25th Medical Genetics: Introduction to Dysmorphology

Author: D. Donnai
Submitted: Friday 6th of July 2012 09:01:20 AM
Submitted by: egf
Language: English
Content type: Learning resource
Educational levels: expert, qc2, qc3

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Abstract

What is dysmorphology? David Smith from the USA first used the term “dysmorphology” in the 1960’s to describe the study of human congenital malformations and patterns of birth defects. The subject is broad, and to be a dysmorphologist one needs to be knowledgeable in many areas, from embryology, through a wide range of clinical disciplines to genetic counselling. Currently, the term “dysmorphology” is most commonly used to refer to a specialty within Medical Genetics dealing with people who have congenital malformations. As well as the benefits for families the study of malformations can also help to identify mechanisms underlying normal development. Why study dysmorphology? Dysmorphologists are regarded by some as mere “collectors” of rare syndromes. In fact there are several good reasons for pursuing the study of dysmorphology that directly benefit patients. A syndrome diagnosis can be helpful for the individuals and families concerned because it can help to answer their questions and in some cases the individual concerned will be spared further, possibly invasive investigations to determine the cause of their problems. The parents of a baby with birth defects usually have many questions: • What is the problem? • Why did it happen? • What will it mean for our baby? • Will it happen again? A dysmorphologist will be able to answer many of these questions for the family. There is no doubt, however, that some families find it difficult at first to have a “syndrome label” attached to their child, and perceive some disadvantages of having such a diagnosis. A dysmorphologist needs to be sensitive to these concerns when dealing with the family. Benefits of Syndrome Diagnosis • Provision of accurate information about the condition, and its natural history and its prognosis, for parents and for professionals involved in the care of the baby. • Often influences the management of the baby e.g. it may direct further investigations or screening for complications • Facilitates accurate genetic counselling, especially as regards prognosis, recurrence risk and possibilities for prenatal diagnosis. • Easier for families to access support from other sources e.g. lay support groups, social services (benefits), education system. • Aids research into normal and abnormal morphogenesis. How do you make a syndrome diagnosis? The steps followed are essentially the same as for other clinical situations i.e. • History • Examination • Investigations • Synthesis (Putting it all together) A different emphasis is placed on the above, however, compared to other clinical situations. The History concentrates particularly on: • Family history. This is usually taken in the form of a pedigree, noting such details as consanguinity or a possible Mendelian pattern of inheritance. It is usual to get details of other affected family members and where they were treated. It may be necessary to approach them to ask for consent to access their medical records. • Past obstetric history. Multiple early miscarriages may suggest a chromosome abnormality, for example • Maternal health. Some maternal diseases e.g. diabetes or SLE may confer a higher risk of fetal abnormality. Mothers with epilepsy also have a 2-3 times increased risk of fetal abnormality. • Maternal vitamin supplements and drug use. Check if any of these are likely to be teratogenic • Pregnancy history. It would be relevant to know, for examples whether abnormalities were detected on scan, whether any invasive procedures were carried out and whether there was any problem with liquor volume. During the Examination of a dysmorphic child the following should be taken into account: • Posture and tone. Some diagnoses can be suggested by observing a child prior to examination. The characteristic flexed posture of the fingers in Trisomy 18, for example, or a very hypotonic posture in Prader-Willi syndrome. • Movements and behaviour patterns are very characteristic in some syndromes. A girl with Rett syndrome will have repetitive hand movements and individuals with Smith Magenis syndrome may hug themselves. • Facial expressions may be typical in some syndromes. An individual with myotonic dystrophy has a mask-like face with poor facial movement. The happy, smiling face of Angelman syndrome is unmistakable. • Characteristic personality can be observed in some syndromes such as Williams syndrome where there is a friendly and talkative manner. Physical examination should include documentation of: • Height and weight, which should be plotted on an appropriate growth chart. Parental height should be taken into consideration. • Proportions, which can be altered in certain conditions e.g. achondroplasia or Marfan’s syndrome • Measurements of head circumference, facial features and other body parts where appropriate. These can be plotted onto charts for normal ranges and for specific conditions (Greenwood Genetic Centre) • Major and minor abnormalities. Document carefully all abnormalities. Where minor anomalies are concerned, be aware of what is abnormal and what is just part of normal variation e.g. with minor 2/3 toe syndactyly. • Photography. It