome 4 facioscapulohumeral muscular dystrophy, 64 Huntington’s disease, 62 testicular cancer, 120 chromosome 5 celiac disease, 23 Crohn’s disease, 20 familial adenomatous polyposis, 103 chromosome 6
Index
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atrial septal defects, 43 familial atypical mole melanoma syndrome, 124 hemochromatosis, 51 chromosome 7 chloride channel disease, 139 cystic fibrosis, 43 familial pancreatitis, 16 pancreatic cancer, 110 papillary renal cancer, 113 William’s syndrome, 42 chromosome 8 prostate cancer, 119 ventricular septal defects, 43 chromosome 9 chronic myeloid leukemia, 54 Ehlers–Danlos syndrome, 45 familial atypical mole melanoma syndrome, 124 gliomas, 128 Gorlin’s syndrome, 122 Kartagener’s syndrome, 46 tuberose sclerosis, 28 chromosome 10 Cowden disease, 80 juvenile polyposis syndromes, 108 multiple endocrine neoplasia type II, 74 multiple endocrine neoplasia type IIB, 76 thyroid cancer, 78 ulcerative colitis, 21 chromosome 11 ataxia–telangiectasia, 97 Beckwith–Wiedemann syndrome, 24 celiac disease, 23 familial mitral valve prolapse, 42 familial paraganglioma syndrome, 84 familial pheochromocytoma, 86 inherited C1 esterase inhibitor deficiency, 141 multiple endocrine neoplasia type I, 73 pituitary tumors, 131 tuberose sclerosis, 28 chromosome 12 chronic lymphocytic leukemia, 55 multiple lipomatosis, 34 Noonan’s syndrome type I, 38 testicular cancer, 120
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ulcerative colitis, 21 chromosome 13 BRCA2 gene, 93 hiatus hernia, 19 retinoblastoma, 132 chromosome 14 α-1 antitrypsin deficiency, 47 cataracts, 68 chromosome 15 gliomas, 128 Marfan’s syndrome, 38 chromosome 16 acute myeloid leukemia, 53 Crohn’s disease, 20 familial mitral valve prolapse, 42 gastric cancer, 109 ulcerative colitis, 21 chromosome 17 Birt–Hogg–Dubé syndrome, 114 BRCA1 gene, 88–92 Carney complex type I, 41 Charcot–Marie–Tooth, 61 esophageal cancer, 112 Li–Fraumeni syndrome, 98 neurofibromatosis type I, 31 prostate cancer, 119 sebaceous cysts, 37 sodium ion channel disease, 140 chromosome 18 chronic lymphocytic leukemia, 55 juvenile polyposis syndromes, 108 chromosome 19 Duchenne muscular dystrophy, 138 malignant hyperthermia, 137 Peutz–Jeghers syndrome, 105 chromosome 20, prostate cancer, 119 chromosome 21, acute myeloid leukemia, 53 chromosome 22 chronic myeloid leukemia, 54 meningiomas, 129 neurofibromatosis type II, 33 primitive neuroectodermal tumors, 130 chronic lymphocytic leukemia (CLL), 55 chronic myeloid leukemia (CML), 54
Index
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Philadelphia chromosome, 54, 54 CLCN1 gene, 139 cleft lip/palate, 50 clones, 151 CMM1 gene, 124 CMM3 gene, 124 codons, 151 COL5A1 gene, 45 COL5A2 gene, 45 COL5A3 gene, 45 colon cancer, 100–12 autosomal recessive, 107–8 hereditary, 6 see also specific types colonoscopy familial adenomatous polyposis, 104 hereditary non polyposis colon cancer, 102 Peutz–Jeghers syndrome, 107 complementary DNA (cDNA), 151 complementation analysis, 151–2 compound heterozygotes, 152 computed tomography (CT) Huntington’s disease, 62 pheochromocytoma, 75 concordant consanguinity, 152 congenital airway problems, 49–50 congenital hip dislocation, 65–6 congenital polycythemia, von Hippel–Lindau syndrome, 83 consanguinity, concordant, 152 consent, pedigree construction, 3–4 contiguous gene syndrome, 152–3, 153 see also microdeletions; microduplications costs, genetic testing, 8–9 Cowden disease, 80 breast cancer, 96 endometrial cancer, 118 familial atypical mole melanoma syndrome vs, 124 gastric cancer, 110 thyroid cancer, 78 creatine phosphokinase, Duchenne muscular dystrophy, 60 Crohn’s disease, 20–1 crossing-over, 153, 189 cutaneous leiomyosarcoma syndrome, 115–16 papillary renal cancer association, 113
