Down Syndrome

Clinical Features, Genes and Therapeutics

Clinical features of Down syndrome
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Down Syndrome (also known as trisomy 21) is a chromosome disorder characterized by craniofacial features such as a flat occiput, epicanthal folds, and a large tongue. In addition, a patient usually has low-set ears, a thick neck, short stature, and obesity. Strongly correlated with advanced maternal age, Down syndrome is the single most common cause of mental retardation.

About 1 child in 800 is born with Down syndrome, and almost live-born children or fetuses of mothers 35 years of age or older, the incidence rate is far higher.

At birth, a baby with Down syndrome will generally present with hypotonia and a single palmar crease along with the typical craniofacial features, which may aid in the diagnosis.

Down syndrome is associated with a host of medical problems. Patients may have congenital disorders involving the intestines and the heart. An atrioventricular defect is present in 50% of patients with Down syndrome.

Down syndrome is also associated with celiac disease, atlanto-axial instability, hypothyroidism, leukemia, and early onset Alzheimer disease.

The syndrome was first described clinically by Langdon Down in 1866, but its cause remained a deep mystery for almost a century. Two noteworthy features of its population distribution drew attention: increased maternal age and a peculiar distribution within families—concordance in monozygotic twins but almost complete discordance in dizygotic twins and other family members. Although it was recognized as early as the 1930s that a chromosome abnormality might explain these observations, at that time no one was prepared to believe that humans are really likely to have chromosome abnormalities.

However, when techniques for detailed analysis of human chromosomes became available, Down syndrome was one of the first conditions to be examined chromosomally. In 1959, it was established that most children with Down syndrome have 47 chromosomes, the extra member being a small acrocentric chromosome that has since been designated chromosome 21.

Phenotype: Gene Expression

Down syndrome can usually be diagnosed at birth or shortly thereafter by its dysmorphic features, which vary among patients but nevertheless produce a distinctive phenotype Opens in new window. Hypotonia may be the first abnormality noticed in the newborn.

In addition to characteristic dysmorphic facial features evident to even the untrained observer, the patients are short in stature and have brachycephaly with a flat occiput. The neck is short, with loose skin on the nape.

The nasal bridge is flat; the ears are low-set and have a characteristic folded appearance; the eyes have Brushfield spots around the margin of the iris; and the mouth is open, often showing a furrowed, protruding tongue. Characteristic epicanthal folds and upslanting palpebral fissures gave rise to the term mongolism, once used to refer to this condition but now considered inappropriate.

The hands are short and broad, often with a single transverse palmar crease (simian crease) and incurved fifth digits, or clinodactyly. The dermatoglyphics (patterns of the ridged skin) are highly characteristic. The feet show a wide gap between the first and second toes, with a furrow extending proximally on the plantar surface.

The major cause for concern in Down syndrome is mental retardation. Even though in early infancy the child may not seem delayed in development, the delay is usually obvious by the end of the first year.

The intelligence quotient (IQ) is usually 30 to 60 when the child is old enough to be tested. Nevertheless, many children with Down syndrome develop into happy, responsive, and even self-reliant persons in spite of these limitations.

Congenital heart disease is present in at least one third of all live-born Down syndrome infants and in a somewhat higher proportion of abortuses with the syndrome. Certain malformations, such as duodenal atresia and tracheoesophageal fistula, are much more common in Down syndrome than in other disorders.

There is a high degree of variability in the phenotype of Down syndrome individuals; specific abnormalities are detected in almost all patients, but other are seen only in a subset of cases.

Each of these birth defects must reflect to some degree the direct or indirect effects of overexpression of one or more genes on chromosome 21 on patterning events during early development.

Large-scale gene expression studies have shown that a significant proportion of genes encoded on chromosome 21 are expressed at higher levels in Down syndrome brain and heart samples than in corresponding samples from euploid individuals. As the complete catalogue of chromosome 21 genes is known, current efforts are directed toward determining which genes are responsible for particular phenotypes.

Prenatal and Postnatal Survival

Because trisomy 21 accounts for about half of all abnormalities identified prenatally, the incidence of Down syndrome seen in live births, in amniocentesis, and in chorionic villus sampling at different maternal ages can provide a basis for estimating the amount of fetal loss between the 11th and 16th weeks and between the 16th week and birth.

At all maternal ages, there is some loss between the 11th and 16th weeks (as would be expected from the high rate of chromosome abnormality seen in spontaneous abortions) and an additional loss later in pregnancy. In fact, probably only 20% to 25% of trisomy 21 conceptuses survive to birth.

Among Down syndrome conceptuses, those least likely to survive are those with congenital heart disease; about one fourth of the live-born infants with heart defects die before their first birthday. There is a 15-fold increase in the risk of leukemia among Down syndrome patients who survive the neonatal period.

Premature dementia Opens in new window, associated with the neuropathological findings characteristic of Alzheimer disease Opens in new window (cortical atrophy, ventricular dilatation, and neurofibrillar tangles), affects nearly all Down syndrome patients, several decades earlier than the typical age at onset of Alzheimer disease in the general population.


No specific treatment has been indicated for Down syndrome. Therapy is generally centered on treating the conditions associated with trisomy 21. Duodenal atresia is treated surgically and congenital heart defects should be treated accordingly.