Incidence

The overall birth incidence, when adjusted for the increasingly widespread impact of antenatal screening, is approximately 1 : 1000 in the United Kingdom, which has a national register. In the United States, the birth incidence has been estimated at approximately 1 : 800. In the United Kingdom, approximately 60% of Down syndrome cases are detected prenatally. There is a strong association between the incidence of Down syndrome and advancing maternal age (Table 18.4).

Table 18.4 Incidence of Down Syndrome in Relation to Maternal Age

Adapted from Cuckle HS, Wald NJ, Thompson SG 1987 Estimating a woman’s risk of having a pregnancy associated with Down syndrome using her age and serum alpha-fetoprotein level. Br J Obstet Gynaecol 94:387–402.

Clinical Features

These are summarized in Box 18.1. The most common finding in the newborn period is severe hypotonia. Usually the facial characteristics of upward sloping palpebral fissures, small ears, and protruding tongue (Figures 18.2 and 18.3) prompt rapid suspicion of the diagnosis, although this can be delayed in very small or premature babies. Single palmar creases are found in 50% of children with Down syndrome (Figure 18.4), in contrast to 2% to 3% of the general population. Congenital cardiac abnormalities are present in 40% to 45% of babies with Down syndrome, with the three most common lesions being atrioventricular canal defects, ventricular septal defects, and patent ductus arteriosus.

FIGURE 18.2 A child with Down syndrome.

FIGURE 18.3 Close-up view of the eyes and nasal bridge of a child with Down syndrome showing upward sloping palpebral fissures, Brushfield spots, and bilateral epicanthic folds.

FIGURE 18.4 The hands of an adult with Down syndrome. Note the single palmar crease in the left hand plus bilateral short curved fifth fingers (clinodactyly).

Natural History

Affected children show a broad range of intellectual ability with IQ scores ranging from 25 to 75. The average IQ of young adults is around 40 to 45. Social skills are relatively well-advanced and most children are happy and very affectionate. Adult height is usually around 150 cm. In the absence of a severe cardiac anomaly, which leads to early death in 15% to 20% of cases, average life expectancy is 50 to 60 years. Most affected adults develop Alzheimer disease in later life, possibly because of a gene dosage effect—the amyloid precursor protein gene is on chromosome 21. This gene is known to be implicated in some familial cases of Alzheimer disease (p. 243).

Chromosome Findings

These are listed in Table 18.5. In cases resulting from trisomy 21, the additional chromosome is maternal in origin in more than 90% of cases, and DNA studies have shown that this arises most commonly as a result of non-disjunction in maternal meiosis I (p. 39). Robertsonian translocations (p. 47) account for approximately 4% of all cases, in roughly one-third of which a parent is found to be a carrier. Children with mosaicism are often less severely affected than those with the full syndrome.

Table 18.5 Chromosome Abnormalities in Down Syndrome

Efforts have been made to correlate the various clinical features in trisomy Down syndrome with specific regions of chromosome 21, by studying children with partial trisomy for different regions. There is some support for a Down syndrome ‘critical region’ at the distal end of the long arm (21q22), because children with trisomy for this region alone usually have typical Down syndrome facial features. Chromosome 21 is a ‘gene-poor’ chromosome with a high ratio of AT to GC sequences (p. 69). At present the only reasonably well-established genotype-phenotype correlation in trisomy 21 is the high incidence of Alzheimer disease.

Recurrence Risk

For straightforward trisomy 21, the recurrence risk is related to maternal age (variable) and the simple fact that trisomy has already occurred (∼1%). The combined recurrence risk is usually between 1 : 200 and 1 : 100. In translocation cases, similar figures apply if neither parent is a carrier. In familial translocation cases, the recurrence risks vary from around 1% to 3% for male carriers up to 10% to 15% for female carriers, with the exception of very rare carriers of a 21q21q translocation, for whom the recurrence risk is 100% (p. 48).

Prenatal diagnosis can be offered based on analysis of chorionic villi or cultured amniotic cells. Prenatal screening programs have been introduced based on the so-called triple or quadruple tests of maternal serum at 16 weeks’ gestation (p. 328).

