Down syndrome is usually suspected at birth because of the baby’s facial appearance. Most affected infants are hypotonic and other useful clinical signs include a flat occiput, single palmar creases, incurved fifth finger and wide ‘sandal’ gap between the big and second toe (Fig. 8.2a–c, Box 8.1). The diagnosis can be difficult to make when relying on clinical signs alone and a suspected diagnosis should be confirmed by a senior paediatrician. Before blood is sent for analysis, parents should be informed that a test for Down syndrome is being performed. The results may take 1–2 days, using rapid FISH (fluorescent in situ hybridisation) techniques. Parents need information about the short- and long-term implications of the diagnosis. They are also likely, at some stage in the future, to appreciate the opportunity to discuss how and why the condition has arisen, the risk of recurrence and the possibility of antenatal diagnosis in future pregnancies.

Down syndrome

Figure 8.2c Pronounced ‘sandal’ gap between the big and second toe.

Box 8.1

Characteristic clinical manifestations of Down syndrome

Typical craniofacial appearance

• Round face and flat nasal bridge

• Upslanted palpebral fissures

• Epicanthic folds (a fold of skin running across the inner edge of the palpebral fissure)

• Brushfield spots in iris (pigmented spots)

• Small mouth and protruding tongue

• Small ears

• Flat occiput and third fontanelle

Other anomalies

• Short neck

• Single palmar creases, incurved fifth finger and wide ‘sandal’ gap between toes

• Hypotonia

• Congenital heart defects (40%)

• Duodenal atresia

• Hirschsprung disease

Later medical problems

• Delayed motor milestones

• Moderate to severe learning difficulties

• Small stature

• Increased susceptibility to infections

• Hearing impairment from secretory otitis media

• Visual impairment from cataracts, squints, myopia

• Increased risk of leukaemia and solid tumours

• Risk of atlanto-axial instability

• Increased risk of hypothyroidism and coeliac disease

• Epilepsy

• Alzheimer’s disease.

It is difficult to give a precise long-term prognosis in the neonatal period, as there is individual variation in the degree of learning difficulty and the development of complications. Over 85% of infants with trisomy 21 survive to 1 year of age. Congenital heart disease is present in 30% and, particularly atrioventricular canal defect, is a major cause of early mortality. At least 50% of affected individuals live longer than 50 years. Parents also need to know what assistance is available from both professionals and family support groups. Counselling may be helpful to assist the family to deal with feelings of grief, anger or guilt.

The Child Development Service will provide or coordinate care for the parents. This will include regular review of the child’s development and health. Children with Down syndrome are at increased risk of hypothyroidism, impairment of vision and hearing and of atlanto-axial instability.

Cytogenetics

The extra chromosome 21 may result from meiotic non-disjunction, translocation or mosaicism.

Meiotic non-disjunction (94%)

In non-disjunction trisomy 21:

• most cases result from an error at meiosis

• the pair of chromosome 21s fails to separate, so that one gamete has two chromosome 21s and one has none (Fig. 8.3)

• fertilisation of the gamete with two chromosome 21s gives rise to a zygote with trisomy 21

• parental chromosomes do not need to be examined.

The incidence of trisomy 21 due to non-disjunction is related to maternal age (Table 8.1). However, as the proportion of pregnancies in older mothers is small, most affected babies are born to younger mothers. Furthermore, meiotic non-disjunction can occur in spermatogenesis so that the extra 21 can be of paternal origin. All pregnant women are now offered screening tests measuring biochemical markers in blood samples and often also nuchal thickening on ultrasound (thickening of the soft tissues at the back of the neck) to identify an increased risk of Down syndrome in the fetus. When an increased risk is identified, amniocentesis is offered to check the fetal karyotype. After having one child with trisomy 21 due to non-disjunction, the risk of recurrence of Down syndrome is given as 1 in 200 for mothers under the age of 35 years, but remains similar to their age-related population risk for those over the age of 35 years.

