J. Langdon Down originally described the syndrome in 1887. Trisomy 21 is associated with Down syndrome, and was first reported by Lejeune and colleagues in 1958. About 1 in 600 live
born children have Down syndrome. The rate increases with increasing maternal age, being about 1 in 2000 at maternal age 20 years and 1 in 100 at maternal age of 40 years.⁽⁴⁾ There are three types of abnormalities affecting chromosome 21. In about 94 per cent of cases, Down syndrome is caused by primary non-disjunction leading to trisomy 21. The risk of recurrence of this abnormality is low if maternal age is also relatively low. In about 2 per cent of cases Down syndrome results from an unbalanced translocation (when material from one chromosome is separated and attached to another with some duplication). This often involves chromosomes 21 and 14. In some cases a parent also has a balanced translocation (with no overall disruption or duplication of genetic material), and this raises the risk of recurrence. Chromosome 21 to 21 translocations can occur. Mosaicism occurs when there are two or more cell lines within the body. In Down syndrome there may be one cell line with trisomy 21 and one without. In about 2 per cent of cases the syndrome results from mosaicism. Some cases may not be diagnosed. The proportion of affected and unaffected cell lines varies, as does the intellectual impairment.

Muscular hypotonia at birth usually improves with development. Most adults are of short stature and have a characteristic facial appearance. The eyes seem to slope upwards and outwards, the nose has a wide bridge and the head has an unusual shape (brachycephaly). Limb abnormalities include a single transverse crease on the palm, a large cleft between the first and second toes, and relatively short upper arms. People with Down syndrome are prone to thyroid abnormalities. About 25 per cent develop hypothyroidism during childhood or adolescence. About half of affected people have a heart abnormality. Abnormalities of the gastro-intestinal tract occur in a significant minority. Life expectancy has improved markedly over the past 50 years. Survival into the eighth decade is unusual but not extraordinary. Changes in blood cells are relatively common. Older texts reported an association between Down syndrome and leukaemia, but recent research suggests that leukaemia is rare, affecting less than 1 per cent of people with Down syndrome.

Adults with Down syndrome are much more likely to develop dementia than the general population. On post-mortem examination, the brains of almost all adults with Down syndrome over the age of 35 show changes characteristic of dementia of Alzheimer type. Only about 38 per cent of those aged 50 to 59 have clinically apparent dementia, with a mean age at diagnosis around 51 years.^(5,6)

The stereotype of people with Down syndrome as happy, placid individuals with a gift for mimicry is not borne out by recent behavioural research. Stubbornness and obsessional features seem to be over-represented, and many people with Down syndrome react adversely in situations involving changes to expected routines or conflict. Autism seems to occur more commonly than would be expected, but few methodologically sound studies have been carried out.⁽⁷⁾

Most adults with Down syndrome have moderate intellectual disability. Almost all children with Down syndrome have some degree of specific speech and language delay. About 25 per cent have features of attention-deficit disorder. Cognitive abilities tend to be greater among people whose Down syndrome is caused by mosaicism for trisomy 21.

Further information: www.downs-syndrome.org.uk

The syndrome was first described in 1943. All ethnic groups are affected equally, with a frequency of about 0.3 per 1000 in men. More recent investigations with modern diagnostic techniques show lower figures than earlier studies.⁽¹³⁾

