Standard Article

You have free access to this content

Down Syndrome

  1. Angela J Villar,
  2. Charles J Epstein

Published Online: 27 JAN 2006

DOI: 10.1038/npg.els.0005711

eLS

eLS

How to Cite

Villar, A. J. and Epstein, C. J. 2006. Down Syndrome. eLS.

Author Information

  1. University of California, San Francisco, California, USA

Publication History

  1. Published Online: 27 JAN 2006

This is not the most recent version of the article. View current version (17 OCT 2011)

Clinical Aspects of Down Syndrome

  1. Top of page
  2. Clinical Aspects of Down Syndrome
  3. Major Congenital Malformations in Down Syndrome
  4. Chromosomal and Molecular Basis of Down Syndrome
  5. Conclusion
  6. See also
  7. References
  8. Further Reading

Dysmorphic features

Down syndrome is characterized by a series of minor anomalies that each occur with a frequency of about 50–80% and will not, therefore, be present in all persons with Down syndrome. Conversely, it will be very rare for any single individual with Down syndrome to have all these anomalies, which include brachycephaly, oblique (upslanting) palpebral fissures, epicanthic folds, Brushfield spots, folded or dysplastic ears, flat nasal bridge, narrow palate, open mouth, protruding tongue and furrowed tongue, abnormal teeth, short neck with loose skin on nape, hyperflexibility, short broad hands, short and incurved fifth finger, transverse palmar crease, gap between first and second toes and altered dermatoglyphic patterns. This variability in phenotypic expression is believed to stem from genetic, stochastic and extrinsic (environmental) sources.

Mental retardation

The condition of overriding critical importance in Down syndrome is mental retardation. Newborns with Down syndrome may appear reasonably normal behaviorally, but developmental retardation generally becomes obvious during the first several months of life. The attainment of developmental landmarks is, on the mean, increasingly more delayed as time goes on. However, because of the great variability in attainment of landmarks, this delay may or may not be obvious for any single child with Down syndrome. Many studies of development during the first decade of life indicate that even with Down syndrome children reared at home there is a progressive and virtually linear decline in developmental quotient (DQ) or intelligence quotient (IQ) starting within the first year. The same appears to be true for social quotient (SQ), but there is a wide range of IQs and SQs among individuals.

Relative to other mentally retarded individuals, persons with Down syndrome are reported to have greater difficulty in recalling sequences of verbal information presented orally, particularly when there is no supporting extralinguistic context. Anomalous dominance (lateralization) of language has been observed in young adults with Down syndrome and altered interregional correlation of rates of glucose utilization are believed to reflect the abnormalities of language function. The identification of these selective deficits is of considerable importance in understanding the nature of the cognitive impairment produced by trisomy 21.

Genetic and environmental effects

The variability of cognitive impairment has raised the question of what factors do or could influence mental development. One possible factor is the intrinsic genetic differences between individuals. Despite evidence against the existence of a correlation between parental education levels or IQs and the IQs of their children with Down syndrome, two studies have affirmed the association (Hanson, 1987). This does not, however, preclude the possibility that social and educational practices in relating to the child are influenced by parental IQ and/or education, and that these environmental factors also play a role. Evidence for the potential impact of environmental factors on intellectual development stems principally from studies of the outcomes of home-reared versus institutionalized individuals with Down syndrome, and the results of early intervention programs (Hanson, 1987). While it appears that early intervention can have a positive effect on early development, the long-term effects of such programs remain to be proven.

Neuropathology

The weight of the brain is in the low normal range, the frontal lobes are shortened and the cerebellum and brainstem are reduced in volume. Defects in neuronal architecture and brain histogenesis have been reported, as have abnormalities of dendritic spines. However, the present consensus is that in the majority of patients with Down syndrome the results of neuropathologic study are normal. Although there is accumulating evidence for abnormalities of neuronal differentiation and migration in fetal and infant brains, it is not certain, when the developmental plasticity of the young brain is taken into account, how many of the changes are permanent or functionally significant.

