Down syndrome - Genetic syndromes: Patterns of inheritance

Down syndrome

Definition

Down syndrome is the clinical condition usually resulting from a trisomy of chromosome 21 first described by Langdon Down in 1865.

Incidence

Rises with increasing maternal age (1 in 3000 when mother is less than 30 years to 1 in 300 when mother is 35–40 years and 1 in 30 in women above 45 years). Because of the high birth rate in mothers below 35, half of all Down syndrome children are born to mothers below 35.

Age

Congenital.

Sex

M = F

Geography

All ethnic communities.

Aetiology

75% of cases result in spontaneous abortions in the first trimester. The additional chromosome 21 is usually (94% of cases) the result of non-disjunction of chromosome 21 during the formation of the maternal ovum. In rare cases there may be a maternal translocation (3%) involving chromosome 21 with the extra 21 attached to another chromosome, e.g. Robertson translocation between 21q and 14 or 22. In about 3% of cases there is mosaicism with some cells demonstrating a normal karyotype.

Pathophysiology

The Alzheimer’s disease seen with Down syndrome is thought to be due to the presence of three copies of the amyloid protein gene on chromosome 21.

Clinical features

Neonatal features include hypotonia, poor Moro reflex, joint hyperflexibility, excess skin at the nape of the neck and flat facies.

Characteristic facies with a small midface, low bridged upturned nose, oblique palpebral fissures, epicanthal folds and enlarged protruding tongue.

Short stature (long bones of limbs are short). Short middle phalynx of little finger, single horizontal palmar crease in broad hands, increased space between the fist and second toe. Lax joints with risk of atlantoaxial dislocation.

Congenital heart disease in 30%, most commonly atrioventricular septal defects.

Tracheo-oesophageal fistula, duodenal atresia, annular pancreas, Hirschsprung’s disease.

Mental retardation, hypotonia, Alzheimer’s disease by age 40 (cortical atrophy, ventricular dilation, neuro-fibrillary tangles).

Complications

Fifteenfold increased risk in developing leukaemia (ALL and AML), hypothyroidism.

Investigations

Prenatal: Reduced maternal serum α feto protein and oestriol, and increased maternal serum β HCG indicates an increased risk of Down syndrome (triple test). Increased nuchal fold thickness on ultrasound at 12–14 weeks has been shown to be as sensitive and specific a test. Definitive diagnosis is made by chorionic villus sampling at 10–11 weeks or amniocentesis early in the second trimester (15–16 weeks). Indications for testing include maternal age and a Down sibling (recurrence risk is 1% overall, higher if a balanced translocation).

Postnatal chromosome analysis is diagnostic.

Prognosis

15–20% die before age 5, usually as a result of severe inoperative heart disease. The remainder survive well into adult life, but by 40 almost all have Alzheimer’s disease.