Fragile-X syndrome is an X-linked disorder with a very unusual pattern of inheritance. It is characterized by a bias to affected men but with some affected women and some unaffected men who have daughters who then have affected sons. When peripheral blood lymphocytes from affected individuals are grown in certain culture conditions, including a lack of folic acid, a fragile site becomes evident on the long (q) arm of the X chromosome at Xq27.3 (fragile site A). Fragile sites may not be seen in some unaffected men who transmit the abnormality to their carrier daughters. These men were historically termed ‘normal transmitting males’. The probability that a child with a fragile-X chromosome will have intellectual disability depends on the sex of the parent from whom the chromosome was inherited (higher risk when the chromosome is passed from the mother). The ‘fragility’ of the X chromosome is now known to be associated with an unstable region of DNA within the fragile-X mental retardation (FMR-1) gene, which was first described in 1991.⁽¹⁴⁾ This region of unstable DNA gradually increases in length and degree of instability in successive generations (a pre-mutation) until a critical point is reached and the gene no longer functions (a full mutation). The instability is caused by an increase in CGG (cytosine-guanine-guanine) repeats from the 50 or so repeats that are usual to 50-100 repeats (pre-mutation)
to over 230 repeats (full mutation). The chance of a child inheriting a lengthened gene is proportional to the length of the unstable region in the carrier mother. The severity of intellectual disability and other fragile-X related phenomena in women probably depends mostly on the proportion of cells in which the abnormal chromosome is inactivated, X inactivation being random. Most women who have children with fragile-X syndrome are premutation carriers of normal intelligence.⁽¹⁵⁾ Carriers of the premutation are intellectually unimpaired but are more vulnerable than other women to anxiety and depression.⁽¹⁶⁾ Variants of fragile-X syndrome have now been identified, with DNA expansions nearer to the end of the long arm of the X chromosome. These include FraX-E and FraX-F.

Physical features are variable. The most characteristic feature is that about 95 per cent of affected men have large testes, although macro-orchidism is not usually apparent until after puberty. Other features include a long face with a large forehead, large ears, a large lower jaw, and high-arched palate. There is a connective tissue disorder that may lead to tissue laxity with hyper-extensible joints, flat feet, heart defects (especially valve abnormalities), and ear infections (the eustachian tube closes easily). Cataracts and other eye abnormalities may occur, and lead to impaired vision. About 30 per cent of affected men have epilepsy. Life expectancy depends on the severity of associated features such as epilepsy and cardiovascular anomalies.

There is usually some degree of social impairment, with social anxiety and avoidance of eye-to-eye contact, but with social responsiveness. Men with fragile-X are usually affectionate, and do not have the aloof quality typical of autism. Self-injury is relatively common, especially hand biting over the anatomical snuff-box (between the bases of the thumb and index finger) in response to frustration, anxiety, or excitement. Stereotyped behaviours such as hand flapping are common.

The associated intellectual disability is usually mild to moderate. Verbal intelligence scores exceed performance scores among populations of affected men and non-disabled women carriers. Speech and language development is delayed. Speech is often disorganized, with rambling and circuitous conversation, incomplete sentences, poor topic maintenance, tangential comments, echolalia, and perseveration. It may be rapid, or include peculiar changes in pitch.

There may be problems with attention and concentration that are disproportionate to the severity of the associated learning disability. Hyperactivity may be the presenting feature among boys with fragile-X who do not have intellectual disability.

Further information can be obtained from Hagerman and Hagerman (2002)⁽¹⁷⁾ and www.fragilex.org.uk.

This is a disorder characterized by additional X chromosomes in phenotypic males. Two-thirds have a 47 XXY chromosome complement. Prevalence at birth is about 1 in 1000 live males, with a frequency in prenatally karyotyped male foetuses of 1 in 470.⁽¹⁹⁾

Height, weight, and head circumference are below average at birth. Increased growth, especially of legs occurs from 3 years of age onwards. Affected men are usually taller than their fathers, and mean heights are around the 75th centile. Head size remains small. Puberty normally occurs, but testosterone production falls in early adult life. Affected adults have a normal-sized penis but small testes. About 60 per cent have some breast enlargement. Life expectancy is thought to be normal.

Boys with XXY are typically introverted and less assertive and sociable than other children, with poorer school performance (especially with regard to reading and spelling). Adults may have increased rates of antisocial behaviour and impulsiveness. The IQ distribution is skewed downwards, although measured full scale IQs run from the 60s to the 130s. Performance scores usually exceed verbal scores. Most affected children receive speech and language therapy, and expressive language deficits are often more pronounced than problems with receptive language. One follow-up study has been reported.⁽²⁰⁾ Further information: www.klinefeltersyndrome.org.