Table 8.1

Risk of Down syndrome (live births) with maternal age at delivery, prior to screening in pregnancy

Maternal age (years)	Risk of Down syndrome
All ages	1 in 650
20	1 in 1530
30	1 in 900
35	1 in 385
37	1 in 240
40	1 in 110
44	1 in 37

Translocation (5%)

When the extra chromosome 21 is joined onto another chromosome (usually chromosome 14, but occasionally chromosome 15, 22 or 21), this is known as a Robertsonian translocation. This may be present in a phenotypically normal carrier with 45 chromosomes (two being ‘joined together’) or in someone with Down syndrome and a set of 46 chromosomes but with three copies of chromosome 21 material. In this situation, parental chromosomal analysis is recommended, since one of the parents may well carry the translocation in balanced form (in 25% of cases) (Fig. 8.4).

In translocation Down syndrome:

• The risk of recurrence is 10–15% if the mother is the translocation carrier and about 2.5% if the father is the carrier.

• If a parent carries the rare 21 : 21 translocation, all the offspring will have Down syndrome.

• If neither parent carries a translocation (75% of cases), the risk of recurrence is <1%.

Mosaicism (1%)

In mosaicism, some of the cells are normal and some have trisomy 21. This usually arises after the formation of the chromosomally normal zygote by non-disjunction at mitosis but can arise by later mitotic non-disjunction in a trisomy 21 conception. The phenotype is sometimes milder in Down syndrome mosaicism.

Inheritance of Down syndrome

Figure 8.4 Translocation Down syndrome. There is a Robertsonian translocation involving chromosomes 21 and 14, which has been inherited from a parent.

Summary

Down syndrome (trisomy 21)

• Natural incidence ∼1.5 per 1000 infants

• Cytogenetics – non-disjunction (most common, related to maternal age), translocation (one parent may carry a balanced translocation) or mosaicism (rare)

• Presentation – antenatal screening, prenatal diagnosis or clinical presentation; confirmed on chromosome analysis

• Immediate medical complications – increased risk of duodenal atresia, congenital heart disease

• Clinical manifestations (see Box 8.1).

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13)

Although rarer than Down syndrome (1 in 8000 and 1 in 14 000 live births, respectively), particular constellations of severe multiple abnormalities suggest these diagnoses at birth; most affected babies die in infancy (Fig. 8.5, Boxes 8.2 and 8.3). The diagnosis is confirmed by chromosome analysis. Many affected fetuses are detected by ultrasound scan during the second trimester of pregnancy and diagnosis can be confirmed antenatally by amniocentesis and chromosome analysis. Recurrence risk is low, except when the trisomy is due to a balanced chromosome rearrangement in one of the parents.

Turner syndrome (45, X)

Usually (>95%), Turner syndrome results in early miscarriage and is increasingly detected by ultrasound antenatally when fetal oedema of the neck, hands or feet or a cystic hygroma may be identified. In live-born females, the incidence is about 1 in 2500. Figure 8.6 and Box 8.4 show the clinical features of Turner syndrome, although short stature may be the only clinical abnormality in children.

Treatment is with:

• Growth hormone therapy

• Oestrogen replacement for development of secondary sexual characteristics at the time of puberty (but infertility persists).

In about 50% of girls with Turner syndrome, there are 45 chromosomes, with only one X chromosome. The other cases have a deletion of the short arm of one X chromosome, an isochromosome that has two long arms but no short arm, or a variety of other structural defects of one of the X chromosomes. The presence of a Y chromosome sequence may increase the risk of gonadoblastoma.

The incidence does not increase with maternal age and risk of recurrence is very low.

Turner syndrome

Klinefelter syndrome (47, XXY)

This disorder occurs in about 1–2 per 1000 live-born males. For clinical features, see Box 8.5. Recurrence risk is very low.

Box 8.5 Clinical features of Klinefelter syndrome

• Infertility – most common presentation

• Hypogonadism with small testes

• Pubertal development may appear normal (some males benefit from testosterone therapy)

• Gynaecomastia in adolescence

• Tall stature

• Intelligence usually in the normal range, but some have educational and psychological problems.

Reciprocal translocations

An exchange of material between two different chromosomes is called a reciprocal translocation. When this exchange involves no loss or gain of chromosomal material, the translocation is ‘balanced’ and usually has no phenotypic effect. Balanced reciprocal translocations are relatively common, occurring in 1 in 500 of the general population. A translocation that appears balanced on conventional chromosome analysis may still involve the loss of a few genes or the disruption of a single gene at one of the chromosomal breakpoints and result in an abnormal phenotype, often including cognitive difficulties. Studying the breakpoints in such individuals has been one way of identifying the location of specific genes.

