Isolated defects

Most birth defects involve a single organ or region of the body. Common examples are CL/P, CHDs, club foot and neural tube defects (NTDs). Except for the involvement of some major genes that show a mendelian pattern of distribution in families, the majority of single defects show a multifactorial aetiology, indicating the involvement of both genetic and non-genetic factors. It is not unusual for different ethnic groups to show different frequencies of congenital anomalies (e.g. NTD incidence is lower in Japan than in Ireland).

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  Example: NTDs represent a failure of closure of neural groove that is usually complete by 28 days’ gestation (see Chs8 , 9 for more information about the antenatal and postnatal diagnosis and prognosis of these conditions). In about 80% of cases this defect occurs in isolation. Such instances are considered multifactorial conditions with several non-genetic factors incriminated to date, including maternal diabetes, prepregnancy obesity and use of anticonvulsant medication, especially folic acid antagonists such as valproate ( ). Folic acid supplementation, an important public health intervention, has reduced the incidence of NTDs between 31% and 78% in countries such as Canada, the USA and Chile, but compliance remains a challenge. In addition, NTD prevalence varies with race and ethnicity. Recurrence risk can be variable (2–10%) and it is influenced by the number of cases identified in the pedigree ( ).

Syndrome

When a constellation of anomalies occurs repeatedly in the same combination, this pattern is called a syndrome. The fundamental point about a syndrome is that all the features may be explained by a common causative factor, whether that be a mutation in a single gene, the presence of additional chromosomal material or a teratogen. The clinical practice of dysmorphology teaches that a single underlying cause of birth defects can result in abnormalities in different organs, or in multiple structures at different times during the intrauterine period, a concept called pleiotropy. Another characteristic encountered in syndromal conditions is variable expressivity, which refers to different severity of a phenotype in individuals with the same genetic defect. Penetrance is a characteristic that refers to the probability that a gene will have a phenotypic expression at all. When an individual has a genetic mutation associated with a phenotype but fails to express it, the gene is said to show reduced penetrance.

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  Example: A recognisable syndrome evident by the time of birth, with multiple dysmorphic features and birth defects, is Cornelia de Lange syndrome ( Fig. 31.2 ). Newborns show marked growth retardation and often fail to thrive, manifesting with swallowing and feeding difficulties, and projectile vomiting. They initially present with hypertonicity and a low-pitched, weak cry. There is microbrachycephaly and the eyebrows are bushy with synophrys, long and curly eyelashes, a short nose with anteverted nostrils, and a long philtrum with thin upper lip. These infants are usually hirsute and may show cutis marmorata. Some 25% manifest severely malformed limbs with phocomelia or micromelia. Life-threatening complications relate to apnoea, aspiration, and complications related to bowel obstruction and cardiac defects.

  
  

  
  

  
  

  

  
  

  
  

  Cornelia de Lange syndrome, showing the typical facial features and associated limb malformations. Note the nasogastric feeding tube.

  
  

Association

Some anomalies and physical features are seen happening together in a non-random fashion more often than would be expected by chance, but the link between these anomalies is not strong enough to justify a definition of a syndrome. This collection of features is called association. Variable expressivity can complicate the picture when deciding on classifying a combination of features a syndrome or an association. A good instance of an association is VACTERL, standing for vertebral anomalies (hemivertebrae, fused vertebrae, ± rib anomalies in upper, midthoracic and lumbar region), anal atresia (or fistulae, ± genital defects including hypospadias, bifid scrotum), cardiac anomalies (in 80% of cases, of various types), tracheo-oesophageal fistula, oesophageal atresia (80% have an associated tracheo-oesophageal fistula), renal anomalies (in 80% of cases including renal agenesis/dysplasia) and limb defects (restricted to the upper limbs, usually bilateral and preaxial). It is found in about 1.6/10 000 newborns, with most patients having three to four features. To secure a diagnosis of VACTERL there is need for at least one anomaly of the limbs, thorax and pelvis/lower abdomen ( ).

Clinical photographs

Clinical photographs often act in conjunction with the physical examination when there is the need to document physical features and/or a facial gestalt. They can be used for different reasons:

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  A genetic condition said to ‘run in the family’ from information collected through family history and pictures of relatives can help in identifying a diagnosis in the index case ( Fig. 31.4 : Sheldon–Hall syndrome and arthrogryposis).

  
  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  This baby was referred with (a) immobile facies, (b) distal arthrogryposis and possible motor delay. However, maternal examination showed the same features with absence of the distal interphalangeal skin creases and distal arthrogryposis since infancy (c and d). The diagnosis is Sheldon–Hall syndrome, an autosomal-dominant cause of distal arthrogryposis associated with normal development.

  
  
  
  
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  Photographs may be used to compare with similar phenotypes already published in the literature in order to reach a diagnosis.

