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Dysmorphism: Syndromes

Hilde Van Esch, Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium Jean-Pierre Fryns, Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium
Dysmorphology is the study of human congenital malformations and combines concepts and knowledge of different medical fields, including embryology, paediatrics and clinical genetics.

Introductory article
Article Contents
. How is Dysmorphism Defined? . Clinical Diagnostic Approach of a Dysmorphic Child . Molecular and Cytogenetic Basis of Dysmorphic Syndromes . Future Perspectives

doi: 10.1038/npg.els.0001880

How is Dysmorphism Defined?

The eld of dysmorphology has expanded dramatically over the last 25 years. New insights have been gained in the pathogenesis of various structural defects, leading to better diagnosis and the possibility for prenatal detection. Given the vast number, a listing of all known recognizable patterns of malformation goes beyond the scope of this review. Rather, this article provides an approach to the child that presents with a congenital malformation. Congenital defects can be divided into single defects in development and multiple malformation defects or syndromes. Single primary defects in development can be further subdivided, according to the underlying morphogenic error that has resulted in the observed defect, into malformations, deformations and disruptions. A malformation is a primary structural defect arising from a localized error during morphogenesis (Figure 1b). In most cases, the defect involves only a single structure as for example a cleft lip or neural tube defect. Genetic as well as environmental factors play an important role in the pathogenesis of malformations. This will be discussed further in this article. A deformation is an alteration in shape or structure of a part that has differentiated normally (Figure 1c). Most deformations involve the musculoskeletal system and are caused by intrauterine pressure. This may be due to intrinsic factors because of neuromuscular problems within the fetus. This occurs, for example, in disorders involving muscle degeneration (e.g. myotonic dystrophy of Steinert (MIM 160900)) and disorders involving motor neurons, such as WerdnigHoman type 2 disease (MIM 253550). Fetal crowding of extrinsic origin is usually due to a decreased volume of amniotic uid. In either case, the ability of the fetus to move and to kick is severely impaired resulting in decreased fetal movements and abnormal development of the musculoskeletal system. The most frequent observed congenital deformities are talipes equinovarus and hip dislocation. These might be isolated ndings in an otherwise perfectly healthy child; however an underlying neuromuscular disorder always has to be excluded. Especially, multiple joint contractures should alert the physician to the possibility of such a disorder. A disruption occurs when there is the destruction of a previously normally formed part (Figure 1a). Two basic mechanisms are known that can produce a disruption. One involves the entanglement followed by the tearing apart or amputation of a normally developed structure, involving mostly the limbs and digits, by amniotic bands. These amniotic bands are strands of amnion, oating within the amniotic uid. The second mechanism involves the interruption of the blood supply to a developing part, leading to infarction, necrosis and ultimately resorption of structures distal to the insult. Genetic factors only play a minor role in the pathogenesis of disruptions and the prognosis is determined by the extent and localization of the structure that is lost. When a single, primary defect during morphogenesis results in multiple abnormalities through a cascade of different effects and errors, this is called a sequence. For example the Potter sequence, consisting of low-birth weight, wrinkled skin, typical facial dysmorphism (Potters

Figure 1 Clinical examples representing (a) a disruption of the fore-arm; (b) a malformation consisting of a polydactyly; and (c) a deformation of the feet, in this case club feet.

ENCYCLOPEDIA OF LIFE SCIENCES & 2005, John Wiley & Sons, Ltd.

Dysmorphism: Syndromes

facies), compression deformities of the limbs, and respiratory distress due to pulmonary hypoplasia. This sequence arises when there is prolonged oligohydramnios mostly due to congenital kidney abnormalities (aplasia, hypoplasia or polycystic kidneys), however also other causes of oligohydramnios such as chronic leakage of amniotic uid can result in this sequence. So, different etiologic factors can result in the same pattern of malformations. A sequence has to be differentiated from a multiple malformation syndrome. In the latter, one or more developmental anomalies of two or more systems have occurred, all of which are thought to result from the same etiologic factor. Multiple malformation syndromes may be caused by genetic, chromosomal and environmental factors (teratogens), and these will be further discussed below.