Unbalanced reciprocal translocations contain an ‘incorrect’ amount of chromosomal material and often impair both physical and cognitive development, leading to dysmorphic features, congenital malformations, developmental delay and learning difficulties. In a newborn baby, the prognosis is difficult to predict but the effect is usually severe. The parents’ chromosomes should be checked to determine whether the abnormality has arisen de novo, or as a consequence of a parental rearrangement. Finding a balanced translocation in one parent indicates a recurrence risk for future pregnancies, so that antenatal diagnosis by chorionic villus sampling or amniocentesis should be offered as well as testing relatives who might be carriers.

Deletions

Deletions are another type of structural abnormality. Loss of part of a chromosome usually results in physical abnormalities and cognitive impairment. The deletion may involve loss of the terminal or an interstitial part of a chromosome arm.

An example of a deletion syndrome involves loss of the tip of the short arm of chromosome 5, hence the name 5p- or monosomy 5p. Because affected babies have a high-pitched mewing cry in early infancy, it is also known as cri du chat syndrome. Parental chromosomes should be checked to see if one parent carries a balanced chromosomal rearrangement. The clinical severity varies greatly, depending upon the extent of the deletion. It is now possible to specify the genes involved in chromosomal deletions as molecular methods are replacing standard cytogenetic investigations.

An increasing number of syndromes are now known to be due to chromosome deletions too small to be seen by conventional cytogenetic analysis. Submicroscopic deletions can be detected by FISH studies using DNA probes specific to particular chromosome regions. FISH studies are useful when a specific chromosome deletion is suspected.

DiGeorge syndrome is associated with a deletion of band q11 on chromosome 22 (i.e. 22q11) (Fig. 8.7). Williams syndrome is another example of a microdeletion syndrome due to loss of chromosomal material at band q11 on the long arm of chromosome 7 (i.e. 7q11) (Fig. 8.18, see also Box 8.12).

Figure 8.7 Fluorescent in situ hybridisation (FISH) demonstrating a microdeletion on chromosome 22 associated with DiGeorge syndrome. Hybridisation signals are seen on one chromosome 22 but not on the other because of the presence of a deletion. (Courtesy of L. Gaunt, St Mary’s Hospital, Manchester.)

Mendelian inheritance

Mendelian inheritance, described by Mendel in garden peas in 1866, is the transmission of inherited traits or diseases caused by variation in a single gene in a characteristic pattern. These Mendelian traits or disorders are individually rare but collectively numerous and important: over 6000 have been described. For many disorders, the Mendelian pattern of inheritance is known. If the diagnosis of a condition is uncertain, its pattern of inheritance may be evident on drawing a family tree (pedigree), which is an essential part of genetic evaluation (Fig. 8.8).

Figure 8.8 Examples of pedigree symbols.

Autosomal dominant inheritance

This is the most common mode of Mendelian inheritance (Box 8.6). Autosomal dominant conditions are caused by alterations in only one copy of a gene pair, i.e. the condition occurs in the heterozygous state despite the presence of an intact copy of the relevant gene. Autosomal dominant genes are located on the autosomes (chromosomes 1–22) so males and females are equally affected. Each child from an affected parent has a 1 in 2 (50%) chance of inheriting the abnormal gene (Fig. 8.9a, b). This appears to be straightforward, but complicating factors include the following factors.

Autosomal dominant inheritance

Figure 8.9b Typical pedigree of an autosomal dominant disorder.

Summary

Autosomal dominant inheritance

• Most common mode of Mendelian inheritance

• Affected individual carries the abnormal gene on one of a pair of autosomes

• 1 in 2 chance of inheriting the abnormal gene from affected parent, but there may be variation in expression, non-penetrance, no family history (new mutation, parental mosaicism, non-paternity) or homozygosity (rare).

Autosomal recessive inheritance

Summary

Autosomal recessive inheritance

• Affected individuals are homozygous for the abnormal gene; each unaffected parent will be a heterozygous carrier

• Two carrier parents have a 1 in 4 risk of having an affected child

• Risk of these disorders is increased by consanguinity and within specific populations

• Autosomal recessive disorders often affect metabolic pathways, whereas autosomal dominant disorders often affect structural proteins.

