Down Syndrome

Down syndrome, previously called “mongolism,” is a relatively common condition resulting from the presence of an extra chromosome, number 21, in all the cells of the body. In each human cell, there are 23 chromosome pairs containing basic genetic mate­rial that organizes the body’s development and phys­iological functioning.

Distribution and Incidence

Recent estimates of overall worldwide incidence of Down syndrome are around 0.8 per 1,000 live births (Janerich and Bracken 1986). In the United States, the 1983 Birth Defects Monitoring Program indi­cated an incidence of 0.82 per 1,000 live births. These figures evidence a decline from those reported 20 years ago in Western countries, where incidence was about 1.7 per 1,000.

Down syndrome occurs in all races and ethnic groups, though good documentation of specific inci­dence in many groups and geographic areas is lack­ing (Lilienfeld 1969). There is some evidence for spatial aggregation, such as in northern Finland and British Columbia (Janerich and Bracken 1986), but these instances appear to be sporadic, and are probably related to environmental sources.

Epidemiology and Etiology

The presence of the additional number 21 chromo­some in all cells of the individual with Down syn­drome is usually the result of an error in cell divi­sion called nondisjunction. In normal cell division, the two members of each of the 23 chromosome pairs separate and move into one of the two resulting cells, whereas in nondisjunction, both members of the chromosome pair end up in a single cell. In Down syndrome, the nondisjunction has usually occurred during meiosis (sex cell division) usually of the fe­male sex cell (the ovum). Thus, when an ovum with two number 21 chromosomes is fertilized, three num­ber 21 chromosomes (two from the mother and one from the father) will be passed on to all the cells in the developing fetus. The occurrence of Down syn­drome is most consistently associated with advanced maternal age, with incidence rising from 0.45 per 1,000 live births in women 20 to 24 years of age (8 studies) to 9.4 per 1,000 live births for women 40 to 44 years (7 studies). The largest risk increase occurs between the age groups 30 to 34 and 34 to 39 years (Lilienfeld 1969).

Four potential reasons for the maternal age asso­ciation have been suggested:

1. Whereas the prenatal incidence of Down syn­drome is constant across all ages, the older uterus is less selective in rejecting the Down syndrome conceptus.

2. Longer delays between intercourse result in a relatively “aged ovum,” more likely to experience nondisjunction.

3. In older women, the ova themselves have aged longer and have an increased rate of nondis­junction.

4. Long-term exposure to environmental agents has resulted in damage to the spindle mechanism that in turn produces meiotic nondisjunction.

Because the additional chromosome can be traced to the father in 20 percent of the cases of Down syn­drome, studies have also evaluated a paternal age effect on incidence. However, such an effect cannot be conclusively demonstrated (Janerich and Bracken 1986).

About 30 to 60 percent of all Down syndrome births, however, are not age dependent, meaning that they occur in mothers of ages under 30 years. Indeed, a high incidence of infants with Down syn­drome has recently been reported in women less than 15 years of age. In both younger and older sibs of index patients, the risk of having offspring with Down syndrome is increased 2- to 10-fold. Younger mothers are more likely to have a second offspring with Down syndrome than are older mothers. The recurrence risk is 1 in 3 for mothers who are translocation carriers.

A number of environmental and metabolic mecha­nisms for Down syndrome have been evaluated, among them maternal drug, tobacco, alcohol, and caffeine use; use of hormonal and nonhormonal con­traceptives; fluoridated water; and radiation expo­sure. However, findings from these studies have been inconsistent. Some investigators have sug­gested that a possible recessive gene producing nondisjunction might explain up to 10 percent of the cases. However, studies in consanguineous mar­riages do not support this suggestion. Dwight Janerich and Michael Bracken (1986) indicate that the association with elevated maternal age is un­doubtedly a surrogate variable for other underlying associated factors, the most important of which are probably endocrine changes associated with aging.

Clinical Manifestations

The most easily recognizable features of Down syn­drome derive from abnormalities in growth of the cranium and face. These include a short, relatively broad head (brachycephaly), hypoplastic maxilla, upslanting palpebral fissures, epicanthal folds, in­creased neck skin, small ears, and flattened nasal bridge.

