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

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

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.

Edwards syndome and Patau syndrome

Box 8.2 Clinical features of Edwards syndrome (trisomy 18)

• Low birthweight

• Prominent occiput

• Small mouth and chin

• Short sternum

• Flexed, overlapping fingers (Fig. 8.5)

• ‘Rocker-bottom’ feet

• Cardiac and renal malformations.

Box 8.3

Clinical features of Patau syndrome (trisomy 13)

• Structural defect of brain

• Scalp defects

• Small eyes (microphthalmia) and other eye defects

• Cleft lip and palate

• Polydactyly

• Cardiac and renal malformations.

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

Box 8.4

Clinical features of Turner syndrome

• Lymphoedema of hands and feet in neonate, which may persist

• Spoon-shaped nails

• Short stature – a cardinal feature

• Neck webbing or thick neck

• Wide carrying angle (cubitus valgus)

• Widely spaced nipples

• Congenital heart defects (particularly coarctation of the aorta)

• Delayed puberty

• Ovarian dysgenesis resulting in infertility, although pregnancy may be possible with in vitro fertilisation (IVF) using donated ova

• Hypothyroidism

• Renal anomalies

• Pigmented moles

• Recurrent otitis media

• Normal intellectual function in most.

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

Box 8.6 Examples of autosomal dominant disorders