Clinical Diagnostic Approach of a Dysmorphic Child

The clinical assessment of a child with dysmorphism and congenital anomalies includes three parts: (1) detailed family history and prenatal and birth history, (2) evaluation of the psychomotor development, and (3) a good clinical examination. For monogenic malformation disorders (autosomaldominant, -recessive or X-linked inheritance), a detailed family history can be very helpful. However, most multiple malformation syndromes occur sporadically and in these cases the family history will be negative. In these situations the clinical diagnosis will depend entirely on the evaluation of the patients phenotype. This evaluation consists of a detailed clinical examination and an assessment of the psychomotor development or cognitive functioning. The latter is very important because it is known that the possibility to nd an etiologic cause is higher in children with moderate to severe mental retardation. This has been shown in different large systematic etiological surveys. Borderline and mild mental retardation is often multifactorial determined and in this category an etiologic diagnosis will only be made in a small minority of patients. Examples of syndromes that are associated with borderline to mild mental retardation are Noonan syndrome (MIM 163950) and syndromes involving the sex chromosomes such as 45X0 or Turner syndrome, 47XYY and 47XXY or Klinefelter syndrome. A good clinical examination must comprise all biometric measurements (head circumference (occipital-frontal circumference, OFC), stature and weight), including values at birth because these reect the growth and development that occurred during fetal life. Micro- or macrocephaly are frequent ndings in dysmorphic children and are often associated with a higher risk of developing a psychomotor retardation. In the majority of cases, an aberrant head

circumference is already present at birth; however in some syndromes, it may gradually develop during the rst year of life. Examples are Rett syndrome (MIM 312750) associated with a progressive microcephaly, and different neurocutaneous disorders such as neurobromatosis (MIM 162200) and Cowden syndrome (MIM 158350) that are characterized by an increasing head circumference. Growth retardation is often found in different syndromes and is rather an aspecific clinical sign. In children with growth retardation, body proportionality (upper body segment/lower body segment ratio) has to be assessed as well, especially when skeletal dysplasia or connective tissue disorders are suspected. Documentation of dysmorphic features is an essential part of the clinical evaluation, because they might reect an aberrant morphogenesis during embryonic development. Moreover, a certain combination of phenotypic features might indicate the presence of a specific syndrome, helping in the diagnostic process. Dysmorphic features are separated into minor and major anomalies. Minor anomalies are dened as unusual morphologic features that are of no serious medical or cosmetic consequence to the patient (Figure 2a). The value of their recognition is that their presence might indicate an altered morphogenesis in a general sense, or that they constitute valuable clues in the diagnosis of a specific malformation pattern. In one study they found in 14% of newborn babies that a single minor anomaly is present, without important implications. However, in the same study they found that in the group of babies with three or more minor anomalies (0.5% of babies) 90% also had one or more major defects leading to serious medical problems. Minor anomalies are most common in areas of complex and variable features, such as hands, feet and the face. Minor anomalies can be further divided in those that can be measured quantitatively, and those that are qualitative features. Examples of the former are interocular distance, distance between the nipples, length of the ears, length of the philtrum, etc. For these measurements special charts are available. Qualitative features, such as epicanthal folds can not be precisely measured, but can be graded as being mild, moderate or severe. Other features such as Brusheld spots, clinodactyly and simian crease are of the presenceabsence type. It is important to note that some of these anomalies may change with age. In contrast to minor anomalies, major malformations have serious medical and/or cosmetic consequences, classical examples being cardiac anomalies, clefts, neural tube defects, etc (Figure 2b). A major malformation occurs often isolated and is not necessarily associated with other developmental problems. In contrast, children with multiple congenital anomalies frequently exhibit psychomotor retardation, indicating that the same cause underlies the different developmental defects. When a major malformation is present, one should always look for associated minor anomalies. This is important for the