Muscle tone

The single most characteristic feature of Down syndrome in newborns and infants is hypotonia, but the basis for the decrease in muscle tone is unknown. In infancy, there are, in addition, delayed dissolution of early reflexes and automatisms – grasp reflexes, the Moro response and automatic stepping.

Alzheimer disease

Pathological, metabolic and neurochemical changes of Alzheimer disease are present after the third decade in the brain of all individuals with Down syndrome. Detailed morphometric analyses suggest that the pathological changes found in adult Down syndrome brains may differ quantitatively in some areas from those found in Alzheimer disease, but the order of progression of involved areas appears to be the same in Down syndrome as in other types of Alzheimer disease. Based on immunocytochemical analyses, it is claimed that the deposition of the A4 amyloid protein in the brains of persons with Down syndrome begins 50 years earlier than it does in normal brains (Rumble et al., 1989). A number of proposals have been put forward to explain the relationship between Alzheimer disease and Down syndrome in adults. The first is that the genetic imbalance present in trisomy 21 indirectly causes Alzheimer disease by enhancing the susceptibility of the brain to exogenous agents that cause Alzheimer disease. The second is that the genetic imbalance in trisomy 21 directly causes Alzheimer disease because the increased dosage of one or more loci such as amyloid beta (A4) precursor protein (protease nexin-II, Alzheimer disease) (APP) on chromosome 21 results in injury to the brain. The third, based on circular reasoning, is that Alzheimer disease is the result of premature aging.

Major Congenital Malformations in Down Syndrome

  1. Top of page
  2. Clinical Aspects of Down Syndrome
  3. Major Congenital Malformations in Down Syndrome
  4. Chromosomal and Molecular Basis of Down Syndrome
  5. Conclusion
  6. See also
  7. References
  8. Further Reading

Congenital heart disease

The most frequent major congenital abnormality in Down syndrome is congenital heart disease. It is believed that most lesions represent variations in the formation of the venous inflow tract of the heart, although defects in other regions, such as aortic anomalies, can also occur. Although much less common than congenital heart disease, there is an increased frequency of specific intestinal anomalies in Down syndrome, especially duodenal atresia and Hirschsprung disease.

Leukemia and leukemoid reactions

There is a 15- to 20-fold increase in the incidence of leukemia in children with Down syndrome, which is predominantly acute nonlymphocytic (megakaryoblastic, M7) in infants and acute lymphoblastic in older children (Zipursky et al., 1987). Leukemoid reactions or transient leukemia occurs in infants, as does macrocytosis and increased hematocrit suggesting a generalized abnormality in stem-cell regulation.

Immunological defects

There is an increased susceptibility to infection, which appears to be the result of abnormalities in the immune system, particularly in the maturation and function of T lymphocytes. Although the literature has been characterized by considerable disagreement and contradiction, anatomical and functional abnormalities of the thymus implicate abnormalities of the T-lymphocyte system in the immunological defects of Down syndrome (Murphy et al., 1995).

Both hypothyroidism and hyperthyroidism have been reported in individuals with Down syndrome. Although it is often stated that persons with Down syndrome have a propensity to develop autoimmune disorders, this is not well documented except for thyroid autoantibodies.

Alterations in cultured cells

Several aspects of the Down syndrome phenotype have been defined in cultured cells which represent an enhanced responsiveness to external stimuli. Although in many instances the differences between trisomic and diploid cells are relatively small, in some cases they are quite marked. The increased responsiveness of Down syndrome cells to a variety of external stimuli has been attributed to the presence of an increased copy of cell-surface receptors located on chromosome 21, such as the interferon-α/β receptor.

Life expectancy and causes of death

The principal causes of death in Down syndrome are infection, congenital heart disease and malignancy. With the changing patterns of institutionalization and of the utilization and methods of medical and surgical therapy, the mean life expectancy for persons with Down syndrome has improved dramatically in the last 50 years. The major determinant of survival during the first decade of life, and especially the first 4–5 years, is the presence or absence of congenital heart disease. When compared with the background (whole) population, the life expectancy of an individual with Down syndrome at any point in time is 10–20 years less, with the difference being greater for females than for males (Baird and Sadovnick, 1987).