  
  
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  Photographs may turn out to be useful at a later follow-up visit in a patient with an unknown diagnosis but nonetheless a likely syndromal presentation. In some conditions patients ‘grow into their syndrome’, meaning that facial gestalt may become more evident with time (Williams syndrome is a case in point).

Radiological images

The utility of X-rays in genetics, especially in regard to the skeletal system, cannot be overemphasised. A good example might be the finding of butterfly vertebrae in a neonate with cholestasis that should suggest a possible diagnosis of Alagille syndrome. In the event of neurological symptoms or the neonate with an abnormal head size (micro- or macrocephaly), or where there is an unusual contour of the skull, a head and brain magnetic resonance imaging will be the modality of choice ( ). For example, in the hypotonic neonate, the recognition of a ‘molar tooth sign’ suggests a diagnosis of Joubert syndrome ( Fig. 31.5 ).

(a) Axial T1-weighted image demonstrating the classical ‘molar tooth’ appearance of the midbrain caused by a narrow isthmus (white arrow) and large superior cerebellar peduncles (black arrows). (b) Sagittal T1-weighted image demonstrating a small dysplastic cerebellar vermis (white arrows) and small narrow isthmus (single solid white arrow).

(Courtesy of Dr Ethna Phelan.)

Chromosomal examination

Chromosomal examination has been part of the armamentarium of clinical geneticists for over 50 years. Many banding techniques have been developed over the years to permit the detection of aneuploidies and the identification of microscopically apparent structural aberrations, including deletions and translocations. Better techniques have improved the resolution of chromosome examination, offering the opportunity for better analysis and identification of microdeletions, microduplications or subtle translocations. At a resolution of more than 650 bands, alterations as small as 3–5 Mb can be detected using chromosome preparation on peripheral blood; for detection of subtle rearrangements in patients with either abnormal or normal standard karyotypes, molecular cytogenetics may be useful (e.g. fluorescence in situ hybridisation – FISH) ( ). A history of a ‘normal’ chromosome examination does not preclude a diagnosis of chromosomal disease, as improved techniques may identify previously unresolved/unresolvable and unidentified chromosomal disease.

Body asymmetry or streaks of pigmentation identified on the physical examination may be indicating an underlying diagnosis of a mosaic condition. A normal chromosome examination on blood may mislead the neonatologist as to the real diagnosis, and chromosome examination of another tissue may reveal the true cause of malformation. The condition of Pallister–Killian syndrome, caused by mosaicism of tetrasome 12p, exemplifies this. Presenting clinically with variable features comprising coarse facial features, temporal alopecia, diaphragmatic hernia, accessory nipples, poor feeding and hypotonia, the abnormal chromosome 12 is often absent on blood chromosomes, being lost in the rapid turnover of lymphocytes. However, skin biopsy and karyotype of the more slowly growing fibroblasts will generally reveal the true cause of the abnormal clinical profile by affording the identification of the abnormal chromosome 12 ( Fig. 31.6 – clinical and cytogenetic). When ordering FISH, there is a need for a clear clinical hypothesis as to underlying diagnosis as this investigation is targeted to specific regions in the genome (e.g. FISH for 22q11.2 deletion syndrome, ELN on chromosome 7q11 for Williams syndrome). Chromosomal microarray is a new method for screening the chromosomes for abnormalities of dosage at a high-resolution scale and, offering a higher diagnostic yield (15–20%) than G-banding, it is suggested that it will become the first-tier cytogenetic diagnostic test for patients with multiple congenital anomalies ( ). The results may be associated with significant counselling and diagnostic pitfalls and, at the time of writing, it is still a specialist tool of the experienced clinical geneticist and not suitable for more widespread use in clinical practice.

(a, b) Newborn baby with Pallister–Killian syndrome. Note the coarse facial features and the paucity of temporal hair.

Molecular genetics analysis

Molecular genetics analysis should always be based upon a strong diagnostic suspicion. The number of tests available in accredited laboratories around the globe continues to expand but the number of positive findings in respect of a specific analysis is often very low (<10%) which, in terms of the cost of these analyses, represents very poor value for money. Molecular testing done on a research basis in unaccredited laboratories may need further validation in a diagnostic laboratory in the event of wishing to use such data for predictive genetic purposes.

Metabolic testing

Metabolic testing needs to be done when specific signs of a metabolic disorder are raised during the neonatal clinical presentation. The metabolic genetics team will be the most appropriate to evaluate the need for specific tests (see Ch. 35, part 3 ). Pre- and postnatal growth deficiency, in a hypotonic neonate with microcephaly, ptosis, downslanting palpebral fissures, short nose, CP, a cardiac defect, hypospadias and/or cryptorchidism, Y-shaped 2–3 syndactyly and postaxial polydactyly, may clinically suggest Smith–Lemli–Opitz syndrome and be confirmed by the demonstration of abnormality of 7-dehydrocholesterol ( Fig. 31.7 ).