Dysmorphism: Syndromes

Genetic imbalance due to gross chromosomal abnormalities

Chromosomal abnormalities occur in approximately 0.4% of live births. They are a very important cause of mental retardation and multiple congenital anomalies (MR-MCA syndromes), because of an imbalance of genetic information. Chromosomal abnormalities include abnormalities in number and structure of the chromosomes. The most common abnormalities of chromosome number are trisomies, of which the best known and most frequent in humans is trisomy 21, or Down syndrome (MIM 190685). This syndrome was rst described in 1866, but its cause was not known until 1959 when Lejeune and Turpin showed that these individuals carried an extra chromosome 21. Trisomy 21 occurs in approximately 1/700 live births and in 95% of cases, three copies of chromosome 21 are present. Approximately 4% of individuals with Down syndrome have a translocation involving chromosome 21 and 1% of individuals are mosaic for both a normal and trisomic cell line. The Down syndrome phenotype is very consistent and specific, which makes it easy to diagnose. Other less frequent occurring trisomies are trisomy 13 and 18. Both are associated with severe congenital malformations and early death. Monosomies occur only when one representative of a chromosome is present. They may be complete or partial, as for the trisomies. However, all complete autosomal monosomies are lethal, early in development and survive only in mosaic forms. Mosaicism is the term used to describe an individual who has two different cell lines derived from a single zygote. Depending on the point at which the new cell line arises during embryogenesis, a patient may have a variety of clinical presentations. Mosaicism may be present in some tissues and not in others leading to an asymmetric distribution of abnormalities. This asymmetry, as well as the presences of hypo- or hyperpigmented streaks or patches on the skin, may provide a clinical clue towards the diagnosis of mosaicism. Often, this mosaicism is not present in chromosome studies performed on blood; therefore chromosome studies on skin broblasts have to be performed. Monosomy of chromosome X results in Turner syndrome (45,X0), characterized by short stature and gonadal underdevelopment and occurring in 1/2000 live born females. Other sex chromosome anomalies include the Klinefelter syndrome (47,XXY), the 47,XYY syndrome and many others in which there is an extra X-chromosome (47,XXX, 48,XXXX, 49,XXXXX, 48, XXXY). In all these syndromes the number of abnormalities increases with the number of X-chromosomes. Often mosaicism is found in these individuals. Structural chromosomal anomalies involve deletions (fragment of a chromosome is missing), inversions (fragment is broken and inverted within the same chromosome), translocations (transfer of chromosomal material from

Figure 2 Clinical example of (a) a minor anomaly, consisting of syndactyly of toes II and III; (b) a major anomaly, in this case a neural tube defect or spina bifida.

recognition of a known pattern of human malformations or syndrome. Besides these dysmorphic features and the level of cognitive functioning, other clinical signs may be of great value to the diagnostic process. In recent years, it has become clear that certain behavioural phenotypes are specific to certain genetic disorders. The rst recognized example is the LeschNyhan syndrome (MIM 300322) characterized by a severe compulsive and self-destructive behaviour. Nowadays typical behavioural phenotypes have been recognized in a series of other syndromes, including the PraderWilli syndrome (MIM 167270), the velo-cardiofacial syndrome (MIM 192430), tuberous sclerosis (MIM 191100), etc. This has contributed not only to a better diagnosis but also to a better management and anticipation of behavioural problems. A good neurological evaluation of the patient is also essential. Some syndromes can be associated with typical neurological signs as is the case, for example, for X-linked mental retardation caused by mutations in the ARX gene. These patients often exhibit mild dystonia that is present only in the hands and the head region. A careful examination for these subtle signs is therefore essential. Once a clinical diagnosis is made for which the underlying genetic defect is known, additional genetic tests (cytogenetic/molecular) can be performed to conrm the diagnosis. This will also enable better counselling, management and medical follow-up of the patients.

Molecular and Cytogenetic Basis of Dysmorphic Syndromes

The enormous growth in cytogenetic and molecular genetic research has contributed to the elucidation of the molecular defects underlying some of these syndromes. Moreover, the discovery of developmental genes has dramatically increased our understanding of human embryonic development.

Dysmorphism: Syndromes

one chromosome to another), duplications (presence of extra material from the same chromosome) and insertions (fragment of one chromosome that is incorporated within another chromosome). Although these structural chromosomal aberrations occur more rarely, some of them are inherited and, therefore, can recur in the same family. The most commonly observed deletions in humans are 4p(MIM 194190), 5p- (MIM 123450), 9p- (MIM 158170), 11p-, 13q-, 18p-, 18q-, which are all associated with a specific, recognizable and well-described phenotype.