No pharmacological therapy as yet has been shown to have a beneficial effect. However, unsuccessful trials with 5-hydroxytryptophan, mixtures of vitamins, minerals, thyroid hormone, Piracetam and other substances have been used in an attempt to improve the development of children with Down syndrome; despite claims for remarkable successes, no form of pharmacological therapy is known to have a reproducibly beneficial effect on the signs or symptoms of Down syndrome.

Incidence and maternal age effect

The incidence of Down syndrome in the newborn population is in the vicinity of one per 700–1000 live births. There is a very strong maternal age dependence in rates of Down syndrome, which appear to be constant over time. These rates rise from 0.58/1000 live births at age 20 years, to 1.04/1000 at 30 years, 2.6/1000 at 35 years, 9.1/1000 at 40 years and 41.2/1000 at 46 years. Rates at amniocentesis are 40–50% higher, and close to double at the time of chorionic villus sampling. The basis for the very strong effect of maternal age on the incidence of Down syndrome is not well understood. The risk for recurrence of nondisjunction is increased in younger mothers (≤30–35 years) of children with Down syndrome, and the risk of aneuploid offspring is much higher in mothers who are carriers of balanced translocations than in carrier fathers. Prenatal diagnosis by amniocentesis or chorionic villus sampling is capable of detecting fetuses with Down syndrome, and maternal serum triple-marker screening and fetal ultrasonography can each identify a portion of pregnancies in which a fetus with Down syndrome is present. Almost without exception males with trisomy 21 are sterile. In contrast, reproduction has been documented in females with Down syndrome.

Chromosomal and Molecular Basis of Down Syndrome

  1. Top of page
  2. Clinical Aspects of Down Syndrome
  3. Major Congenital Malformations in Down Syndrome
  4. Chromosomal and Molecular Basis of Down Syndrome
  5. Conclusion
  6. See also
  7. References
  8. Further Reading

Down syndrome region

Chromosome 21 is an acrocentric chromosome with a genetic length estimated to be 46 cM. With one possible exception, all genes of known function are located on the long arm of chromosome 21, and only this arm is essential for normal development and function. As one of the first triumphs of the Human Genome Project, the sequence of the long arm of chromosome 21 has been completed with an estimated 99.7% coverage (Hattori et al., 2000). This arm has a length of 33.7 megabase pairs (Mbp) and is relatively gene poor, with less than half the number of identified genes found on the similarly sized chromosome 22. It contains 127 known genes, 98 predicted genes (of which 69% have no similarity to known proteins) and 59 pseudogenes. Among the known genes are at least 10 kinases, five genes in the ubiquitination pathway, five cell adhesion molecules, seven ion channels, five members of the interferon receptor family and several transcription factors. About 22.4% of the chromosome consists of interspersed Alu sequences and LINE-1 elements.

Molecular basis of trisomy 21

In more than 99% of cases, Down syndrome results from trisomy 21, the presence of an extra chromosome 21, either free or as part of a Robertsonian fusion chromosome or isochromosome. In these forms, all cells of the body are trisomic, except for the 2–4% of cases in which mosaicism exists. The nature of the mechanism leading to aneuploidy is the subject of considerable debate. Alterations in chiasma formation initiated during meiosis (Lamb et al., 1997) as well as environmental and other genetic factors have been considered with regard to their potential roles in the etiology of nondisjunction and causation of trisomy 21. A reduced rate of recombination is associated with meiosis I errors and an increased rate with meiosis II errors.