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cutis laxa, familial mitral valve prolapse vs, 42 CX32 gene, 61 cyclin-dependent kinase inhibitor 1C, 24 CYP1A1 gene, 48 cystic fibrosis, 43–4 familial pancreatitis vs, 16 genetic testing, 7 cystic hygroma, 35, 35–6 cysts, sebaceous, 36–7 cytogenetics, 153 cytosine, 153, 155 cytotrophoblasts, 153 D deletions, 154 dental defects, tuberose sclerosis, 27, 28 Dercum’s disease (adiposis dolorosa), 34 diagnostic testing, 6–9 digital rectal examination, 120 diploidy, 155 disomy, uniparental, 189 DMD gene, 59, 138 DNA, 155–6 complementary, 151 methylation, 157 replication, 157 dominant traits, 158 Down’s syndrome (trisomy 21), 40–1 acute myeloid leukemia, 53 DRD2 gene, 48 Duchenne muscular dystrophy, 59–60, 138–9 genetic testing, 7 duodenal atresia, 27 Dupuytren’s contracture, 65 dynamic mutations, 158, 159 dystrophin, Duchenne muscular dystrophy, 59 E E-cadherin, gastric cancer, 109 echocardiography, Noonan’s syndrome type I, 38 ectopia lentis, familial, Marfan’s syndrome vs, 38 Edwards syndrome (trisomy 18), 26 Ehlers–Danlos syndrome, 45 familial mitral valve prolapse vs, 42
Index
205
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Marfan’s syndrome vs, 38 elastin, William’s syndrome, 42 electrophoresis, 158 ELN gene, 42 endocrine cancers, 73–86 see also specific diseases/disorders endometrial cancer, 118 endonucleases, 159 ependymomas see gliomas epidermolysis bullosa, 127 esophageal cancer, 112–13 hiatus hernia link, 19 euchromatin, 159 euploidy, 159 exomphalos/omphalocele, 24 exons, 160 expression, 6 expressivity, variable, 160, 190 F facial angiofibromas, 27, 28, 29 factor VIII deficiency, 52 factor IX deficiency, 52 familial adenomatous polyposis (FAP), 103–5, 104 colonoscopy, 104 familial atypical mole melanoma syndrome (FAMM), 124–5 familial diseases see inherited conditions familial ectopia lentis, Marfan’s syndrome vs, 38 familial glomus tumor, 83–4 familial history BRCA1 gene, 89 breast cancer, 85 familial medullary thyroid cancer (FMTC), 75 familial mitral valve prolapse see mitral valve prolapse, familial familial pancreatitis, 16 familial paraganglioma syndrome, 83–4 familial pheochromocytoma see pheochromocytomas familial polyposis coli see polyposis coli, familial family histories, 2–4 see also pedigree construction family members, genetic testing, 12 Fanconi anemia, acute myeloid leukemia vs, 53 facioscapulohumeral muscular dystrophy (FSHD), 64 FBN1 gene, 38
206
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FH gene, 115 fibrillin 1, Marfan’s syndrome, 38 fistulae, tracheoesophageal, 49–50 Flegel disease, 125 fluorescence in situ hybridization (FISH), 166, 167 FMR1 gene, 63 founder effect, 160 fragile X syndrome, 63, 159 frame-shift mutation, 160, 161 Friedreich’s ataxia, 159 G gall bladder cancer, BRCA2 gene, 95 Gardner syndrome see familial adenomatous polyposis (FAP) gastric cancer, 109–10 gastroschisis, 24 GATA1 gene, 53 GATA4 gene, 43 gel electrophoresis, 158 genes, 161 homologous, 165 genetic code, 161–2, 162 genetic counseling, 4–5, 162 examples, 11–12 genetic heterogeneity, 162–3 genetic maps, 163 genetic markers, 163 genetic screening/testing, 6–9, 163 ataxia–telangiectasia, 98 BRCA1 gene, 90–1 BRCA2 gene, 94 breast cancer, 85 in children, 7 costs, 8–9 cystic fibrosis, 7, 44 Duchenne muscular dystrophy, 7 examples, 10–11 family members, 12 high-throughput screening, 9 Li–Fraumeni syndrome, 99 limitations, 8 multiple endocrine neoplasia type IIB, 77 neural tube defects, 67 practical approaches, 9–12