Consanguinity

It is thought that we all carry 6–8 abnormal recessive genes. Fortunately, our partners usually carry different ones. Marrying a cousin or another relative increases the chance of both partners carrying the same abnormal autosomal recessive gene. Cousins who marry have a small increase in the risk of having a child with a recessive disorder.

The frequencies of disease alleles at recessive gene loci vary between racial groups. When the gene occurs sufficiently often and the gene or its effect can be detected, population-based carrier screening can be performed and antenatal diagnosis offered for high-risk pregnancies where both parents are carriers. Disorders that can be screened for in this way include sickle cell disease in black Africans and Afro-Americans, the thalassaemias in those from Mediterranean or Asian populations and Tay–Sachs disease in Ashkenazi Jews.

X-linked inheritance

X-linked conditions are caused by alterations in genes found on the X chromosome. These may be inherited as X-linked recessive or X-linked dominant traits but the distinction between these is much less clear than in autosomal traits because of the variable pattern of X chromosome inactivation in females.

In X-linked recessive inheritance (Box 8.8, Fig. 8.12a,b):

• Males are affected

• Female carriers are usually healthy

• Occasionally a female carrier shows mild signs of the disease (manifesting carrier)

• Each son of a female carrier has a 1 in 2 (50%) risk of being affected

• Each daughter of a female carrier has a 1 in 2 (50%) risk of being a carrier

• Daughters of affected males will all be carriers

• Sons of affected males will not be affected, since a man passes a Y chromosome to his son.

The family history may be negative, since new mutations and (gonadal) mosaicism are fairly common. Identification of carrier females in a family requires interpretation of the pedigree, the search for mild clinical manifestations and performing specific biochemical or molecular tests. Identifying carriers is important because a female carrier has a 50% risk of having an affected son regardless of who her partner is, and X-linked recessive disorders are often very severe.

Summary

X-linked recessive inheritance

• Males are affected; females can be carriers but are usually healthy or have mild disease

• Family history may be negative – new mutations and gonadal mosaicism

• Identifying female carriers is important to be able to provide genetic counselling.

X-linked dominant inheritance

X-linked disorders where the mutation has a dominant effect are rare. Both males and females are affected, e.g. hypophosphataemic (vitamin D-resistant) rickets. In some disorders, male lethality is expected and the only affected individuals seen will be female, e.g. incontinentia pigmenti. In others, the condition may affect females because it arises predominantly through mutations at spermatogenesis.

Y-linked inheritance

Y-linked traits are extremely rare. Y-linked inheritance would result in only males being affected, with transmission from an affected father to all his sons. Y-linked genes determine sexual differentiation and spermatogenesis, and mutations are associated with infertility and so are rarely transmitted.

Unusual genetic mechanisms

Trinucleotide repeat expansion mutations

This is a class of unstable mutations caused by unstable expansions of trinucleotide repeat sequences inherited in Mendelian fashion. Fragile X syndrome and myotonic dystrophy were among the first disorders found to be due to such mutations. Other disorders include Huntington disease, spinocerebellar ataxia and Friedreich’s ataxia. These disorders follow different patterns of inheritance but share certain unusual properties due to the nature of the underlying mutation. Clinical anticipation is often seen, with the disorders presenting at an earlier age and becoming more severe in successive generations of a family as the triplet expands, and with entirely new mutations being exceptionally rare. There are two major categories of triplet repeat disorder, depending upon whether or not the triplet repeat is in the coding sequence of the gene.

Fragile X syndrome

The prevalence of significant learning difficulties in males due to fragile X syndrome is about 1 in 4000 (Fig. 8.13 and Box 8.9). This condition was initially diagnosed on the basis of the appearance of an apparent gap or break (a fragile site) in the distal part of the long arm of the X chromosome. Diagnosis is now achieved by molecular analysis of the CGG trinucleotide repeat expansion in the relevant gene (FMR1).

Although it is inherited as an X-linked recessive disorder, a substantial proportion of obligate female carriers have learning difficulties (usually mild to moderate) and around one-fifth of males who inherit the mutation are phenotypically normal but may pass the disorder on to their grandsons through their daughters.