The ability to assign a particular feature of an aneuploid phenotype to specific regions of the unbalanced genome is referred to as phenotypic mapping. Molecular analyses to define the extent of triplication of regions of chromosome 21 assign the full Down syndrome phenotype to bands distal q22.1 to proximal q22.3. The immediate consequence (or primary effect) of an aneuploid state is a gene dosage effect of each of the loci present on the unbalanced chromosome or chromosome segment. Such gene dosage effects, amounting to the expected 1.5 times diploid levels, have been reported for nine chromosome 21 loci. It is possible to make arguments that changes in the concentrations of enzymes, structural proteins, transport system components, regulatory molecules, receptors and cell-surface constituents can each produce an effect on the development or functioning of an organism. One such mechanistic link has been established between increased expression of Cu/Zn-superoxide dismutase and decreased platelet serotonin content (Groner, 1995).

Animal models of Down syndrome

Many of the consequences of aneuploidy in humans arise during early gestation, a period that is technically impractical, and so far legally and ethically impossible, to study. In addition, the brain, which is also difficult to study in vivo, is significantly affected. It is for these reasons that animal models have been developed. The mouse has been the model of choice for several reasons, including ease of manipulation and genetic control, and the similarities to humans in the processes of morphogenesis and (probably) of central nervous system function, in neurobiological if not psychological terms. Furthermore, despite considerable rearrangements of the mammalian genome, sizable chromosomal regions carrying many genes remain intact and structurally similar in both humans and mice.

The first mouse model for human trisomy 21 was trisomic for mouse chromosome 16, the chromosome that most closely resembles human chromosome 21. However, because of the genetic discrepancies between mouse chromosome 16 and human chromosome 21, considerable effort was put into the development of segmentally trisomic mice in which only the human chromosome 21 homologous region was triplicated. Such animals, designated Ts65Dn, were made by Davisson and collaborators (Reeves et al., 1995). Their salient phenotypic abnormalities include major deficits in learning and behavior, atrophy of basal forebrain cholinergic neurons, abnormal craniofacial morphogenesis, decreased pain perception and male sterility. Two additional segmental trisomy 16 mice have been developed. The first, Ts1Cje is functionally trisomic for the region of mouse chromosome 16 distal to Sod1, which still includes the region responsible for the major phenotypic abnormalities in Down syndrome. These animals are somewhat less impaired in learning than are the Ts65Dn (Sago et al., 2000), but display craniofacial and cerebellar alterations similar to Ts65Dn. The second segmental trisomy, designated Ms1CjeTs65Dn, is derived by breeding Ts65Dn females with T (12;16)1Cje males and produces a mouse that is segmentally trisomic for the region that represents the difference between Ts65Dn and Ts1Cje (Sago et al., 2000). These animals have only minimal learning deficits but are still not normal, indicating that the majority of genes responsible for the behavioral and learning abnormalities of Ts65Dn are located distal to Sod1. The ability to generate these various segmental trisomics and to compare their phenotype directly provides a precedent for the systematic creation of a smaller and smaller segmental trisomics and the dissection of the trisomic phenotype. A complementary approach that permits the analysis of the effects of increased dosage of an individual gene or set of genes is the construction of transgenic mice (Groner, 1995), and several such animals have been generated, one of which, with the human minibrain gene (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A)), demonstrates abnormalities of learning and behavior similar to those observed in the segmental trisomics.

Conclusion

  1. Top of page
  2. Clinical Aspects of Down Syndrome
  3. Major Congenital Malformations in Down Syndrome
  4. Chromosomal and Molecular Basis of Down Syndrome
  5. Conclusion
  6. See also
  7. References
  8. Further Reading

No single gene or mechanism can explain how trisomy 21 produces its deleterious consequences. However, with the rapid advances in molecular genetics, it is now possible to envision that the genetic structure of human chromosome 21 will be completely defined and that the pathogenic relationship between the presence of an extra set of chromosome 21 genes and the many features of Down syndrome phenotype will be understood. It is hoped that this will permit the development of therapeutic approaches to ameliorate the cognitive deficits and development of Alzheimer disease that are the most serious components of Down syndrome.

