Down Syndrome
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P80-83
2025-12-04
100
Down syndrome is by far the most common and best known of the chromosome disorders and is the single most common genetic cause of moderate intellectual disability. The population incidence of Down syndrome in live births is currently estimated to be approximately 1 in 700, reflecting the maternal age distribution for all births and the proportion of older mothers who make use of prenatal diagnosis and selective termination. At ~30 years of age, the risk begins to rise sharply, approaching 1 in 10 births in the oldest maternal age group (Fig. 1). Even though younger mothers have a much lower risk, their birth rate is much higher, and therefore more than half of the mothers of all newborns with Down syndrome are younger than 35 years.
Fig1. Maternal age dependence on the incidence of trisomy 21. Comparison of mean maternal ages at the time of birth. Case (top): maternal age at birth of infant with trisomy 21; control: maternal age at birth of infant without trisomy 21; population: maternal ages at birth of infants in the population from cases and controls. (Data from Allen EG, Freeman SB, Druschel C, et al: Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects, Hum Genet 125:41–52, 2009; Bull MJ: Down syndrome, NEJM 382:2344–2352, 2020.)
Down syndrome can usually be diagnosed at birth or shortly thereafter by its characteristic features, which vary among patients but nevertheless produce a distinctive phenotype. Hypotonia may be the first abnormality noticed in the newborn. In addition to characteristic dysmorphic facial features, the patients are short in stature and have brachycephaly with a flat occiput. The neck is short, with loose skin on the nape. The hands are short and broad, often with a single transverse palmar crease and incurved fifth digits (termed fifth finger clinodactyly).
A major cause for concern in Down syndrome is intellectual disability. 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. Although the extent of intellectual disability varies among individuals from moderate to mild, many children with Down syndrome develop into interactive and even self-reliant persons, and most attend local schools.
There is a high degree of variability in the phenotype of Down syndrome individuals; specific abnormalities are detected in almost all patients, but others are seen only in a subset of cases. Congenital heart disease is present in about half of all liveborn infants with Down syndrome. Certain malformations, such as duodenal atresia and tracheoesophageal fistula, are much more common in Down syndrome than in other disorders.
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; approximately one-fourth of the liveborn infants with heart defects die before their first birthday. There is a 15-fold increase in the risk for leukemia among individuals with Down syndrome who survive the neonatal period. Premature dementia, associated with the neuropathologic findings characteristic of Alzheimer disease (cortical atrophy, ventricular dilatation, and neurofibrillary tangles), affects nearly all individuals with Down syndrome several decades earlier than the typical age at onset of Alzheimer disease in the general population.
As a general principle it is important to think of this constellation of clinical findings, their variation, and likely outcomes in terms of gene imbalance—the relative overabundance of specific gene products; their impact on various critical pathways in particular tissues and cell types, both early in development and throughout life; and the particular alleles present in an individual’s genome, both for genes on the trisomic chromosome and for the many other genes inherited from the parents.
The Chromosomes in Down Syndrome
The clinical diagnosis of Down syndrome usually presents no particular difficulty. Nevertheless, karyotyping is necessary for confirmation and to provide a basis for genetic counseling. Although the specific abnormal karyotype responsible for Down syndrome usually has little effect on the phenotype of the patient, it is essential for determining the recurrence risk.
Trisomy 21. In at least 95% of all patients, the Down syndrome karyotype has 47 chromosomes, with an extra copy of chromosome 21. This trisomy results from meiotic nondisjunction of the chromosome 21 pair. As noted earlier, the risk for having a child with trisomy 21 increases with maternal age, especially after the age of 30 years (see Fig. 1). The meiotic error responsible for the trisomy usually occurs during maternal meiosis (~90% of cases), predominantly in meiosis I, but ~10% of cases occur in paternal meiosis, often in meiosis II. Typical trisomy 21 is a sporadic event, and thus recurrences are infrequent, as will be further discussed later in this chapter.
Approximately 2% of Down syndrome patients are mosaic for two cell populations – one with a normal karyotype and one with a trisomy 21 karyotype. The phenotype may be milder than that of typical trisomy 21, but there is wide variability in phenotypes among mosaic patients, presumably reflecting the variable proportion of trisomy 21 cells in the embryo during early development.
Robertsonian Translocation. Approximately 4% of Down syndrome patients have 46 chromosomes, one of which is a Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22). The translocation chromosome replaces one of the normal acrocentric chromosomes, and the karyotype of a Down syndrome patient with a Robertsonian trans location between chromosomes 14 and 21 is therefore 46,XX or XY,rob(14;21)(q10;q10),+21 for. Despite having 46 chromosomes, patients with a Robertsonian translocation involving chromosome 21 are trisomic for genes on the entirety of 21q.
A carrier of a Robertsonian translocation, involving, for example, chromosomes 14 and 21, has only 45 chromosomes; one chromosome 14 and one chromosome 21 are missing and are replaced by the translocation chromosome. The gametes that can be formed by such a carrier are shown in Fig.2, and such carriers are at risk for having a child with translocation Down syndrome.
Fig2. Chromosomes of gametes that theoretically can be produced by a carrier of a Robertsonian translocation, rob(14;21). (A) Normal and balanced complements. (B) Unbalanced, with one product containing both the translocation chromosome and the normal chromosome 21, and the reciprocal product containing chromosome 14. (C) Unbalanced, one product with both the translocation chromosome and chromosome 14, and the reciprocal product with chromosome 21 only. Theoretically, there are six possible types of gametes, but three of them appear unable to lead to viable offspring. Only the three shaded gametes (left) can lead to viable offspring. Theoretically, the three types of gametes will be produced in equal numbers, and thus, the theoretical risk for a child with Down syndrome should be 1 in 3. However, extensive population studies have shown that unbalanced chromosome complements appear in only ~10% to 15% of the progeny of carrier mothers and in only a few percent of the progeny of carrier fathers who have translocations involving chromosome 21.
Unlike standard trisomy 21, translocation Down syndrome shows no relation to maternal age but has a relatively high recurrence risk in families when a parent, especially a mother, is a carrier of the translocation. For this reason, karyotyping of the parents and possibly other relatives is essential before accurate genetic counseling can be provided.
A 21q21q translocation chromosome is seen in a few percent of Down syndrome patients and is thought to originate as an isochromosome. It is particularly important to evaluate if a parent is a carrier because all gametes of a carrier of such a chromosome must either contain the 21q21q chromosome, with its double dose of chromosome 21 genetic material, or lack it and have no chromosome 21 representative at all. The potential progeny therefore inevitably have either Down syn drome or monosomy 21, which is not viable. Mosaic carriers are at an increased risk (100%) for recurrence, and thus prenatal diagnosis should be considered in any subsequent pregnancy.
Partial Trisomy 21. Very rarely, Down syndrome is diagnosed in a patient in whom only a part of the long arm of chromosome 21 is present in triplicate. These patients are of particular significance because they can show what region of chromosome 21 is likely to be responsible for specific components of the Down syndrome phenotype and what regions can be triplicated without causing that aspect of the phenotype. The most notable success has been the identification of a less than 2-Mb region that is critical for the heart defects seen in ~40% of Down syndrome patients. Sorting out the specific genes crucial to the expression of the Down syndrome phenotype from those that merely happen to be syntenic with them on chromosome 21 is critical for determining the pathogenesis of the various clinical findings.
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