Trisomy

Trisomy 8 [47,XX or XY,+8] was first reported by Grouchy et al. in 1971 (93). It is rare, with an unknown incidence. More than 100 cases have been reported in the literature (94-97), most of them mosaics [47,+8/46]. The male-to-female ratio is 2-3 : 1.

Growth and the degree of mental deficiency are variable. Mild to severe retardation is seen, and a proportion of patients have normal IQs. Craniofacial dysmorphism (see Fig. 8) includes prominent forehead, deep-set eyes, strabismus, broad nasal bridge, upturned nares, long upper lip, thick and everted lower lip, high arched or cleft palate, micrognathia, and large dysplastic ears with prominent antihelices. Skeletal abnormalities include a long, thin trunk, hemivertebrae, spina bifida, kyphoscoliosis, hip dysplasia, multiple joint contractures, camptodactyly, dysplastic nails, and absent or dysplastic patella. The presence of deep palmar and plantar furrows is characteristic. Renal and ure-teral anomalies and congenital heart defects are common. A few cases of hematological malignancy

Big Lips Genetics
Fig. 8. An infant with mosaic trisomy 8. Note prominent forehead, strabismus, broad nasal bridge, upturned nares, long upper lip, and everted lower lip.

have been reported in mosaic trisomy 8 patients (98,99). This is of particular interest because trisomy 8 is a frequently acquired cytogenetic abnormality in myeloid disorders (see Chapter 15). When studied, the abnormal cells in these patients appeared to have developed from the trisomic cell population. The significance of this is not clear, but the possibility remains that constitutional trisomy 8 could predispose individuals to myeloid neoplasia.

There is no direct correlation between the proportion of the trisomy 8 cells and the severity of the phenotype. The percentage of trisomic cells is usually greater in skin fibroblasts than in blood lymphocytes. In addition, the proportion in lymphocytes usually decreases with time.

The risk for recurrence is not known.

Trisomy 9

The first cases of trisomy 9 in either nonmosaic [47,XX or XY,+9] or mosaic [47,+9/46] form were reported in 1973 (100,101). More than 40 cases of liveborns or term stillborns with trisomy 9 have been reported. Most were mosaics (102-106). The male-to-female ratio is close to 1 : 1.

Clinical features include craniofacial anomalies (high narrow forehead, short upward slanting palpebral fissures, deep-set eyes, microphthalmia, low-set malformed auricles, bulbous nose, prominent upper lip, micrognathia), skeletal malformations (abnormal position/function of various joints, bone dysplasia, narrow chest, 13 ribs), overlapping fingers, hypoplastic external genitalia, and cryptorchidism. Cardiac anomalies are seen in more than 60% of cases, most frequently VSD. Renal malformations are present in 40% of patients. The majority of patients die in the early postnatal period. With rare exceptions, all survivors have severe mental deficiency. Mosaic patients tend to survive longer, but the proportion of trisomy 9 cells does not predict the severity of the condition or the length of survival. It is possible that a normal cell line could be present in some tissues in apparently nonmosaic patients.

A recent study showed that the mean maternal age of women bearing trisomy 9 offspring is significantly increased over that of the general population (103). This suggests that the occurrence of trisomy 9 might also be associated with advanced maternal age. The risk for recurrence is not known.

Trisomy 16

Trisomy 16 is the most frequently observed autosomal aneuploidy in spontaneous abortuses (see Chapter 13). Full trisomy 16 is almost always lethal during early embryonic or fetal development, although a single case of a stillborn at 35 weeks gestation has been recorded (107).

Mosaic trisomy 16 fetuses, however, can occasionally survive to term. At least ten such cases have been reported (108-114). Intrauterine growth retardation is invariable. An elevated maternal serum human chorionic gonadotropin (hCG) or a-fetoprotein level during pregnancy was noted in more than 50% of cases. Congenital cardiac defects (mainly VSD or ASD) were present in 60% of patients. Other clinical findings included postnatal growth retardation, mild developmental/speech delay, cran-iofacial asymmetry, ptosis, flat broad nasal bridge, low-set dysplastic ears, hypoplastic nipples, umbilical hernia, deep sacral dimple, scoliosis, nail hypoplasia, and single transverse palmar crease. Approximately 50% of the patients died within the first year of life. Long-term follow-up is not available; however, survival to more than 5 years to date has been observed (Hajianpour and Wang, personal observation).