References

  1. Top of page
  2. Clinical Aspects of Down Syndrome
  3. Major Congenital Malformations in Down Syndrome
  4. Chromosomal and Molecular Basis of Down Syndrome
  5. Conclusion
  6. See also
  7. References
  8. Further Reading
  • Baird PA and Sadovnick AD (1987) Life expectancy in Down syndrome. Journal of Pediatrics 110: 849.
  • Groner Y (1995) Transgenic models for chromosome 21 gene dosage effects. In: Epstein CJ, Hassold T, Lott IT, Nadel L and Patterson D (eds.) Etiology and Pathogenesis of Down Syndrome, p. 193. New York, NY: Wiley-Liss.
  • Hanson MJ (1987) Early intervention for children with Down syndrome. In: Pueschel SM, Tingey C, Rynders JE, Crocker AC and Crutcher DM (eds.) New Perspectives on Down Syndrome, p. 149. Baltimore, MD: PH Brooks.
  • Hattori M, Fujiyama A, Taylor TD, et al. (2000) The DNA sequence of human chromosome 21. Nature 405: 311.
  • Lamb NE, Feingold E, Savage A, et al. (1997) Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Human Molecular Genetics 6: 1391.
  • Murphy M, Insoft RM, Pike-Nobile L and Epstein CJ (1995) A hypothesis to explain the immune defects in Down syndrome. In: Epstein CJ, Hassold T, Lott IT, Nadel L and Patterson D (eds.) Etiology and Pathogenesis of Down Syndrome, p. 147. New York, NY: Wiley-Liss.
  • Reeves RH, Irving NG, Moran T, et al. (1995) A mouse model for Down syndrome exhibits learning and behavioral and deficit. Nature Genetics 11: 177.
  • Rumble B, Retallack R, Hilbich C, et al. (1989) Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. New England Journal of Medicine 320: 1446.
  • Sago H, Carlson EJ, Smith DJ, et al. (2000) Genetic dissection of the region associated with behavioral abnormalities in mouse models for down syndrome. Pediatric Research 48: 606613.
  • Zipursky A, Peeters M and Poon A (1987) Megakaryoblastic leukemia and Down's syndrome – a review. In: McCoy EE and Epstein CJ (eds.) The Oncology and Immunology of Down Syndrome, p. 33. New York, NY: Liss.

Further Reading

  1. Top of page
  2. Clinical Aspects of Down Syndrome
  3. Major Congenital Malformations in Down Syndrome
  4. Chromosomal and Molecular Basis of Down Syndrome
  5. Conclusion
  6. See also
  7. References
  8. Further Reading
  • Dellarco VL, Voytek PE and Hollaender A (eds.) (1985) Aneuploidy: Etiology and Mechanisms. New York, NY: Plenum.
  • Epstein CJ (1986) The Consequences of Chromosome Imbalance. Principals, Mechanisms, and Models. New York, NY: Cambridge University Press.
  • Epstein CJ (ed.) (1991) The Morphogenesis of Down Syndrome. New York, NY: Wiley-Liss.
  • Epstein CJ (ed.) (1993) The Phenotype Mapping of Down Syndrome and Other Aneuploid Conditions. New York, NY: Wiley-Liss.
  • Epstein CJ (2001) Down syndrome (trisomy 21). In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds.) The Metabolic Basis of Inherited Disease, 8th edn. pp. 11231256, New York, NY: McGraw-Hill.
  • Epstein CJ, Hassold T, Lott IT, Nadel L and Patterson D (eds.) (1995) Etiology and Pathogenesis of Down Syndrome. New York, NY: Wiley-Liss.
  • McCoy EE and Epstein CJ (eds.) (1987) The Oncology and Immunology of Down Syndrome. New York, NY: Liss.
  • Nadel L and Epstein CJ (eds.) (1992) Downs Syndrome and Alzheimer Disease. New York, NY: Wiley-Liss.
  • Pueschel SM, Sassaman EA, Scola PS, et al. (1982) Biomedical aspects in Down syndrome. In: Pueschel SM and Rynders JE (eds.) Down Syndrome. Advances in Biomedicine and the Behavioral Sciences, p. 169. Cambridge, MA: Ware.
  • Smith GF and Berg JM (1976) Down's Anomaly. Edinburgh, UK: Churchill Livingstone.