The genetic abnormality in Turner syndrome is the loss or abnormality of one X chromosome in women. The 45,X karyotype is found in about 1 in 10000 live female births. The abnormality is much more common at conception. About 99 per cent of affected foetuses are miscarried, and 45,X is the most common karyotype found in chromosomally aborted foetuses. About 50 per cent have a 45,X chromosome complement (a very small proportion of normal cell lines may be present). Most of the other cases are the result of mosaicism, some are the result of structural abnormalities of an X chromosome.

Affected children have a short stature in childhood. Ovarian failure occurs before birth, and puberty does not usually occur naturally, although childbirth has, rarely, been reported. Dysmorphic features include a webbed neck, low hairline at the rear of the head, widely spaced nipples and multiple pigmented naevi. About 12 per cent have coarctation of the aorta or a ventricular septal defect.

Hyperactivity and distractibility are common in childhood. Poor social skills, with immature social relationships and low self-esteem in adolescence were reported in one study.⁽²¹⁾ Women with Turner syndrome are usually of normal intelligence and verbal abilities are usually unimpaired or enhanced. Specific cognitive abnormalities including deficits in spatial perception, visual motor integration, affect recognition, visual memory, and attention have been reported.⁽²²⁾ The relative strength in verbal tasks may lead to an
overestimation of abilities. There is considerable variation in cognitive profile between affected women. Further information: www.tss.org.uk

The 47,XXX syndrome occurs about 1 in 1000 female births.⁽²³⁾ Many are not diagnosed. There is a primary non-disjunction of a maternal or paternal X chromosome. The 48,XXXX chromosome complement is much rarer (about 40 cases have been reported so far).

In 47,XXX syndrome newborn babies have a low birth weight and small head circumference. Height in adult life is usually increased, with a low body mass index. Fertility is not usually impaired, although there are reports of premature ovarian failure and recurrent spontaneous abortion. There may be deficits in balance or fine motor coordination. Life expectancy is thought to be normal.

Underactivity and withdrawal have been reported. Emotional development may be slowed. About a quarter of affected women in one follow-up study had repeated episodes of abdominal pain as teenagers for which no organic cause could be found.⁽²⁴⁾ Most appear to adapt to adult life without difficulties. Women with the syndrome usually have IQs between 80 and 90. Women with XXXX syndrome have lower IQs (55 to 75). An expressive language delay is typical. Some have a relatively poor short-term auditory memory. Further information: www.triplo-x.org.

This karyotype is associated with 1 in 1000 live male births.⁽²³⁾ There is a primary non-disjunction of the Y chromosome. About 10 per cent have mosaic 46,XY/47,XYY chromosome complement. Offsprings rarely have two Y chromosomes. Affected individuals show increase in body and leg length between years 4 and 9. Most are over 10 cm taller than their fathers as adults. Sexual development and fertility are unaffected. Balance and coordination may be minimally compromised. Life expectancy is normal.

Early research found an increased frequency of XYY men among inmates of special prisons.^(25,26) More recent studies examining the relationship between 47,XYY karyotype and behaviour have concluded that affected men have lower mean intelligence scores (with a large overlap with the normal range) and poorer social adaptation. Distractibility, hyperactivity, temper tantrums, and speech and language problems appear relatively common in childhood. There is little evidence to suggest a significant link with seriously aggressive criminal conduct in adult life.^(27,28)

Exposure of the developing foetus to significant amounts of alcohol leads to cognitive impairment. The effect can occur during any stage of pregnancy, because brain development continues during all three trimesters. Dysmorphology, including a facial dysmorphology, can also occur. Foetal alcohol spectrum disorder (FASD) includes a number of subtypes including foetal alcohol syndrome (FAS), and more subtle abnormalities subsumed under the terms possible foetal alcohol effects (PFAE), prenatal exposure to alcohol (PEA), or alcohol-related neurodevelopmental disorder (ARND).

Foetal alcohol exposure is thought to be a common cause of intellectual disability in the United States and other developed countries. In the United States, an estimate of 0.33 per 1000 births has been given for the prevalence of foetal alcohol syndrome.⁽²⁹⁾ Alcohol inhibits N-methyl-D-aspartate receptors, which mediate postsynaptic excitatory effects of glutamate, and this is thought to have an effect on cell proliferation.⁽³⁰⁾