Index
207
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presymptomatic, 6–9 BRCA1 gene, 91 BRCA2 gene, 94 tuberose sclerosis, 28 genomes, 163 genotype, 163 germline mutations, 3 germ lines, 163–4 glioblastomas see gliomas gliomas, 127–9 Gorlin’s syndrome, 127 Li–Fraumeni syndrome, 127 neurofibromatosis type I, 127 non polyposis colon cancer, 100–3 tuberose sclerosis vs, 127 glomus tumor, familial, 83–4 GNAS1 gene, 131 Gorlin’s syndrome, 122–3 gliomas, 127 meningiomas vs, 129 ovarian fibroma, 118 primitive neuroectodermal tumors vs, 130 guanine, 155, 164 gynecological cancers, 116–19 prophylactic surgery, 118 H hamartin, tuberose sclerosis, 28 hamartomas, retinal, 28 haploidy, 164 haploinsufficiency, 164 Helicobacter pylori infections, gastric cancer, 110 hemizygosity, 164 hemochromatosis, 51 hemophilia, 52 hereditary angioneurotic edema, 141 hereditary colon cancer, 6 hereditary motor neuropathy, 60–1 hereditary non polyposis colon cancer (HNPCC), 102 Amsterdam criteria, 102 colonoscopy, 102 endometrial cancer, 118 extracolonic features, 100 gastric cancer, 110
208
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lifestyle issues, 103 Muir–Torre variant, 100 ovarian epithelial carcinoma, 118 hereditary sensory neuropathy, 60–1 heterochromatin, 164 heterodisomy, uniparental, 189 heterogeneity, allelic, 146 heterozygosity, 164 compound, 152 synergistic, 185 HFE gene, 51 hiatus hernia, 19–20 high-throughput screening, 9 hip dislocation, congenital, 65–6 histones, 164–5 HLA (human leukocyte antigen), celiac disease, 23 hMRE11 gene, 98 Hodgkin’s lymphoma, 57 Holt–Oram syndrome, 43 homologous genes, 165 homologous recombination, 190 HPC1 gene, 119 HPC2 gene, 119 HPC20 gene, 119 HPCX gene, 119 hSNF5 gene, 130 Human Genome Project, 165 human leukocyte antigen (HLA), celiac disease, 23 Huntington’s disease, 61–2, 159 insurance, 5 hybridization, 156, 165 hydrocephalus, 68 hyperkalemic periodic paralysis (HPP), 140 hyperkeratosis lenticularis perstans, 125 hyperthermia, malignant, 137–8 hypoglycemia, Beckwith–Wiedemann syndrome, 24 hyposplenia, 25–6 I IBD1 gene Crohn’s disease, 22 ulcerative colitis, 21 IBD2 gene, 21 IBD3 gene, 21
Index
209
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immotile cilia syndrome, 46–7 imprinting, 166 incomplete penetrance, 166 index cases, 166 ING gene, 127 inheritance multifactorial, 176 triallelic, 188 inherited C1 esterase inhibitor deficiency, 141 inherited conditions cardiac system, 37–43 family member implications, 3–4 gastrointestinal tract, 15–27 hematologic system, 50–8 insurance, 5 investigations, 2–4 neurologic system, 59–69 respiratory system, 43–50 skin, 27–37 see also specific conditions insertion, 166 insurance, 5 intestinal atresia, 26–7 introns, 167 inversions, 167 isodisomy, uniparental, 189 Ivemark triad, 25 J jaundice, pancreatic cancer, 111 juvenile polyposis syndromes (JPS), 108 K Kartagener’s syndrome, 46–7 karyotypes, 168, 169 Knudson hypothesis, 188–9 L L1CAM gene, 68 LAMB (Lentigenes, Atrial myxoma, Myxoid tumors, Blue nevi) syndrome, 41–2 Landouzy–Dejerine muscular dystrophy, 64 laryngeal atresia, 49 fetal ascites, 50
210