Microdeletion syndromes
Sometimes the chromosomal deletions are so small that they can only be detected by high-resolution cytogenetic analysis and uorescence in situ hybridization (FISH). A number of microdeletion syndromes have been detected this way. The clinical phenotype associated with a chromosomal microdeletion is the result of the loss of one copy of a gene or multiple genes contained within the deleted segment. Most of these microdeletion phenotypes are specific and clinically recognizable, however, significant phenotypic variability between affected individuals occurs. This is very well illustrated in the velo-cardio-facial syndrome (MIM 192430), caused by a 1.53 Mb microdeletion of chromosome 22q11. This syndrome is characterized by velopharyngeal insufciency, congenital heart defects, learning difculties, and typical facies. Although most patients carry the same 3 Mb deletion, the associated phenotypes can be very discordant even within the same family. This variability points to the existence of other stoichastic factors, environmental as well as genetic. This has also been observed in other microdeletion syndromes. In case of the WilliamsBeuren syndrome (WBS) (MIM 194050), a uniform deletion size of  2 Mb is detected in almost all WBS patients, despite obvious clinical variability. This syndrome is characterized by mental retardation, typical facies, supravalvular aortic stenosis and a very characteristic cocktail party personality. Other examples of microdeletion syndromes are SmithMagenis syndrome [del(17p11.2)] (MIM 182290), LangerGiedion syndrome [del(8q24.11-8q24.13)] (MIM 150230) and PraderWilli/ Angelman syndrome [del(15q11-15q13)] (MIM 167270 and 105830). Most microdeletion syndromes arise spontaneously by inter- or intrachromosomal crossover events within duplicated regions of high sequence identity, resulting in a uniform deletion size.

important role during embryonic development and defects in imprinting lead to human disorders. The classical examples of imprinting defects in humans are the phenotypic differences seen in PraderWilli and Angelman syndromes, both caused by a deletion on, or by uniparental disomy (UPD) of chromosome 15. In PraderWilli syndrome, the deletion occurs on the paternally derived chromosome 15, indicating that the PraderWilli phenotype is due to a lack of paternally derived genetic information. A deletion is found in 75% of cases, an UPD in 24% and in 1% of PraderWilli patients a defect at the imprinting centre is the underlying cause. The clinical manifestations of this syndrome constitute of severe hypotonia and feeding problems in infancy, progressing into mild to moderate mental retardation, hypogonadotrophic hypogonadism and behavioural problems, mostly due to excessive appetite and obsession with eating. Some of the PraderWilli patients also exhibit psychotic disorders. Interestingly, it has been shown recently that the psychotic illness in PraderWilli syndrome is almost exclusively associated with chromosome 15 maternal UPD. In contrast, Angelman syndrome is caused by a deletion on the maternal derived chromosome 15. These children feature severe psychomotor retardation, epilepsy, ataxia, absence of speech and a characteristic facies. Approximately 70% of patients show a deletion involving the maternally inherited chromosome 15q11-q13, encompassing a cluster of g-aminobutyric acid receptor subunit genes, 3% show chromosome 15 paternal UPD, 1% harbour a mutation in the imprinting centre and 6% harbour intragenic mutations of the ubiquitin-protein ligase E3A (UBE3A) gene. Individuals with chromosome 15q11-q13 deletions have a more severe clinical picture and are more prone to develop severe epilepsy than patients with a UBE3A mutation or UPD. Another example of an imprinting disorder on human chromosome 11p15 is the BeckwithWiedemann syndrome (BWS) (MIM 130650). The cardinal features of this syndrome are macroglossia, organomegaly, omphalocoele and increased risk for developing specific tumours. The 11p15 region is organized into two imprinted domains in which genomic imprinting is controlled by separate imprinting control regions. BWS patients (2550%) have biallelic rather than monoallelic expression of the insulin-like growth factor 2 (IGF2) gene. Another 50% of BWS patients have an epigenetic mutation resulting in loss of imprinting.

Genomic imprinting refers to the observation that the expression of a gene depends on its parental origin. This means that some genes are only expressed from the maternal chromosome and others only from the paternal chromosome. It has been shown that imprinting plays an

Gene defects
In the last few years, the identication of genes involved in human malformation syndromes and birth defects has evolved dramatically. Mutation in genes that code for transcription factors, receptors, cell adhesion molecules, growth factors, structural proteins, signal molecules, enzymes and transporters have been identied. It is impossible

