The Principles of Clinical Cytogenetics - Extra Materials - Springer

Autosomal Aneuploidy 139
forming ability, thus explaining their observation for trisomy 21 that although an altered recombination
pattern is not maternal age dependent, meiotic disturbance is age dependent (47). The same
argument was used by Hassold et al. to explain their findings with trisomy 16 (21).
The possibility of the presence of a genetic predisposition to nondisjunction has also been proposed.
One study involving consanguineous families in Kuwait showed that the relative risk for the
occurrence of Down syndrome was approximately four times greater for closely related parents (first
cousins, first cousins once removed, second cousins) than for unrelated parents (48). As consanguinity
is usually perpetuated in certain families or sections of the population, these results were taken as
evidence for the existence of an autosomal recessive gene that facilitates meiotic nondisjunction in
homozygous parents. Thus, in a subgroup of trisomy 21 patients, nondisjunction might be genetically
determined.
Our understanding of the mechanism and etiology of nondisjunction is not complete. It is possible
that more than one mechanism contributes to the observed maternal age effect. Thus, the “two-hit,”
“limited oöcyte pool,” and “production line” models, along with other hypothetical explanations,
could explain a portion of the cases involving some chromosomes. Further studies are needed.
Nondisjunction occurring at mitosis, on the other hand, will result in mosaicism, usually with both
normal and abnormal cell lines.
Discussion of autosomal aneuploidies in this chapter will be limited largely to those observed in
liveborns only.
AUTOSOMAL TRISOMIES
Trisomy 21
Incidence
Trisomy 21 [47,XX or XY,+21] (see Fig. 4) was the first chromosomal abnormality described in
humans (49). The phenotype was delineated by John Langdon Down (1828–1896) in 1866 and is
referred to today as Down syndrome (50). It is the most common single known cause of mental
retardation. The frequency in the general population is approximately 1 in 700. Down syndrome is
more frequent in males, with a male-to-female ratio of 1.2 : 1. A recent study using multicolor FISH
showed that among sperm disomic for chromosome 21, significantly more were Y-bearing than
X-bearing (51). This finding was consistent with earlier reports showing an excess of males among
trisomy 21 conceptuses that resulted from paternal meiotic errors (19). This preferential segregation
of the extra chromosome 21 with the Y chromosome contributes to a small extent to the observed sex
ratio in trisomy 21 patients. Other mechanisms, such as in utero selection against female trisomy 21
fetuses, must also exist.
Trisomy 21 accounts for approximately 95% of all cases of Down syndrome. Mosaicism and
Robertsonian translocations (see Chapter 9) comprise the remaining 5%. As described previously,
the incidence of trisomy 21 in newborns is closely associated with maternal age (see Table 2).
Phenotype
The clinical phenotype of Down syndrome has been well described (54,55). Briefly, there is a
characteristic craniofacial appearance with upward-slanting palpebral fissures, epicanthal folds, flat
nasal bridge, small mouth, thick lips, protruding tongue, flat occiput, and small, overfolded ears.
Hands and feet are small and might demonstrate clinodactyly, hypoplasia of the midphalanx of the
fifth finger, single palmar crease (see Fig. 5), and a wide space between the first and second toes.
Hypotonia and small stature are common, and mental retardation is almost invariable. Cardiac anomalies
are present in 40–50% of patients, most commonly endocardial cushion defects, ventricular septal
defects (VSDs), patent ductus arteriosus (PDA), and auricular septal defects (ASDs). Other
observed major malformations include duodenal atresia, annular pancreas, megacolon, cataracts, and
choanal atresia. In addition, a 10- to 20-fold increase in the risk for leukemia has been observed in