The Principles of Clinical Cytogenetics - Extra Materials - Springer

142 Jin-Chen Wang
Recurrence
The empirical recurrence risk is about 1% in women under 30 years of age and includes trisomies
other than 21. For women over 30, the recurrence risk is not significantly different from the agespecific
risk (65).
One study of 13 families with two trisomy 21 children showed that three had a parent who was
mosaic for trisomy 21 (by cytogenetic studies) and two had a parent who was potentially mosaic (by
DNA polymorphism analysis) (66). In a family with three trisomy 21 children, Harris et al. reported
that the mother was mosaic for trisomy 21 in lymphocytes and skin fibroblasts (67). In another singlecase
report involving a family with four trisomy 21 children, the mother was found to have a trisomy
21 cell line in an ovarian biopsy specimen (68). Thus, gonadal mosaicism in one parent is an important
cause of recurrent trisomy 21 and should be looked for in families with more than one affected
child. When present, the recurrence risk will be high and will depend on the proportion of trisomy 21
cells in the gonad.
The recurrence risk for mosaic trisomy 21 that results from mitotic nondisjunction should, in
general, not be increased. However, several studies investigating the mechanism and origin of mosaic
trisomy 21 have shown that in a relatively high proportion of cases (probably over 50%), the mosaicism
results from the loss of one chromosome 21 during an early mitotic division in a zygote with
trisomy 21 (69,70). In such cases, the recurrence risk for nondisjunction will be the same as for
nonmosaic trisomy 21.
Trisomy 18
Incidence
Trisomy 18 [47,XX or XY,+18] was first described by Edwards et al. (71). The incidence is 1 in
6000–8000 births. It is more frequent in females, with a male-to-female ratio of 1 : 3–4. The risk for
trisomy 18 also increases with maternal age.
Phenotype
The most common features of trisomy 18 include mental and growth deficiencies, neonatal hypotonicity
followed by hypertonicity, craniofacial dysmorphism (prominent occiput, narrow bifrontal diameter,
short palpebral fissures, small mouth, narrow palate, low-set malformed ears, micrognathia) (see
Fig. 6), clenched hands with a tendency for the second finger to overlap the third and the fifth finger to
overlap the fourth, short dorsiflexed hallux, hypoplastic nails, rocker bottom feet, short sternum, hernias,
single umbilical artery, small pelvis, cryptorchidism, hirsutism, and cardiac anomalies (mainly
VSD, ASD, and PDA). Recent studies show that median survival averages approximately 5 days, with
1-week survival at 35–45% (72–75). Fewer than 10% of patients survive beyond the first year of life. A
few patients over 10 years of age, all females with one exception (76), have been described (77,78),
however, the presence of a normal cell line in these patients was not always investigated.
Mosaic trisomy 18 patients have, in general, milder phenotypes. At least six mosaic trisomy 18
patients, again all females, with normal intelligence and long-term survival have been reported (79–84).
Two recent molecular studies, performed on a total of ten patients with partial trisomy 18, suggest
that the region proximal to band 18q12 does not contribute to the syndrome, whereas two critical
regions, one proximal (18q12.1 → q21.2) and one distal (18q22.3 → qter), could work in cooperation
to produce the typical trisomy 18 phenotype (85,86). In addition, severe mental retardation in these
patients could be associated with trisomy of the region 18q12.3 → q21.1.
Recurrence
There are not enough data regarding the recurrence risk for trisomy 18. Single-case reports of trisomy
18 in sibs (e.g., ref. 87) and of trisomy 18 and a different trisomy in sibs or in prior or subsequent
abortuses (e.g., refs. 88 and 89) are recorded. For genetic counseling purposes, a risk figure of less than
1% for another pregnancy with any trisomy is generally used and might be appropriate.