(a, b) The combination of ambiguous genitalia, syndactyly and postaxial polydactyly in this neonate signals the diagnosis of Smith–Lemli–Opitz syndrome.

Down syndrome

Down syndrome is by far the most common chromosomal disorder with prevalence highly dependent on maternal age. While about 1 in 1500 children are born with Down syndrome in mothers 20 years old, this incidence is about 1 in 100 in women 40 years of age. With the advent of prenatal diagnosis programmes for advanced maternal age the majority of children with Down syndrome are now born to younger women. About 78% of Down syndrome pregnancies end in spontaneous abortion. Babies are usually recognisable by their distinctive pattern of facial and extrafacial features. One of the first signs in a neonate with Down syndrome is hypotonia. Down syndrome babies can be microcephalic with a brachycephalic skull (short anteroposterior length), large fontanelles and midface hyoplasia that gives a flat appearance from the profile. The face is round in the neonate, and there are upslanted palpebral fissures and epicanthal folds. In children with light-coloured eyes, a pattern of peripheral spots on the irises can be observed (Brushfield spots: Fig. 31.8 ). The nose is short with a low nasal bridge and small nares and the mouth is small with downturned corners. Lips can be cracked, and the tongue can have a fissured aspect and a tendency to protrude that may give the impression of macroglossia. The ears are small, can have a cupped or squared shape and overfolded helices. It is not unusual for infants to have cutis marmorata and there can be an excess of folds in the nuchal area. The hands are short with a triangular shape of the middle phalanx on the fifth finger that gives a lateral curved aspect called clinodactyly. There can be a gap between the hallux and second toe, known as a sandal gap.

Brushfield spots in the iris of a baby with Down syndrome.

In addition to the distinctive physical features, children with Down syndrome frequently have congenital anomalies that may affect their chances of survival, especially CHDs. About half of Down syndrome neonates are found to have a heart defect, often requiring surgical repair. The most common heart defect is perimembranous ventricular septal defect (VSD), followed by patent ductus arteriosus and atrial septal defects (ASDs). Overall the incidence of congenital defects in Down syndrome children is increased twofold, including duodenal atresia and stenosis, and Hirschprung disease.

In all, 95% of Down syndrome cases result from an extra full chromosome 21, known as trisomy 21. Most of the remaining 5% of cases arise from a robertsonian translocation (see Ch. 8 , Fig 8.8 for definition) between chromosome 21 and another acrocentric chromosome, most commonly chromosome 14, in a parent, while a small number of cases represent mosaicism for trisomy 21. In the very rarely encountered situation where a robertsonian translocation involves the two chromosomes 21 in a parent, the recurrence risk approaches 100%. These cases involving parental chromosomal anomalies need specific counselling, best undertaken by specialists in a genetics clinic.

Turner syndrome

Turner syndrome is a rare sex chromosomal aneuploidy characterised by a complete or partial monosomy for one of the X chromosomes. It occurs in 1 in 5000 births, and in most cases is due to a 45,XO chromosomal complement that results from chromosomal nondisjunction and no maternal age effect has been noted. Over 95% of 45,XO conceptions are spontaneously aborted, mostly because of hydrops and nuchal cystic hygroma. Other characteristics include cardiac anomalies (20%), especially bicuspid aortic valve (30%) and coarctation of aorta (10%). In the surviving fetuses signs of congenital lymphoedema appear as residual puffiness over the dorsum of the fingers and toes with narrow, hyperconvex and/or deep-set nails. Small stature is also evident from birth and some subtle dysmorphic features may include low posterior hairline with the appearance of short neck with lateral webbing and loose skin. Facies may have a narrow maxilla (palate) with a relatively small mandible, inner canthal folds and prominent auricles. Newborns may have cubitus valgus, dislocated hips and broad chest with widely spaced nipples. About 60% of Turner syndrome patients can have renal anomalies, including horseshoe kidney, double or cleft renal pelvis, so an abdominal ultrasound as well as an echocardiogram is recommended in the neonatal period. A standard chromosomal examination will diagnose the condition. Girls with Turner syndrome are usually of normal intelligence; only about 10% have significant delays, need special education and require ongoing assistance in adult life.