The risk for recurrence is probably negligible.

Trisomy 20

Although mosaic trisomy 20 is one of the most frequent autosomal aneuploidies detected prenatally, its occurrence in liveborns is very rare (115). The majority of prenatally diagnosed cases are not cytogeneti-cally confirmed in postnatal life. It appears that in conceptuses capable of surviving to the second trimester, trisomy 20 cells are largely confined to extraembryonic tissues. Very few liveborns with documented mosaic trisomy 20 have been reported and all were phenotypically normal at birth (116-121). In cases with long-term follow-up, hypopigmentation was reported in three, but no major malformation or intellectual impairment was observed. No case of liveborn nonmosaic trisomy 20 has been recorded.

Phenotypic abnormalities in abortuses with cytogenetically confirmed mosaic trisomy 20 include microcephaly, facial dysmorphism, cardiac defects, and urinary tract anomalies (megapelvis, kinky ureters, double fused kidney) (122).

Trisomy 20 cells have been found in various fetal tissues, including kidney, lung, esophagus, small bowel, rectum, thigh, rib, fascia, and skin (115,122,123). Postnatally, they have been detected in cultured foreskin fibroblasts and urine sediments (116-121). The detection of trisomy 20 cells in newborn cord blood has been reported in one case, but subsequent study of peripheral blood at 4 months of age produced only cytogenetically normal cells (118). There are no other reports of trisomy 20 cells in postnatal blood cultures.

The risk for recurrence is probably negligible.

Trisomy 22

Trisomy 22 was first reported in 1971 (124). Since then, more than 20 liveborns have been reported in the literature (reviewed in ref. 125,126-129). Although most cases were apparently nonmosaic full trisomies, the presence of an undetected, normal cell line confined to certain tissues cannot be excluded, as pointed out by Robinson and Kalousek (130).

The most consistent phenotypic abnormalities include intrauterine growth retardation, low-set ears (frequently associated with microtia of varying degrees plus tags/pits), and midfacial hypoplasia. Other frequently seen abnormalities are microcephaly, hypertelorism with epicanthal folds, cleft palate, micrognathia, webbed neck, hypoplastic nails, anal atresia/stenosis, and hypoplastic genitalia. Cardiac defects, complex in some cases, are seen in 80% of patients. Renal hypoplasia/dysplasia are also common. Skin hypopigmentation (hypomelanosis of Ito) is usually present in mosaic cases. Most nonmosaic patients die in the first months of life. The longest survival reported is 3 years (131). That patient had severe growth and developmental delay and died a few days before his third birthday. Prolonged survival to over 20 years has been observed in mosaic patients.

Trisomy 22 cells can be detected in both blood lymphocytes and skin fibroblasts. The risk for recurrence is unknown.

Other Rare Autosomal Trisomies

As noted in the Introduction, mosaic or nonmosaic autosomal trisomies for chromosomes other than 1 and 11 have been reported in liveborns. Trisomies are detected much more frequently in spontaneous abortuses or in prenatal diagnostic specimens, following which elective terminations are often performed. Thus, the occurrence of such trisomies in liveborns is extremely rare and only isolated case reports are available. The risks for recurrence for these rare trisomies are probably negligible. The following discussion will include cytogenetically confirmed postnatal cases only.

