Described first in 1866 by Langdon Down, this is easily the best known of the chromosomal dysgeneses. Its frequency is 1 in 600 to 700 births, and it accounts for approximately 10 percent of all cases in every large series of cases of severe mental retardation. One cannot distinguish the Down syndrome with the common triplication of chromosome 21 from that caused by a translocation, and therefore duplication, of one arm, specifically the distal portion of the long arm that seems to contain the region responsible for the syndrome. Two genes have been of greatest interest in that region: DYRK1A and DSCR1.
Familiarity with the condition permits its recognition at birth, but the somatic appearance becomes more obvious with advancing age. The round head, open mouth, stubby hands, slanting palpebral fissures, and short stature impart an unmistakable appearance. The ears are low-set and oval, with small lobules. The palpebral fissures slant slightly upward and outward owing to the presence of medial epicanthal folds that partly cover the inner canthi (hence the old term mongolism, considered pejorative and not in use). The bridge of the nose is poorly developed and the face is flattened (hypoplasia of the maxillae). The tongue is usually enlarged, heavily fissured, and protruded. Gray-white specks of depigmentation are seen in the irides (Brushfield spots). The little fingers are often short (hypoplastic middle phalanx) and incurved (clinodactyly). The fontanels are patent and slow to close. The hands are broad, with a single transverse (simian) palmar crease and other characteristic dermal markings. Lenticular opacities and congenital heart lesions (septal and other defects), as well as gastrointestinal abnormalities (stenosis of duodenum), are frequent. The patient with Down syndrome is slightly below average size at birth and is characteristically of short stature at later periods of life. The height attained in adult life seldom exceeds that of a 10-year-old child.
Hypotonia of the limbs is a prominent finding. At first, the Moro response is reduced or absent, and feeding is difficult. Most affected children do not walk until 3 to 4 years of age; their acquisition of speech is delayed, but over 90 percent talk by 5 years. The IQ is variable, and that of a large group follows a Gaussian curve with the median IQ being 40 to 50 and the range, 20 to 70. A placid, docile, and affectionate personality characterizes most Down patients. A high incidence of atlantoaxial instability puts these individuals at risk of traumatic spinal cord compression in athletic ventures.
An increased incidence of myelocytic and lymphocytic leukemia takes its toll. A number of patients have had embolic strokes and brain abscesses secondary to cardiac abnormalities and there is disproportionate occurrence of the rare cerebrovascular disorder, moyamoya (see Chap. 33). Life expectancy is later shortened by the almost universal development of Alzheimer disease by the 40th year of life. This is explained by the presence on the duplicate copy of chromosome 21 of the gene for the precursor of the protein amyloid, a central factor in the development of Alzheimer disease. As Alzheimer disease develops, the usual clinical picture is marked by inattentiveness, reduced speech, impairment of visuospatial orientation, loss of memory and judgment, and seizures.
The triplication is found mostly in the offspring of older mothers, whereas the less-frequent translocation is found equally in the offspring of young and older women. In other subtypes of the Down syndrome, referred to as mosaics, some cells share in the chromosomal abnormality and others are normal. Affected individuals have atypical forms of the syndrome, and some such individuals are of normal intelligence.