These unusual findings are explained by the nature of the mutation, which occurs in ‘pre-mutation’ and ‘full mutation’ forms. The normal copy of the gene contains fewer than 50 copies of the CGG trinucleotide repeat sequence and is stable when transmitted to offspring. Genes with the pre-mutation contain 55–199 copies of the repeat sequence. This expansion causes no intellectual disability in male or female carriers, but is unstable and may become larger during transmission through females. Genes with the full mutation contain more than 200 copies of the repeat sequence. This affects gene function, causing the clinical features of fragile X syndrome in virtually all males and around half of female carriers. These full mutations always arise from expansion of pre-mutations, and never arise directly from normal genes. Hence all mothers of affected males are carriers.

Fragile X

Box 8.9

Clinical findings in males in fragile X syndrome

• Moderate–severe learning difficulty (IQ 20–80, mean 50)

• Macrocephaly

• Macro-orchidism – postpubertal

• Characteristic facies – long face, large everted ears, prominent mandible and broad forehead, most evident in affected adults

• Other features – mitral valve prolapse, joint laxity, scoliosis, autism, hyperactivity.

Fragile X syndrome is the commonest familial form of learning difficulties and the second most common genetic cause of severe learning difficulties after Down syndrome.

Mitochondrial or cytoplasmic inheritance

Mitochondria are cytoplasmic organelles that function as major energy producers for the cell and contain their own DNA (mtDNA). Each cell contains thousands of copies of the mitochondrial genome. Inherited disorders of the mitochondria may result from mutations in the nuclear genome (the chromosomal genome of the cell nucleus) or in the mitochondria’s own genome. In disorders of the mtDNA, the mutation may be present in all or only some of the mitochondria, so that the tissues affected and the severity of the condition can be highly variable. Large deletions of the mtDNA can only be present in a proportion of the mitochondria as they would otherwise be lethal to the cell. Mutations in mtDNA cause overlapping clusters of disease phenotypes (e.g. Leber hereditary optic neuropathy and various mitochondrial myopathies and encephalopathies, MERFF, MELAS, NARP). Mitochondrial DNA mutations show only maternal transmission, since only the egg contributes mitochondria to the zygote.

Imprinting and uniparental disomy

In the past, it was assumed that the activity of a gene is the same regardless of whether it is inherited from the mother or father. It has been shown that the expression of some genes is influenced by the sex of the parent who had transmitted it. This phenomenon is called ‘imprinting’. An example involves Prader–Willi syndrome (PWS) (hypotonia, developmental delay, hyperphagia and obesity). The PWS chromosomal region is found at 15q11–13 (i.e. at bands 11–13 on the long arm of chromosome 15). The paternal copy of this chromosomal region has to function for normal development; in its absence, a child will develop PWS. Failure to inherit a functioning maternal copy of this chromosomal region results in an entirely different condition, Angelman syndrome (AS) (causing severe cognitive impairment, a characteristic facial appearance, ataxia and epilepsy), because only the maternal copy of one particular gene in this region is able to function (the paternal copy is inactive because of imprinting). There are two main ways that a child can develop one or other condition:

• De novo deletion (Fig. 8.14). Parental chromosomes are normal, and a deletion occurs as a new mutation in the child. If the deletion occurs on the paternal chromosome 15, the child has Prader–Willi syndrome. If the deletion affects the maternal chromosome 15, the child has Angelman syndrome.

• Uniparental disomy (Fig. 8.15). This is when a child inherits two copies of a chromosome from one parent and none from the other parent. In Prader–Willi syndrome the affected child has no paternal (but two maternal) copies of chromosome 15q11–13. In Angelman syndrome, the affected child has no maternal (but two paternal) copies of chromosome 15q11–13. This can be detected with DNA analysis.

• There exist other mechanisms that can lead to these conditions.

Imprinting

Figure 8.15 Genetic disorder resulting from uniparental disomy affecting imprinted chromosome region. A child who inherits two maternal chromosome 15s will have Prader–Willi syndrome. A child who inherits two paternal chromosome 15s will have Angelman syndrome.

Imprinting is the unusual property of some genes that express only the copy derived from the parent of a given sex.

Polygenic, multifactorial or complex inheritance

There is a spectrum in the aetiology of disease, from environmental factors (e.g. trauma) at one end to purely genetic causes (e.g. Mendelian disorder) at the other. Between these two extremes are many disorders which result from the interacting effects of several genes (hence the term polygenic) with or without the influence of environmental or other unknown factors, including chance (multifactorial or complex). The terms are used interchangeably (Box 8.10).