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laryngeal tumors, BRCA2 gene, 95 late-onset diseases, genetic counseling, 4–5 learning difficulties, neurofibromatosis type I, 30 leiomyosarcomas, cutaneous see cutaneous leiomyosarcoma syndrome Lentigenes, Atrial myxoma, Myxoid tumors, Blue nevi (LAMB) syndrome, 41–2 Lhermitte Duclos disease, 81 lifestyle issues, hereditary non polyposis colon cancer, 103 Li–Fraumeni syndrome, 98–100 bone sarcoma, 98, 99 BRCA2 gene, 100 breast cancer, 96 familial atypical mole melanoma syndrome vs, 124 gastric cancer, 110 genetic testing, 99 gliomas, 127 lung cancer, 47 pancreatic cancer, 110 primitive neuroectodermal tumors vs, 130 linkage, 168 linkage analysis, 168–70, 170 linkage disequilibrium, 170, 171 linkage maps, 171 lipomatosis, multiple, 34 Lisch nodules, neurofibromatosis type I, 30, 31 LKB1 gene, 105 locus, 171 logarithm of the odds (LOD) score, 172 Louis–Bar syndrome see ataxia–telangiectasia lung cancer, 47–9 chest X-rays, 48 Li–Fraumeni syndrome, 47 Lynch syndromes see hereditary non polyposis colon cancer (HNPCC) lyonization, 172 M macrocephaly, neurofibromatosis type I, 30 macrophage scavenger receptor, prostate cancer, 119 MAD-related protein, juvenile polyposis syndromes, 108 Maffucci syndrome, ovarian granulosa cell tumors, 118 magnetic resonance imaging (MRI) BRCA1 gene carriers, 91 neurofibromatosis type II, 33 malignant hyperthermia, 137–8
Index
211
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mammography BRCA1 gene, 91 BRCA2 gene, 94 Peutz–Jeghers syndrome, 107 Marfan’s syndrome, 37, 37–8 familial mitral valve prolapse vs, 38, 42 pectus carinatum vs, 46 pectus excavatum vs, 46 pneumothorax vs, 44–5 McCune–Albright syndrome, 131–2 MCUL1 gene, 115 Meckel’s diverticulum, 27 medullary thyroid cancer multiple endocrine neoplasia type II, 74, 75 multiple endocrine neoplasia type IIB, 76, 77 meiosis, 172 melanoma, 124–5, 125 MEN1 gene multiple endocrine neoplasia type I, 73 pituitary tumors, 131 Mendelian inheritance, 172 meningiomas, 129–30 menin, pituitary tumors, 131 messenger RNA (mRNA), 173 MET gene, 113 methylation, DNA, 157 microdeletions, 173 see also contiguous gene syndrome microduplications, 174 see also contiguous gene syndrome microsatellites, 174 missense mutations, 174 mitochondrial defects, 174 cataracts, 68 inheritance, 175 mitosis, 175 mitral valve defects, 42 mitral valve prolapse, familial, 42 Marfan’s syndrome vs, 38, 42 MLH1 gene endometrial cancer, 118 expression, 6 gliomas, 127 gynecological cancers, 116
212
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hereditary non polyposis colon cancer, 101 penetrance, 6 MLH3 gene gliomas, 127 hereditary non polyposis colon cancer, 101 monosomy, 175 monozygosity, 175 mosaicism, 175–6 motor neuropathy, hereditary, 60–1 mRNA, 173 MSH2 gene endometrial cancer, 118 gliomas, 127 gynecological cancers, 116 hereditary non polyposis colon cancer, 101 MSH3 gene gliomas, 127 hereditary non polyposis colon cancer, 101 MSH6 gene endometrial cancer, 118 gliomas, 127 gynecological cancers, 116 hereditary non polyposis colon cancer, 101 MSR1 gene, 119 MTHFR gene, 67 Muir–Torre variant, hereditary non polyposis colon cancer, 100 multifactorial inheritance, 176 multiple endocrine neoplasia type I (MEN1), 73–4 multiple endocrine neoplasia type II (MEN2), 74–6 medullary thyroid cancer, 74, 75 parathyroid hyperplasia, 74, 75 pentagastrin testing, 74 pheochromocytoma, 74, 75 stimulated calcitonin testing, 74 thyroid cancer, 78 multiple endocrine neoplasia type IIA (MEN2A), 136 multiple endocrine neoplasia type IIB (MEN2B), 76–7 familial pheochromocytoma, 86, 136 Marfan’s syndrome vs, 38 medullary thyroid cancer, 76, 77 multiple lipomatosis, 34 multiple myeloma, 58 muscle diseases, 138–9 see also specific diseases/disorders
Index
213