A single case of liveborn mosaic trisomy 2 has been reported (132). The mosaicism was detected in amniocytes and confirmed postnatally in liver biopsy fibroblasts (4 of 100 cells) but not in blood, skin fibroblasts, or ascites fluid cells. At 16 months of age, the child had hypotonia, microcephaly, and growth and developmental delay. Another case of possible mosaic trisomy 2, detected at amnio-centesis and observed in a single cell of a foreskin fibroblast culture following the birth of a dysmorphic child, was reported in an abstract (133). Three cases of mosaic trisomy 3 have been reported (10,134,135); one of these, a severely mentally retarded woman, was alive at age 32. Clinical features in the three cases vary, except all had prominent forehead, ear and eye anomalies. One case each of postnatally confirmed mosaic trisomy 4 (136) and mosaic trisomy 5 (137) has been reported. In both cases, the trisomic cells were detected in prenatal amniocytes and confirmed postnatally in skin fibroblasts, but not in blood lymphocytes. Both patients had multiple congenital anomalies. One case of mosaic trisomy 6 has recently been reported (138). This child was born at 25 weeks of gestation. Clinical features included heart defects (ASD and peripheral pulmonary stenosis), large ears, cleft right hand, cutaneous syndactyly, overlapping toes of irregular shape and length, and epidermal nevi. Growth was considerably delayed, but development was relatively normal at age 2. Trisomy 6 cells were detected in skin fibroblasts but not in blood. At lease six cases of cytogeneti-cally documented mosaic trisomy 7 in skin fibroblasts have been recorded (reviewed in ref. 139, 140,141). All patients were phenotypically abnormal. Common features included growth and developmental delay, skin pigmentary dysplasia with hypopigmentation and hyperpigmentation, facial or body asymmetry, and facial dysmorphism. One mentally retarded male was 18 years old at time of report. A few cases of liveborn mosaic trisomy 10 have been reported (reviewed in ref. 142,143). One patient was mosaic for trisomy 10 and monosomy X in skin fibroblasts, whereas only monosomy X cells were present in blood. This infant died at 7 weeks of age from heart failure. The common clinical phenotype included growth failure, craniofacial dysmorphism (prominent forehead, hypertelorism, upslanted palpebral fissures, blepharophimosis, dysplastic large ears, retrognathia), long slender trunk, deep palmar and plantar fissures, cardiac defects, and short survival.

At least six cases of trisomy 12 have been reported in liveborns; all were mosaics (144-148). The earliest reported case was that of an infertile man, whereas the most recent case involved an infant with multiple malformations and pigmentary dysplasia who died at 2 monts of age. Phenotypic presentation was variable and included facial dysmorphism, scoliosis, ASD, PDA, dysplastic pulmonary and tricuspid valves, short stature, and mental retardation. Trisomy 12 cells have been found in lymphocytes, skin fibroblasts, urine sediments, and internal organs including liver, spleen, adrenal, and thymus.

At least 15 cases of mosaic trisomy 14 have been reported in liveborns (reviewed in ref. 149,150). The most consistent phenotypic abnormalities were growth and mental retardation, broad nose, low-set dysplastic ears, micrognathia, congenital heart defects, and micropenis/cryptorchidism in males. One prenatally diagnosed patient had alobar holoprosencephaly and died at 36 days of age (150). Survival varied from days to more than 29 years. Trisomy 14 cells were detected in both lymphocytes and fibroblasts, with a generally higher percentage in lymphocytes. There was no clear correlation between the proportion of trisomic cells and the severity of the phenotype. In patients with body asymmetry, trisomic cells were usually limited to the atrophic side.

At least ten cases of liveborn trisomy 15 have been recorded (reviewed in refs. 151 and 154;153,154), two of them were reportedly nonmosaics (155,156). In some cases, the trisomy 15 cell line was present only in skin fibroblasts and not in peripheral blood lymphocytes. The concurrent finding of maternal uniparental disomy 15 (see Chapter 19) in the normal cell line was reported in two of the cases (152,154). These cases appeared to have the most severe phenotype. Phenotypic abnormalities include hypotonia, various craniofacial dysmorphisms, minor skeletal anomalies, congenital heart defects, and short survival.

Two cases of confirmed mosaic trisomy 17 have been reported (157,158). The trisomic cells were not seen in lymphocytes, but were found in high percentage in skin fibroblasts. One patient, age 8 years at the time of reporting, had mental and growth retardation, microcephaly, minor dysmorphism, seizures, hearing loss, attention deficit hyperactivity disorder, and autistic behavior. The other patient had mild dysmorphic features and moderate neurological involvement that the authors suggested could be related to prematurity. Two cases of mosaic trisomy 19 are in the literature, one of them was a stillborn male and the other died on day 13. Clinical features were varied and included facial dysmorphism with no report of major malformation (159,160).

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