Normal quantitative traits such as height and intelligence are inherited in this fashion, with many relevant influences including genetic constitution, environmental exposures and early life (including intrauterine) experiences. These parameters show a Gaussian (or ‘normal’) distribution in the population. Similarly, the liability of an individual to develop a disease of multifactorial or polygenic aetiology has a Gaussian distribution. The condition occurs when a certain threshold level of liability is exceeded. Relatives of an affected person show an increased liability due to inheritance of genes conferring susceptibility, and so a greater proportion of them than in the general population will fall beyond the threshold and will manifest the disorder (Fig. 8.16). The risk of recurrence of a polygenic disorder in a family is usually low and is most significant for first-degree relatives. Empirical recurrence risk data are used for genetic counselling. They are derived from family studies that have reported the frequency at which various family members are affected. Factors that increase the risk to relatives are:

• having a more severe form of the disorder, e.g. the risk of recurrence to siblings is greater in bilateral cleft lip and palate than in unilateral cleft lip alone

• close relationship to the affected person, e.g. overall risk to siblings or children is greater than to more distant relatives

• multiple affected family members, e.g. the more siblings already affected, the greater the risk of recurrence

• sex difference in prevalence, with the recurrence risk greater in the more commonly affected sex and if the affected individual is of the less commonly affected sex.

The phenotype (clinical picture) of a disorder may have a heterogeneous (mixed) basis in different families; e.g. hyperlipidaemia leading to atherosclerosis and coronary heart disease can be due to a single gene disorder such as autosomal dominant familial hyper-cholesterolaemia, but some forms of hyperlipidaemia are polygenic and result from an interaction of the effect of several genes and dietary factors on various lipoproteins.

In some complex disorders, such as Hirschsprung disease, the molecular genetic basis and the important contribution of new mutations is becoming clear.

Multifactorial, polygenic or complex inheritance

Figure 8.16 Diagram showing the increased liability to a multifactorial disorder in relatives of an affected person.

In many multifactorial disorders, the ‘environmental factors’ remain obscure. Clear exceptions include dietary fat intake and smoking in atherosclerosis, and viral infection in insulin-dependent diabetes mellitus. For neural tube defects, the risk of recurrence to siblings is lowered from about 4% to 1% or less in future pregnancies if the mother takes folic acid before conception and in the early weeks of pregnancy.

Refers to a pattern of multiple abnormalities occurring after one initiating defect. Potter syndrome (fetal compression and pulmonary hypoplasia) is an example of a sequence in which all abnormalities may be traced to one original malformation, renal agenesis.

Association

A group of malformations that occur together more often than expected by chance, but in different combinations from case to case, e.g. VACTERL association (Vertebral anomalies, Anal atresia, Cardiac defects, Tracheo-oEsophageal fistula, Renal anomalies, Limb defects).

Syndrome

When a particular set of multiple anomalies occurs repeatedly in a consistent pattern and there is known or thought to be a common underlying causal mechanism, this is called a ‘syndrome’. Multiple malformation syndromes are often associated with moderate or severe cognitive impairment and may be due to:

• chromosomal defects

• a single gene defect (dominant, recessive or sex-linked)

• exposure to teratogens such as alcohol, drugs (especially anticonvulsants such as valproate, carbamazepine and phenytoin) or viral infections during pregnancy

• unknown cause.

Syndrome diagnosis

Although most syndromes are individually rare, recognition of a dysmorphic syndrome is worthwhile as it may give information regarding:

• risk of recurrence

• prognosis

• likely complications which can be sought and perhaps treated successfully if detected early

• the avoidance of unnecessary investigations

• experience and information which parents can share with other affected families through family support groups.

Examples of syndromes recognisable by facial appearance are shown in Figures 8.17–8.19 (see also Boxes 8.11–8.13). The importance and impact of syndrome diagnosis is demonstrated in Case History 8.1. Databases are available to assist with the recognition of thousands of multiple congenital anomaly syndromes (e.g. London Dysmorphology Database (LDDB) & POSSUM).