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mutations, 176 dynamic, 158, 159 frame-shift, 160, 161 germline, 3 missense, 174 nondynamic, 176 nonsense, 176, 176, 177, 177 nonstable, 158, 159 silent, 184 stable, 176 myeloma, 58 MYH gene, 107 myotonia congenita, 139 myotonic dystrophy, 159 N NAME (Nevi, Atrial myxoma, Myxoid neurofibromata, Ephelides) syndrome, 41–2 neural tube defects, 66–8 neurofibromatosis type I (NF1), 30–2 acute myeloid leukemia association, 53 familial pheochromocytoma, 86, 136 gliomas, 127 macrocephaly, 30 meningiomas vs, 129 neurofibromatosis type II vs, 32 neurofibromatosis type II (NF2), 33 gliomas, 127 meningiomas vs, 129 neurofibromatosis type I vs, 32 neurofibromin 1, 31 Nevi, Atrial myxoma, Myxoid neurofibromata, Ephelides (NAME) syndrome, 41–2 NF1 gene familial pheochromocytomas, 136 gliomas, 127 neurofibromatosis type I, 31 NF2 gene gliomas, 127 neurofibromatosis type II, 33 nitric oxide synthase 1, pyloric stenosis, 19 NKX2-5 gene, 43 NOD2 gene, 20 nondisjunction, 176
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nondynamic mutations, 176 non-Hodgkin’s lymphoma (NHL), 56, 56–7 non penetrance, 176 nonsense mutations, 176, 177 nonstable mutations, 158, 159 Noonan’s syndrome type I, 38 acute myeloid leukemia, 53 aortic valve stenosis, 42 pulmonary valve stenosis, 42 Northern blotting, 176 NOS1 gene, 19 nucleotide-binding oligomerization domain 2, 20 nucleotides, 176 O OCTN gene, 20 oculocutaneous albinism, 123, 125 oligodendromas see gliomas Ollier disease, 118 omphalocele, 24 oncogenes, 177 organic cation transporter, 20 osteogenesis imperfecta, familial mitral valve prolapse vs, 42 ovarian cancer, 116–19 genetic disorder association, 118 ovarian epithelial carcinoma, 118 ovarian fibroma, Gorlin’s syndrome, 118 ovarian granulosa cell tumors, 118 P P2PRX7 gene, 55 palindromic sequences, 178 pancreatic cancer, 110–12 BRCA2 gene, 95, 110 jaundice, 111 Li–Fraumeni syndrome, 110 prophylactic surgery, 112 pancreatitis, familial, 16 papillary renal cancer, 113–14 tuberose sclerosis vs, 113, 114 paraganglioma syndrome, familial, 83–4 paramyotonia congenita, 140 parathyroid hyperplasia, 74, 75 patent ductus arteriosus, 43
Index
215
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PCAP gene, 119 pectus carinatum, 46 pectus excavatum, 46 pedigree (family tree) construction, 2–4, 178 breast cancer, 2–3 consent, 3–4 examples, 10–11, 11 germline mutations, 3 symbols, 179 penetrance, 178 hemochromatosis, 51 hereditary colon cancer, 6 incomplete, 166 Marfan’s syndrome, 38 non, 176 pentagastrin testing, 74 peroneal muscular atrophy, 60–1 Peutz–Jeghers syndrome, 105–7 bile duct cancers, 18 colonoscopy, 107 gastric cancer, 110 mammography, 107 ovarian granulosa cell tumors, 118 skin pigmentation, 105, 106 testicular examination, 107 Peyronie’s disease, 65 phenotypes, 178 pheochromocytomas, 86, 136–7 computed tomography, 75 multiple endocrine neoplasia type II, 74, 75 Philadelphia chromosome, 54, 54 physical maps, 178 pituitary tumors, 131–2 plasmids, 178 pleiotropy, 178 plexiform neuromas, neurofibromatosis type I, 32, 32 ploidy, 178 PMP22 gene, 61 PMS1 gene gliomas, 127 hereditary non polyposis colon cancer, 101 pneumothorax, 44–5 PO gene, 61 polyacrylamide gel electrophoresis, 158