In an extensive recent survey of 1,341 children with Down syndrome bom between 1952 and 1981 in British Columbia, Patricia Baird and Adel Sadovnick (1987) reported survival rates up to 30 years of age in 50 percent for those with CHD, but nearly 80 percent for those without CHD. The sur­vival rate for the latter group, however, was less than that for a comparison group of mentally re­tarded individuals without Down syndrome.

Children with Down syndrome experience abnor­mal physical and cognitive development. Birth weight and length are near normal, but the growth rate in the first 3 years of life is significantly slower than normal, and most children are less than the fifth percentile in height by the time they are 3 years of age. Growth rate during childhood is near normal, but the adolescent growth spurt is often absent (Cronk et al. 1988). Deficient growth differen­tially affects distal segments of the long bones. Whereas some early developmental milestones are normal, more marked delays in walking, talking, and other motor and cognitive skills usually become apparent by the end of the first year of life. Mild to moderate mental retardation (IQ: 30 to 67) is com­monly present by childhood. Recent innovations in early intervention and new special education pro­graming allow individuals with Down syndrome to hold jobs as adults in sheltered work situations.

History and Geography

Probably the earliest record of Down syndrome was a Saxon skull excavated in the seventh century show­ing OSteological changes consistent with the condi­tion. There are also accounts of sixteenth-century paintings of children having the features of the syn­drome. The first accounts of Down syndrome, how­ever, did not appear until the nineteenth century. In 1846 E. Sequin wrote of a specific type of mental retardation case, which he described as a “furfura- ceous cretin with its white, rosy, and peeling skin, with its shortcomings of all the integuments, which give an unfinished aspect to the truncated fingers and nose; with its cracked lips and tongue; with its red ectropic conjunctiva, coming to supply the cur­tailed skin at the margin of the lids” (quoted in Brousseau and Brainerd 1928). The first formal de­scription was given in a report by J. Langdon Down in 1866. He described a type of congenital defect bearing resemblance to the Tartar race which he called Kalmuc or Mongolian. Down, who had been influenced by the racial hypothesis and the writings of Charles Darwin, suggested that the entity repre­sented a reversion to an earlier phylogenetic type. This hypothesis never gained wide acceptance, and in fact, Down’s own son, also a doctor, disagreed with it, suggesting that the features of the syndrome were accidental and superficial (Brain 1967).

The next important reports were presented by John Fraser and Arthur Mitchell in 1875 at the Royal College of Physicians in Edinburgh. Mitchell pointed out the similarities between the syndrome and “cretinism” (congenital hypothyroidism). Re­ports by W. W. Ireland and G. E. Shuttleworth fol­lowed during the 1870s and 1880s. Shuttleworth suggested that children with the condition were actu­ally “unfinished,” representing the persistence of anatomy characteristic of a particular phase in fetal development. He specifically cited the already recog­nized association between the syndrome and ad­vanced maternal age, pointing out the large number of children with Down syndrome who were the last- born in large families.

From the initial description in the mid-nineteenth century to 1959, a large number of etiologic hypothe­ses were advanced for the syndrome, including ma­ternal syphilis, familial tuberculosis, familial inci­dence of epilepsy, insanity, instability, and mental retardation. Once the increased incidence of congeni­tal heart disease in the syndrome was recognized by John Thomson and A. E. Garrod in 1898, a cause in early fetal existence was sought. Among theories advanced were maternal alcoholism, fetal hyperthy­roidism, maternal dysthyroidism, hypoplasia of the adrenals, dysfunction of the pituitary, abnormality of the thymus, chemical contraceptives, curettage, faulty implantation, degeneration of the ovum, and emotional shock in early pregnancy.