Syndromes recognised by ‘Gestalt’ (clinical recognition)

Figure 8.18 Williams syndrome is usually sporadic.

Box 8.11

Clinical features of Noonan syndrome

• Characteristic facies

• Occasional mild learning difficulties

• Short webbed neck with trident hair line

• Pectus excavatum

• Short stature

• Congenital heart disease (especially pulmonary stenosis, atrial septal defect).

Box 8.12

Clinical features of Williams syndrome

• Short stature

• Characteristic facies

• Transient neonatal hypercalcaemia (occasionally)

• Congenital heart disease (supravalvular aortic stenosis)

• Mild to moderate learning difficulties.

Summary

Dysmorphology

• comprises birth defects and abnormal clinical features originating during embryogenesis

• may be a malformation, deformation, disruption or dysplasia

• may be classified as a single-system defect, sequence, association or syndrome

• syndromes are recognised by ‘Gestalt’ (clinical recognition).

Case History

8.1 Syndrome diagnosis and genetic counselling

Sean, the second child of healthy parents, was born at term by emergency caesarean section for fetal distress. The pregnancy had been uneventful and no abnormalities were detected on antenatal ultrasound scan. He developed respiratory distress and investigation for a cardiac murmur revealed an interrupted aortic arch and ventricular septal defect that required surgical correction in the neonatal period.

The parents asked about recurrence risk for congenital heart disease and were referred to the genetic clinic. At that time, Sean was thriving and early developmental progress appeared normal. On examination, there were minor dysmorphic features, including a short philtrum, thin upper lip and prominent ears (Fig. 8.20). There was no family history of congenital heart disease or other significant problems and no abnormalities were detected on examination of the parents.

Figure 8.20 Sean’s facial appearance showing the short philtrum (vertical groove in the upper lip), thin upper lip and prominent ears.

Because of an association between outflow tract abnormalities of the heart and deletions of chromosome 22, cytogenetic analysis was performed using fluorescent in situ hybridisation (FISH). A submicroscopic deletion of the long arm of one chromosome 22 (band 22q11) was detected. Other features of DiGeorge syndrome (hypocalcaemia and T-cell deficiency), which occurs with the same chromosome deletion, were excluded by appropriate tests but could have been important in Sean’s medical management.

Parental chromosome analysis showed no deletion at chromosome 22q11 in either parent, indicating a low recurrence risk for future pregnancies since gonadal mosaicism for this deletion is very rare. The older sibling was also normal on testing. Because the parents had normal karyotypes, their own brothers and sisters did not need to be offered tests.

Identification of a 22q11 deletion indicated that other associated problems were likely. Subsequently, Sean required assessment by a multidisciplinary child development team (for developmental delay), that led to educational statementing and recommendation for appropriate placement in a school for children with special educational needs (learning difficulty), input from a clinical psychologist when behavioural problems appeared (ritualistic behaviour and obsessional tendencies), input from speech therapist and plastic surgeon (indistinct speech due to velopharyngeal incompetence) and audiology review (conductive hearing loss due to recurrent otitis media).

The impact of the diagnosis and its implications was considerable for the family and the parents needed support from a variety of professionals while coming to terms with the various problems as they became apparent. Written information and details of the 22q11 support group were given to the parents. Medical care was coordinated by the paediatrician.

There was the additional worry for the family about a subsequent pregnancy. Fetal echocardiography showed no evidence of congenital heart disease, but invasive tests for cytogenetic analysis were declined because of the low recurrence risk. The baby was born unaffected, with chromosome studies performed on a cord blood sample revealing no abnormality.

Gene-based therapies

The treatment of most genetic disorders is based on conventional therapeutic approaches.

Gene therapy involves the repair, suppression or artificial introduction of genes into genetically abnormal cells with the aim of curing the disease and is at an experimental stage for most genetic conditions being studied. There are still many technical and safety issues to be resolved. Gene therapy has been initiated in adenosine deaminase deficiency (a rare recessive immune disorder), malignant melanoma and cystic fibrosis, and some clinical benefit has been reported in a few patients. At present, it is generally accepted that gene therapy should be limited to somatic (not germline) cells, so that the risk of adversely affecting future generations is minimised.