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polycythemia, congenital, 83 polydactyly, cleft lip/palate, 50, 50 polygenic diseases, 179 see also specific diseases/disorders polymerase chain reaction (PCR), 147, 156, 179, 181 polymorphisms, 180 polyposis coli, familial gastric cancer, 110 primitive neuroectodermal tumors vs, 130 polysplenia syndrome, 25–6 premutations, 180 prenatal diagnosis, Duchenne muscular dystrophy, 60 presymptomatic genetic testing see genetic screening/testing primary ciliary dyskinesia, 46–7 primitive neuroectodermal tumors (PNETs), 130–1 PRKAR1A gene, 41 probands, 180 probes, 180 promoter regions, 180 prophylactic surgery BRCA1 gene, 91, 92, 92 BRCA2 gene, 94 pancreatic cancer, 112 prostate cancer, 119–20 BRCA1 gene carriers, 92 BRCA2 gene, 95, 119 digital rectal examination, 120 prostate-specific antigen, 119 prostate-specific antigen (PSA), 119 proteases, 180 inhibitors, 180 protein-tyrosine phosphatase non receptor type 11 acute myeloid leukemia, 53 Noonan’s syndrome type I, 38 proto-oncogenes, 180 PRSS1 gene familial pancreatitis, 16 pancreatic cancer, 110 pseudogenes, 180 pseudoxanthoma elasticum, familial mitral valve prolapse vs, 42 PTCH gene gliomas, 128 Gorlin’s syndrome, 122 PTEN gene
Index
217
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Cowden disease, 80 epidermolysis bullosa, 127 PTPN11 gene acute myeloid leukemia, 53 Noonan’s syndrome type I, 38 pulmonary valve defects, 42 pulsed field gel electrophoresis, 158 purine, 181 pyloric stenosis, 18–19 pyrimidines, 181 R RB1 gene, 132 recessive traits, 181 reciprocal translocation, 182 recombination, 154, 182 homologous, 190 recurrence risk, 182 celiac disease, 23 cystic hygroma, 36 Down’s syndrome (trisomy 21), 41 patent ductus arteriosus, 43 pyloric stenosis, 19 spleen disorders, 26 renal angiomyolipomas, 28 renal cancer, papillary, 113–14 renal cell carcinomas (RCCs) tuberose sclerosis, 28 von Hippel–Lindau syndrome, 81, 82 replication, DNA, 157 restriction enzymes, 182 restriction fragment length polymorphisms (RFLPs), 170, 182 restriction maps, 182 RET gene multiple endocrine neoplasia type II, 74 multiple endocrine neoplasia type IIB, 76 thyroid cancer, 78 retinal angiomas, 81 retinal examination, retinoblastoma, 133 retinal hamartomas, 28 retinoblastoma, 132–3 reverse genetics, 182 reverse transcriptase, 151, 183 RFLPs (restriction fragment length polymorphisms), 170, 182
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Rhombo syndrome, 123 Riley–Smith syndrome, 81 risk assessment, genetic counseling, 4 RNA (ribonucleic acid), 183 messenger RNA, 173 transfer RNA, 186 Robertsonian translocation, 183 Rothmund–Thomson syndrome, 125 runt-related transcription factor, 53 RUNX1 gene, 53 Ruvalcaba syndrome, 81 RYD1 gene, 138 RYR1 gene, 137 S SCC (squamous cell carcinoma), 125–7, 126 Shwachman–Diamond syndrome, familial pancreatitis vs, 16 SCN4A gene, 140 SDHB gene, 86 SDHC gene, 84 SDHD gene familial paraganglioma syndrome, 84 familial pheochromocytoma, 86, 136 sebaceous cysts, 36–7 segmental aneusomy syndrome (SAS), 183 seminomas, 121, 121 sensory neuropathy, hereditary, 60–1 serine protease inhibitors, familial pancreatitis, 16 serine/threonine protein kinase 11, 105 sex chromosomes, 183 sex-linked trait, 183–4 sibship, 184 silent mutations, 184 single gene disorders, 184 site-specific familial basal cell carcinoma, 123 skin cancer, 121–7 see also specific types skin pigmentation, Peutz–Jeghers syndrome, 105, 106 SMAD4 gene, 108 SMA-related protein, 108 sodium ion channel disease, 140 somatic cells, 184 Southern blotting, 156, 184, 185 spina bifida, 66–8
Index
219