Hypomelanosis of Ito

Several children with mosaicism for diploidy/triploidy have been identified. These can demonstrate the clinical picture seen in full triploidy but in a milder form. An alternative presentation occurs as the condition known as hypomelanosis of Ito. In this curious disorder, the skin shows alternating patterns of normally pigmented and depigmented streaks that correspond to the embryological developmental lines of the skin known as Blaschko’s lines (see Figure 18.7). Most children with hypomelanosis of Ito have moderate learning difficulties and convulsions that can be particularly difficult to treat. There is increasing evidence that this clinical picture represents a non-specific embryological response to cell or tissue mosaicism. A similar pattern of skin pigmentation is sometimes seen in women with one of the rare X-linked dominant disorders (p. 117) with skin involvement, such as incontinentia pigmenti (see Figure 7.18, p. 118). Such women can be considered as being mosaic, as some cells express the normal gene, whereas others express only the mutant gene.

FIGURE 18.7 Mosaic pattern of skin pigmentation on the arm of a child with hypomelanosis of Ito.

(Reproduced with permission from Jenkins D, Martin K, Young ID 1993 Hypomelanosis of Ito associated with mosaicism for trisomy 7 and apparent ‘pseudomosaicism’ at amniocentesis. J Med Genet 1993; 30:783–784.)

Clinical Features

In childhood the presentation may be with clumsiness or mild learning difficulties, particularly in relation to verbal skills. The overall verbal IQ is reduced by 10 to 20 points below unaffected siblings and controls, and children can be rather self-obsessed in their behavior. Adults tend to be slightly taller than average with long lower limbs. Approximately 30% show moderately severe gynecomastia (breast enlargement) and all are infertile because of the absence of sperm in their semen (azoospermia), with small, soft testes. Fertility has been achieved for a small number of affected males using the techniques of testicular sperm aspiration and intracytoplasmic sperm injection. There is an increased incidence of leg ulcers, osteoporosis, and carcinoma of the breast in adult life. Treatment with testosterone from puberty onward is beneficial for the development of secondary sexual characteristics and the long-term prevention of osteoporosis.

Chromosome Findings

Usually the karyotype shows an additional X chromosome. Molecular studies have shown that there is a roughly equal chance that this will have been inherited from the mother or from the father. The maternally derived cases are associated with advanced maternal age. A small proportion of cases show mosaicism (e.g., 46,XY/47,XXY). Rarely, a male with more than two X chromosomes can be encountered, for example 48,XXXY or 49,XXXXY. These individuals are usually quite severely retarded and also share physical characteristics with Klinefelter men, often to a more marked degree.

Clinical Features

Presentation can be at any time from pregnancy to adult life. Increasingly, Turner syndrome is being detected during the second trimester as a result of routine ultrasonography, showing either generalized edema (hydrops) or swelling localized to the neck (nuchal cyst or thickened nuchal pad) (Figure 18.8). At birth many babies with Turner syndrome look entirely normal. Others show the residue of intrauterine edema with puffy extremities (Figure 18.9) and neck webbing. Other findings may include a low posterior hairline, increased carrying angles at the elbows, short fourth metacarpals, widely spaced nipples, and coarctation of the aorta, which is present in 15% of cases.

FIGURE 18.8 Ultrasonographic scan at 18 weeks’ gestation showing hydrops fetalis. Note the halo of fluid surrounding the fetus.

(Courtesy Dr. D. Rose, City Hospital, Nottingham, UK.)

FIGURE 18.9 The foot of an infant with Turner syndrome showing edema and small nails.

Intelligence in Turner syndrome is normal. However, studies have shown some differences in social cognition and higher order executive function skills according to whether the X chromosome was paternal or maternal in origin (p. 105). The two main medical problems are short stature and ovarian failure. The short stature becomes apparent by mid-childhood, and without growth hormone treatment the average adult height is 145 cm. This short stature is due, at least in part, to haploinsufficiency for the SHOX gene, which is located in the pseudoautosomal region (p. 118). Ovarian failure commences during the second half of intrauterine life and almost invariably leads to primary amenorrhea and infertility. Estrogen replacement therapy should be initiated at adolescence for the development of secondary sexual characteristics and long-term prevention of osteoporosis. In vitro fertilization using donor eggs offers the prospect of pregnancy for women with Turner syndrome.

Chromosome Findings

These are summarized in Table 18.6. The most common finding is 45,X (sometimes erroneously referred to as 45,XO). In 80% of cases, it arises through loss of a sex chromosome (X or Y) paternal meiosis. In a significant proportion of cases, there is chromosome mosaicism and those with a normal cell line (46,XX) have a chance of being fertile. Some cases with a 46,XY cell line are phenotypically male, and all cases with some Y-chromosome material in their second cell line must be investigated for possible gonadal dysgenesis—intracellular male gonads can occasionally become malignant and require surgical removal.

Table 18.6 Chromosome Findings in Turner Syndrome