However, other treatments based upon a genetic understanding of disease are being introduced into practice. Two examples are:

• Suppressors of nonsense (stop codon, chain-terminating) mutations, which are under trial in patients with cystic fibrosis and Duchenne muscular dystrophy caused by the appropriate mutations.

• Antisense oligo-DNA molecules that cause the skipping of specific exons in the Duchenne muscular dystrophy gene, i.e. complementary DNA molecules that bind and block exons around the faulty part of the gene (often deletions or duplications in Duchenne muscular dystrophy). This approach can restore the reading frame of the message downstream of the causal deletion; it is hoped that this will result in a milder form of the disease.

Genetic services

In the UK, all health regions have a clinical genetics centre where specialist genetic services are provided by consultants and other medical staff, genetic counsellors and laboratory scientists. Specialist genetic investigations and counselling are provided at the centre and at secondary and primary care. Increased recognition of disorders antenatally has necessitated expansion of perinatal genetic services in addition to paediatric and adult services.

Genetic investigations

For many years genetic investigation relied on determining the karyotype by visualisation under the microscope. This has been transformed by the tremendous advances in molecular testing.

DNA analysis using polymerase chain reaction (PCR) allows rapid analysis on small samples. Its main impact for genetic counselling is:

• Confirmation of a clinical diagnosis of an increasing number of single gene disorders

• Detection of female carriers in X-linked disorders, e.g. Duchenne and Becker muscular dystrophies, haemophilia A and B

• Carrier detection in autosomal recessive disorders, e.g. cystic fibrosis

• Presymptomatic diagnosis in autosomal dominant disorders, e.g. Huntington disease, myotonic dystrophy, familial cancer syndromes

• Antenatal diagnosis of an increasing number of Mendelian conditions.

These are accomplished by the following.

Mutation analysis

For an increasing number of Mendelian disorders, it is possible to directly detect the actual mutation causing the disease. This provides very accurate results for confirmation of diagnosis, and presymptomatic or predictive testing. Identifying the mutation in an affected individual may be very time-consuming, but once this has been done, testing other relatives is usually fairly simple. Examples are:

• Deletions: large deletion mutations are common in a variety of disorders including Duchenne and Becker muscular dystrophies, alpha-thalassaemia and 21-hydroxylase deficiency (congenital adrenal hyperplasia).

• Point mutations and small deletions: these can be readily identified if the same mutation causes all cases of the disorder, as in sickle cell disease. For most disorders, however, there is a spectrum of mutations. About 78% of cystic fibrosis carriers in the UK possess the ΔF508 mutation, but over 900 other mutations have been identified. Most laboratories test for a certain number of the most common mutations in the population they serve.

• Trinucleotide repeat expansion mutations: these are readily tested for because the mutation in a given disease is virtually always at the same site and can be amplified from the same oligo-DNA primers used in the amplification by PCR: the only difference is the size of the repeat sequence, which can be determined from the size of the DNA fragment containing the repeat.

Genetic linkage

If mutation analysis is not available, it may be possible to use DNA sequence variations (markers) located near to, or within, the disease gene to track the inheritance of this gene through a family. This type of analysis requires a suitable family structure and several key members need to be tested to identify appropriate markers before linkage testing can be used in diagnostic, predictive or prenatal testing.

Some of the genetic investigations now available are summarised in Table 8.2.

Table 8.2

Genetic investigations

Investigation	Application
Cytogenetic analysis – karyotype	Chromosomes stained and visualised under a microscope
Cytogenetic analysis – karyotype	Detects alterations in chromosome number and structural rearrangements; this method is being replaced by molecular methods such as CGH.
Molecular cytogenetic analysis – FISH (fluorescent in situ hybridisation)	Fluorescent-labelled DNA probes to detect the presence, number and chromosomal location of specific chromosomal sequences
	Useful for microdeletion syndromes
Microarray comparative genomic hybridisation (aCGH)	Detects chromosomal imbalances using thousands of DNA probes to investigate a whole genome with much greater sensitivity than cytogenetic methods
DNA analysis	Polymerase chain reaction (PCR) to amplify the DNA and determine the sequence of the relevant gene
High throughput DNA sequencing	Rapid sequencing of whole genomes or many loci within the genome
Linkage disequilibrium and genome-wide association studies (GWAS)	Comparing the frequency of combinations of alleles at nearby loci in a given population to identify genetic variants associated with complex diseases