Dysmorphism: Syndromes

to list here all the genes involved in dysmorphic syndromes and therefore we selected some interesting examples, based on the type of protein function. A great part of malformation syndromes are caused by mutations in genes that code for transcription factors, which are known to play an important role during human embryonic development. Transcription factors contain specific motifs that are able to bind to the deoxyribonucleic acid (DNA) and in this way regulate transcription of downstream genes. Several different DNA binding motifs are known, including zinc-nger motifs, paired box motifs, helixloophelix zippers and homeobox motifs. For example, mutations in the gene GLI3, a zinc nger containing transcription factor, have been identied in patients with the Greig cephalosynpolydactyly syndrome (MIM 175700), characterized by syndactyly, polydactyly (extra ngers/toes) and an abnormal shape of the skull. Interestingly, a deletion of the homologous gli3 gene in the mouse results in a similar phenotype named extra-toes, and suggested the role of this gene in the pathogenesis of this syndrome. There are many other examples of genes responsible for human birth defects, that were identied through the study of lower organisms. Although transcription factors are central to the regulation of gene expression, developmental processes rely on the transfer of information between and within cells. Mutations in genes that code for signalling proteins and their respective receptors were identied in numerous malformation syndromes, especially those involving skeletal anomalies. Very well-known examples are the broblast growth factor (FGF)/broblast growth factor receptor (FGFR) signalling pathways that are crucial during skull and limb development. The FGFRs represent a family of four tyrosine kinase receptors (FGFR14) that bind FGFs with variable afnity. Mutations in these genes have been identied in various different craniosynostosis syndromes. Craniosynostosis refers to the premature fusion of cranial sutures leading to abnormal skull growth and associated important medical problems. A last example presented here is the gene lamin A/C that codes for two important structural proteins, lamin A and lamin C, by alternative splicing. These lamins are intermediate lament proteins that are major components of the nuclear laminae, and are expressed in nearly all somatic cells. Interestingly, mutations in the lamin A gene cause tissue-specific diseases that affect striated muscle, adipose tissue and peripheral nerve or skeletal development. Different mutations in these proteins cause muscle disease (Emery-Dreisfuss muscular dystrophy (MIM 181350), Limb girdle muscular dystrophy 1B (MIM 159001), Charcot-Marie-Tooth disease type 2B1 (MIM 605588), dilated cardiomyopathy 1A (MIM 115200)), partial familial lipodystrophy (MIM 151660), Mandibulo-acral dysplasia (MIM 248370) and recently also the HutchinsonGilford progeria syndrome (MIM 176670). The paradox is, therefore, how these different pathologies arise from mutations

in the same gene that is almost ubiquitously expressed. Different hypotheses have been proposed and most interest has been focused on the mechanical stress and altered gene regulation hypotheses. The mechanical stress hypothesis describes the possibility that mutant lamins may affect the structural integrity of the nucleus resulting in a greater susceptibility of the cell to physical stress. The altered gene regulation hypothesis describes that LMNA mutations may affect nuclear structure/function with consequent effects on gene expression by other routes.

Future Perspectives
The enormous growth in molecular genetic research has resulted in the identication of a number of genes implicated in human disorders. Although most of the genes identied so far have been associated with autosomaldominant monogenic disorders, multifactorial diseases and recessive disorders are also being unravelled at a rapid pace. Traditional techniques such as candidate gene approach and positional cloning are still very valuable to identify new genes implicated in human birth defects. Especially homozygosity mapping has proven to be a useful tool in the location and identication of recessive genes. The recent development of array-based comparative genomic hybridization is another powerful tool to detect small, submicroscopic chromosomal aneuploidy in patients presenting with MRMCA. As discussed above, chromosomal aneuploidy, whether monosomies/deletions or trisomies/duplications, is a major cause of MCA. Further genetic dissection of these, mostly unique, submicroscopic regions of imbalance will certainly lead to the identication of a number of new genes. Further efforts are orientated towards functional analyses of these newly identied proteins and their respective pathways. This will definitely increase our understanding of normal and abnormal human embryonic development. In summary, a good clinical evaluation of a dysmorphic child is indispensable in the diagnostic process. This assessment must contain a detailed family history, prenatal and birth history, an evaluation of the psychomotor development and a good clinical examination, including biometry, neurology and detailed description of minor and major anomalies.

Further Reading
Aase JM (1990) Diagnostic Dysmorphology. New York: Plenum Medical Book Company. Epstein CJ (1995) The new dysmorphology: application of insights from basic developmental biology to the understanding of human birth defects. Proceedings of the National Academy of Sciences of the USA 92(19): 85668573. Gorlin RJ, Cohen MM and Levin SL (2001) Syndromes of the Head and Neck, 4th edn. Oxford: Oxford University Press.

Dysmorphism: Syndromes

Jones KL (1996) Smiths Recognizable Patterns of Human Malformation, 5th edn. Philadelphia, PA: Saunders W.B. Marden PM, Smith DW and McDonald MJ (1964) Congenital anomalies in the newborn infant, including minor variations. A study of 4,412 babies by surface examination for anomalies and buccal smear for sex chromatin. Journal of Pediatrics 64: 357371.

Shapira SK (1998) An update on chromosome deletion and microdeletion syndromes. Current Opinion in Pediatrics 10(6): 622627. 5 OMIM