As early as 1932, a chromosomal anomaly was suggested as a possible cause of the disorder (Bleyer 1934). In 1959, shortly after the correct diploid number of chromosomes in the human cell was es­tablished, a small sample of children with Down syndrome were demonstrated to have an extra acro­centric chromosome and a total chromosome num­ber of 47 in cultures of fibroblasts. This finding was verified by subsequent studies. Later in the same year, J. A. Book and co-workers (Book, Fraccaro, and Lindsten 1959) concluded that the extra chro­mosome was most similar to number 21 in the Den­ver classification. In 1960, other investigators reported the case of a girl with Down syndrome having only 46 chromosomes, and postulated a re­ciprocal translocation occurring between two chro­mosome groups (Polani et al. 1960).

Initially, Down syndrome was thought to occur only in the Caucasian race. Subsequently, however, reports have shown that it occurs in every racial group and country although thorough, well-designed studies have not allowed an accurate picture of its true distribution across racial and ethnic groups. Early reports indicated a low incidence in African and black American groups. However, recent investi­gations in Ibadan, Nigeria, and in Memphis, Tennes­see, found black incidence rates much the same as those of white populations (Janerich and Bracken 1986). Similarly, although detection in Oriental populations is thought to be' inhibited by sameness of features, recent studies in Japan reveal rates much like those in the United States. An extensive study from the World Health Organization in 1966 indicated that a low incidence of Down syndrome is reported in India, Malaysia, and Egypt (Lilienfeld 1969), whereas by contrast a high incidence was reported in Yugoslavia, Czechoslovakia, and at least one location in Melbourne, Australia.

A. M. Lilienfeld (1969) summarized 11 studies that attempted to indicate the spatial and temporal clustering of the syndrome. However, even the most sophisticated of these, carried out in Melbourne, Aus­tralia (Collman and Stoller 1962), failed to give satis­factory statistical proof for clustering. A 1983 report by P. M. Sheehan and I. B. Hillary describes a cluster of children with Down syndrome born to women who attended the same boarding school in their youth. This suggests that in some instances, an environ­mental agent may influence the incidence of Down syndrome.

Christine E. Cronk

Bibliography

Baird, P. A., and A. D. Sadovnick. 1987. Life expectancy in Down syndrome. Journal OfPediatrics 110: 849—54.

Bleyer, A. 1934. Indications that mongoloid imbecility is a gametic mutation of degressive type. American Jour­nal OfDiseases of Children 17: 342—8.

Book, M. A., M. Fraccaro, and J. Lindsten. 1959. Cytogen­etical observations in mongolism. ActaPaediatrica 48: 453-68.

Brain, L. 1967. Historical introduction. In Mongolism, CIBA Foundation Study Group No. 25, 1-5. London.

Brousseau, K., and H. G. Brainerd. 1928. Mongolism: A study of the physical and mental characteristics of mongolian imbeciles. Baltimore.

Collman, R. D., and A. Stoller. 1962. Epidemiology of congenital anomalies of the central nervous system with special reference to patterns in the State of Victo­ria, Australia. Journal of Mental Deficiency Research 7: 60-8.

Cronk, C. E., et al. 1988. Growth charts for children with Down syndrome, one month to 18 years. Pediatrics 81: 102-110.

Down, J. Langdon. 1867. Observations on ethnic classifica­tion of idiots. Journal of Mental Science 13: 121-3.

Janerich, D. T., and M. B. Bracken. 1986. Epidemiology of trisomy 21: A review and theoretical analysis. Jour­nal of Chronic Disease 39: 1079—93.

Lilienfeld, A. M. 1969. Epidemiology of mongolism. Balti­more.

Penrose, L. S. 1954. Observations on the aetiology of mon­golism. Lancet 2: 505-9.

Polani, P. E., et al. 1960. A mongol girl with 46 chromo­somes. Lancet 1: 721-4.

Pueschel, S. M. 1984. The young child with Down syn­drome. New York.

Pueschel, S. M., and L. S. Steinberg. 1980. Down syn­drome: A comprehensive bibliography. New York.

Sheehan, P. M., and I. B. Hillary. 1983. An unusual cluster of babies with Down’s syndrome bom to former pupils of an Irish boarding school. British Journal of Medi­cine (Clinical Research) 287: 1428—9.