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SPINK1 gene, 16 spinocerebellar ataxia, 159 spleen disorders, 25–6 spleen heterotaxy syndrome, 25–6 spleen laterality disorders, 25–6 splicing, 184 squamous cell carcinoma (SCC), 125–7, 126 stable mutations, 176 start codon, 184 stimulated calcitonin testing, 74 STK11 gene gynecological cancers, 116 Peutz–Jeghers syndrome, 105 stop codon, 184 succinate dehydrogenase complex subunit D familial paraganglioma syndrome, 84 familial pheochromocytoma, 86, 136 SUFU gene, 130 synergistic heterozygosity, 185 T tamoxifen BRCA1 gene, 91 BRCA2 gene, 95 telomeres, 185 teratogens, 185 testicular cancer, 120–1 testicular examination, Peutz–Jeghers syndrome, 107 testicular teratomas, 121, 121 Thomsen’s disease, 139 thymine, 155, 186 thyroid cancer, 78–80, 79 Cowden disease, 78 multiple endocrine neoplasia type II, 78 TNFRSF10B gene, 127 TOC gene, esophageal cancer, 112 TP53 gene breast cancer, 96 gliomas, 128 Li–Fraumeni syndrome, 98 pancreatic cancer, 110 tracheal agenesis, 49–50 tracheoesophageal fistulae, 49–50 traits
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dominant, 158 recessive, 181 sex-linked, 183–4 X-linked dominant, 191, 192 X-linked recessive, 191, 192 transcription, 186, 186 transferrin testing, 51 transfer RNA (tRNA), 186 translation, 186–7, 187 translocation, 187 reciprocal, 182 Robertsonian, 183 X-autosome, 191 triallelic inheritance, 188 tricuspid valve defects, 42 triplet repeats, 188 trisomy, 188 trisomy 18 (Edwards syndrome), 26 trisomy 21 see Down’s syndrome (trisomy 21) trypsinogen, cationic, 16 TSC1 gene, 28 TSC2 gene, 28 tuberin, tuberose sclerosis, 28 tuberose sclerosis, 27–30 dental defects, 27, 28 facial angiofibromas, 27, 28, 29 gliomas, 127 meningiomas vs, 129 papillary renal cancer vs, 113, 114 renal angiomyolipomas, 28 renal cell carcinomas, 28 retinal hamartomas, 28 tumors, 73–133 see also specific types tumor suppressor genes, 188–9 Turcot syndrome see familial adenomatous polyposis (FAP) Turner syndrome, cystic hygroma, 35 tylosis, 112–13 U ulcerative colitis, 21–2, 22 ultrasound, Down’s syndrome, 41 uniparental disomy (UPD), 189 uniparental heterodisomy, 189
Index
221
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uniparental isodisomy, 189 UPD (uniparental disomy), 189 uracil, 189 urogenital cancer, 113–21 see also specific types V van der Woude syndrome, 50 variable expressivity, 160, 190 variable number of tandem repeats (VNTR), 190 VATER (Vertebral defects, Anal atresia, TracheoEsophageal fistula and Renal dysplasia) syndrome, 27 intestinal atresia, 26 tracheoesophageal fistulae, 49–50 ventricular septal defects, 43 Vertebral defects, Anal atresia, TracheoEsophageal fistula and Renal dysplasia (VATER) syndrome see VATER (Vertebral defects, Anal atresia, TracheoEsophageal fistula and Renal dysplasia) syndrome VHL gene pheochromocytomas, 136 von Hippel–Lindau syndrome, 82 VNTR (variable number of tandem repeats), 190 von Hippel–Lindau syndrome, 81–3 cerebellar hemangioblastoma, 81 congenital polycythemia, 83 familial pheochromocytoma, 86, 136 renal cell carcinomas, 81, 82 retinal angioma, 81 vulval cancer, 119 W Wagenmann–Froboese syndrome see multiple endocrine neoplasia type IIB (MEN2B) Western blotting, 190 William’s syndrome, 153 aortic valve stenosis, 42 Woods lamp examination papillary renal cancer, 114 tuberose sclerosis, 28 X X-autosome translocation, 191 X chromosome, 183 central core disease, 138
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Charcot–Marie–Tooth, 61 cystic hygroma, 35 Duchenne muscular dystrophy, 59, 138 familial mitral valve prolapse, 42 fragile X syndrome, 63 hemophilia, 52 hydrocephalus, 68 prostate cancer, 119 spleen heterotaxy syndrome, 25 xeroderma pigmentosum, 123, 125 X-linked dominant (XLD) traits, 191, 192 X-linked recessive (XLR) traits, 191, 192 Y Y chromosomes, 183 Z Zollinger–Ellison syndrome, 73
Index
223