Common microdeletion/duplication syndromes

Microdeletion/duplications are not usually visible by routine karyotype and may be the cause of several multiple congenital anomalies/mental retardation syndromes. Microdeletion/duplication means that an area of the chromosome (of several megabases) containing usually tens of genes is missing or duplicated respectively (contiguous gene syndrome). This large genetic imbalance explains the complexity of the phenotypes observed. While specific FISH analysis can be ordered to confirm a clinical diagnosis of such a microdeltion syndrome, syndromes caused by microdeletion/duplication may also be diagnosed using targeted microarray-based comparative genomic hybridisation (array-CGH) studies. Deletion and duplication are expected to occur with the same frequency, with the former expected to have more severe clinical consequences as the general rule, that trisomy is better tolerated than monosomy, may apply. Below are listed the most common microdeletion/duplication syndromes that can be diagnosed in the neonate or small infant and their chromosomal location:

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  Sotos syndrome – 5q35

  
  
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  Williams syndrome – 7q11.23

  
  
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  Langer–Giedion syndrome – 8q24

  
  
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  Wilms tumour–aniridia syndrome (Wilms, aniridia, genitourinary anomalies and mental retardation: WAGR) – 11p13

  
  
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  Beckwith–Wiedemann syndrome (BWS) – 11p15

  
  
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  Prader–Willi and Angelman syndrome – 15q11-13

  
  
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  Smith–Magenis syndrome – 17p11.2

  
  
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  Miller–Dieker syndrome – 17p13.3

  
  
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  Velocardiofacial/22q11.2 deletion syndrome – 22q11.2.

Since velocardiofacial/22q11.2 deletion syndrome represents the most common microdeletion syndrome, a more detailed discussion is required. It is an extremely pleiomorphic condition, having been described by several different paediatric subspecialties in the absence of recognition that the different reports represented the same condition ( ; ). A prevalence of 1 in 4000 births is based on a more severe phenotype and generally thought to be an underestimate ( ). This condition encompasses DiGeorge sequence, characterised by a pattern of malformations as a result of developmental abnormalities in third and fourth branchial arches, emphasised by defects of thymus, parathyroids and great vessels ( ). Hypoplasia (aplasia) of thymus with consequent deficit of cellular immunity is responsible for a predisposition to severe infections and the use of live vaccines should be avoided if this diagnosis is suspected or confirmed. Blood products should be irradiated to eliminate the risk of graft-versus-host disease. Hypoparathyroidism is responsible for hypocalcaemia that can produce easily treatable seizures in the neonatal period and thereafter.

Cardiovascular malformations derive from anomalies of the conotruncus and are found in 74% of affected individuals, representing the most important cause of death associated with this syndrome ( ). The most common heart defect is VSD followed closely by aortic arch defects and tetralogy of Fallot ( ). Most patients have palatal dysfunction, if not necessarily cleft, resulting in velopharyngeal insufficiency and a minority having overt CP ( ). Neonatal feeding problems, in particular nasal regurgitation of milk in term babies, is one of the most common clues to this syndrome, and should be an indication for genetic evaluation. Antenatal diagnosis is possible and indeed should be offered in the event of a conotruncal defect being identified – FISH for 22q11.2 is undertaken on amniocytes. The syndrome is inherited from one of the parents in about 7% of cases, in which event a history of learning disability and possible psychiatric disorder may be divined. The risk of learning difficulty reaches 70–90% in children with DiGeorge syndrome.

The face

The face offers many possible diagnostic clues to a clinical geneticist and it is often the recognition of an abnormal facial appearance by neonatologists that sets in train the chain of events leading to a diagnosis. As seen in the physical examination section, a large variety of facial features need to be observed by the trained eye in recognising normal and abnormal variants, and their interpretation in the context of the general clinical presentation. Facial structures develop from 4 weeks’ gestational age and at about 8 weeks the embryonal face is recognisable. There are five primordial structures that contribute to face development, including paired maxillary and mandibulary prominences and a frontonasal prominence, and they derive from migration of the neural crest cells. A multitude of intrinsic genetic factors and local conditions contribute to the growth and development of these structures in a certain way that will culminate with a person’s individual facial appearance ( ).

A classical example of syndrome described in dysmorphology as having a recognisable gestalt is Rubinstein–Taybi syndrome (RTS) ( Fig. 31.9 ). RTS is characterised by postnatal onset of growth deficiency and a well-described gestalt. Patients can have microcephaly with large anterior fontanelle, downslanting palpebral fissures, heavy eyebrows and long eyelashes and hypoplastic maxilla with narrow palate. There is a characteristic prominent or beaked nose with or without nasal septum extending below alae nasi and short columella ( ). The classic hallmark of the condition is the broad great toes and thumbs, sometimes angled in a radial direction. Respiratory infections, constipation and feeding difficulties are frequent problems in infancy. The majority of cases are sporadic. Mutation of the CREBBP locus (>60%) is the main cause of the phenotype while mutation at a second locus, EP300, has been reported in a handful of cases in whom CREBBP analysis proved negative ( ).

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