is often useful to document major and minor anomalies by taking photographs if the patient/parents permit. One has to be sensitive about removing clothes for photographs, especially in older children, as this is not always necessary. It is useful to remove as much “clutter” as possible from the background and avoid patterned backgrounds. Sequential photos of children at different ages are especially helpful in studying the evolution of phenotypes • Parents. Some of the distinctive features may just be family characteristics. Taking a look at the rest of the family in person or from a family photograph is helpful. Terminology used in dysmorphology Malformation: A morphologic abnormality that arises because of an abnormal developmental process. (A primary error in morphogenesis e.g. cleft lip). Malformation sequence: a pattern of multiple defects resulting from a single primary malformation e.g. talipes and hydrocephalus can result from a lumbar neural tube defect. Malformation syndrome: a pattern of features, often with a unifying underlying cause, that arises from several different errors in morphogenesis. (“syndrome” from the Greek “running together”) Deformation. Distortion by a physical force of an otherwise normal structure Disruption. Destruction of a tissue which was previously normal Dysplasia. Abnormal cellular organisation within a tissue resulting in structural changes e.g. within cartilage and bone in skeletal dysplasias Association. The occurrence of two or more features which are seen together more frequently than would be expected by chance alone but are not known to have a common cause. Investigations The dysmorphologist can be aided by many different types of investigation including: • Cytogenetics. Routine karyotype is still offered as the first-line test in most centres and where a specific microdeletion syndrome is suspected the appropriate FISH test is done. Mosaic chromosome disorders may not be detectable on lymphocyte chromosome analysis and skin chromosome tests may be needed. Chromosome breakage studies may be indicated in some patients, particularly in those who are small, have microcephaly and other features such as radial aplasia and café au lait patches. However there is now increasing use of newer techniques such as array CGH, often as a first-line test, with phasing out of traditional karyotyping. Interpretation of such tests is complex and may require parental samples and consultation of databases of CNV variants to elucidate whether a finding is clinically significant. • Single gene molecular genetic tests are now available for many different conditions and the range of tests is widening rapidly as more genes are associated with the many hundreds of single gene syndromes. There are databases which can be used to identify laboratories offering testing for specific disorders. Unfortunately testing may not be available on a service basis at the present time for many rare conditions. • Whole exome sequencing offers the promise of an almost ‘comprehensive’ genetic test where all coding exons of all genes are screened but it will be a few years before this is widely available in a diagnostic setting. Some laboratories are developing focused diagnostic panels enriched for exons associated with various groups of conditions such as retinal dystrophies, Noonan-like disorders etc. • Metabolic testing. E.g. amino acids, organic acids, peroxisomal disorders, disorders of cholesterol metabolism. There may be diagnostic pointers to metabolic disease such as hepatosplenomegaly or seizures occurring soon after birth. • Infection screen is helpful where congenital infection is suspected from the history or from clinical signs. • Imaging. X-rays are of paramount importance in the diagnosis of skeletal dysplasias. They must be of good quality and you must make sure to request the necessary X-rays as some departments do only limited skeletal surveys. Radiographs of the hands and feet can be particularly useful. CT scans are useful to look for intracranial calcification; otherwise MRI scans provide more information and do not expose patients to radiation. • Pathology/Autopsy. Pathology investigations are useful in the diagnosis of syndromes with specific pathological features and for defining the full extent of abnormalities. With fetal pathology it is important to take into account the gestation of the fetus, the timing of death and the possibility of traumatic abnormalities sustained during delivery. • Other miscellaneous investigations may be needed e.g. Hb electrophoresis in ATR-X, white cell count in Cohen syndrome etc. Expert opinions Although dysmorphic conditions can involve all body systems it is impossible for a dysmorphologist to be an expert in all areas, and it is often necessary to refer for a specialist opinion. A detailed ophthalmological or dermatological examination is often needed, for instance and skeletal dysplasias are notoriously difficult to diagnose unless you are a specialist in this area. How do you put all this information together to make a syndrome diagnosis? (Synthesis) 1. Ask some basic questions: • Are you dealing with a single malformation or multiple malformations? • Is the child likely to have a multiple anomaly syndrome? • Are there deformations that might tie in with the pregnancy history? • Does the family history help? 2. Think about the various mechanisms by which birth defects come about: • Chromosomal abnormalities • Single gene defects (consider different types of genes e.g. genes encoding structural proteins, transcription factors etc) Also consider disturbances in gene expression e.g. imprinted genes. Many syndromes are now known to be due to mutations in genes involved in chromatin configuration. • Effects of multiple gene mutations/polymorphisms e.g. as in Hirschsprung Disease • Multifactorial disorder (a combination of genetic predisposition and environmental factors e.g. NTD) • Mainly environmental e.g. mechanical compression and teratogens (although in the latter genetic predisposition may play a part) • Mosaicism – chromosomal, single gene mutation or in gene expression 3. When chromosomal syndromes have been ruled out and a single gene cause is strongly suspected • Consider possible syndrome diagnoses in broad categories or ‘syndrome families’ including; o Skeletal dysplasias o Overgrowth syndromes o Low birth weight and proportionate dwarfism syndromes o Prader Willi-like and obesity syndromes o Angelman/Rett-like syndromes o Noonan-like syndromes o Neurocutaneous and Vascular syndromes o Ectodermal dysplasias and other skin disorders o Distinct MCA/MR syndromes with a ‘gestalt’ o Etc.etc 4. Think whether you have seen this before. Personal experience is helpful and people get better and more experienced at dysmorphology over time. You may be able to recognise a “gestalt” which is familiar to you from a previous presentation or from literature you have read. 5. Seek help from the literature There are numerous textbooks and journals that can be of help to the dysmorphologist. Gorlin’s “Syndromes of the Head and Neck” is particularly useful and is not confined to the head and neck, covering chromosomal and other disorders too. 6. Search the Dysmorphology Databases There are several available including the London Dysmorphology Database and POSSUM. Other databases such as REAMS and OSSUM specialize in skeletal dysplasias. You get most help from databases if you search on features which are very distinctive (“hard” diagnostic handles) and if you know something about dysmorphology already so as to be able to sift out which syndromes are least likely matches with your patient. 7. Seek help from colleagues. Share information and photographs/images with other colleagues within your department and specialists in the field. It’s hard to be a good dysmorphologist in isolation. Present distinctive cases at dysmorphology meetings. The ability to send images by e-mail (if you have parent’s permission) makes getting this type of help even easier. Increasingly ‘Networks of Experts’ are being established to assist diagnosis of rare distinct conditions. These include ESDN (European Skeletal Dysplasia Network) (www.esdn.org) and DYSCERNE (www.dyscerne.org) a new European initiative for dysmorphic syndromes which will have at least one ‘node’ in each EU country. Following the Diagnosis • Clinical diagnosis should be confirmed with a diagnostic test if available • Even experienced doctors should consult with colleagues to see if they agree with the diagnosis • Further consultation with parents to explain child’s problems and full discussion of the implications • Arrange appropriate screening investigations if the condition is associated with complications. • Make sure parents have support e.g. from local services/family doctor/parent support group/follow-up by genetic associate. What if the diagnosis remains unknown? A child should not be labelled as having a particular dysmorphic syndrome unless the clinician is absolutely sure about this. It is far more difficult to remove an incorrect diagnosis than to attach one in the first place. Where a syndromic diagnosis is still likely but not apparent at the first consultation it is important for the child to be followed up and re-evaluated at a later stage. A few years later new syndromes may have been delineated or more investigations might be available. Where patients have very distinctive features, either representing a ‘new’ syndrome or showing unusual features of one already described, it is sometimes useful to document the findings in the form of a case report for the literature. Someone else may have seen a similar child before, or may come across the report when searching the literature for one of their own patients. This type of case report serves a useful purpose in the delineating new syndromes. References and useful textbooks Smith’s Recognisable Patterns of Human Malformations. 5th edition. Saunders, Editor KL Jones Gorlin's Syndromes of the Head and Neck 5th Edition (2010) Raoul C.M. Hennekam, Ian D. Krantz and Judith Allanson. Oxford University Press Human Malformations and Related Anomalies. Eds Stephenson, Hall, Goodman, Oxford University Press (2nd edition published 2005) Management of Genetic Syndromes. (3rd edition 2010) Eds SB Cassidy, JE Allanson Databases LDDB, London Dysmorphology Database (www.lmdatabases.com) POSSSUM (Pictures of Standard Syndromes and Undiagnosed Malformations) Melbourne: The Murdoch Research Institute, 2001(www.possum.net.au)

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D. Donnai. 25th Medical Genetics: Introduction to Dysmorphology. EUROGENE portal. July 2012. online: http://eurogene.open.ac.uk/content/25th-medical-genetics-introduction-dysmorphology

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