Polyploidy

Polyploidies are numerical chromosome abnormalities with changes in the number of complete sets of chromosomes. They are usually incompatible with fetal survival and are extremely rare in liveborns.

Triploidy

The chromosome number in triploidy is 3n=69 (see Fig. 9). It is estimated to occur in approximately 1% of all human conceptions and is found in 17-18% of all chromosomally abnormal abortuses (175,176). Only very rarely do triploid conceptuses survive to term. Two distinct phenotypes have been recognized (177). One type presents as a relatively well-grown fetus with or without microcephaly and an abnormally large and cystic placenta usually classified as partial hydatidiform moles. The parental origin of the extra haploid set of chromosomes in such cases is determined to be paternal (diandry) by analysis of cytogenetic heteromorphisms (177,178) or DNA polymorphisms (179). Diandry results from the fertilization of a normal ovum with either two sperm (dispermy) or a sperm that has a diploid chromosome complement resulting from a failure of meiotic division. The other type is characterized by severe intrauterine growth retardation with relative macrocephaly and a small and noncystic placenta. The extra haploid set of chromosomes in such cases is maternal (digyny) (177-180). Digyny can result from a failure of the first maternal meiotic division, generating a diploid egg, or from retention of the second polar body. Although the occurrence of triploidy does not appear to be associated with maternal age, digyny can play a major role in the generation of triploidy in the advanced maternal age group (176). Early cytogenetic studies indicated that the majority of triploid conceptuses were diandric partial moles (178,181). Later studies based on DNA polymorphisms have suggested that a maternal contribution to triploidy could occur more frequently than was previously realized (179,182). Yet, in a most recent study of 87 informative cases of triploid spontaneous abortuses at 5-18 weeks of gestation, Zaragoza et al. (183) showed that approximately two-thirds are androgenetic in origin and that many, but not all, androgenetic triploids developed a partial molar phenotype. The sex chromosome complement in triploidy is either XXX or XXY, with XYY occurring only rarely. For example, the reported numbers of XXX : XXY : XYY cases in two studies performed on spontaneous abortuses were 82 : 92 : 2 (3) and 26 : 36 : 1 (176), and in one study performed on amniotic fluid cells, this ratio was 6 : 8 : 0 (184). It has been suggested that 69,XYY triploid conceptuses are incompatible with significant embryonic development (3).

The observation that the phenotype of triploidy depends on the parental origin of the extra set of chromosomes is an example of genomic imprinting, or the differential expression of paternally and maternally derived genetic material (185,186). It correlates well with observations obtained from mouse embryo studies using nuclear transplantation techniques, which demonstrated that maternal and paternal genomes function differently and are both required for normal development (187-189) (see Chapter 19).

More than 50 cases of apparently nonmosaic triploidy, either 69,XXX or XXY, have been reported in liveborns. Most patients died shortly after birth. Eight patients with survival longer than 2 months have been reported (reviewed in ref. 190), with the longest being 10 months (191). The origin of the extra set of chromosomes was determined by cytogenetic polymorphisms or human leukocyte antigen (HLA) to be maternal in three cases and paternal in one case (192). One study based on DNA polymorphism in an infant who survived for 46 days indicated a maternal meiosis II failure as the origin of the triploid (reviewed in ref. 192). These findings suggest that, in general, digynic triploids survive longer than diandric triploids. The most frequent phenotypic abnormalities include intrauter-ine growth retardation, hypotonia, craniofacial anomalies (macro/hydrocephalus, low-set dysplastic ears, broad nasal bridge), syndactyly, malformation of the extremities, adrenal hypoplasia, cardiac defects, and brain anomalies.

Mosaic triploidy (diploid/triploid mixoploidy) has been reported in approximately 20 patients. Trip-loid cells were found in both lymphocytes and fibroblasts, although in a number of cases, the triploid cell line was limited to fibroblasts (193). Patients with such mixoploidy are less severely affected than nonmosaics and survival beyond 10 years has been observed. Usual clinical features include intrauterine growth retardation, psychomotor retardation, asymmetric growth, broad nasal bridge, syndactyly, genital anomalies, and irregular skin pigmentation (194). Truncal obesity was seen in some patients (195).

Mitotic nondisjunction cannot readily explain the occurrence of diploid and triploid cell lines in the same individual. One possible mechanism is double fertilization of an ovum by two sperms; one sperm nucleus fuses with the ovum nucleus, producing the diploid line, followed by a second sperm fertilizing one of the early blastomeres producing the triploid line. Cytogenetic evidence for such a mechanism has been reported in at least one case (196). Another proposed mechanism supported by molecular evidence is delayed incorporation of the second polar body into one of the early blas-tomeres. The triploid cell line in this case is digynic (197).

Tetraploidy

The chromosome number in tetraploidy is 4n=92. It is rarer than triploidy in spontaneous abortuses, seen in approximately 6-7% of such specimens with chromosome abnormalities (175,176). Tetraploid conceptuses usually abort spontaneously early in gestation and only rarely do they survive to term. A probable origin of tetraploidy is chromosome duplication in the zygote resulting from a failure of cytoplasmic cleavage during the first division. Other theoretically possible mechanisms require the occurrence of two independent, rare events and are, thus, highly unlikely.

At least eight apparently nonmosaic tetraploid liveborns have been reported (reviewed in ref. 198). The sex chromosome complement was either XXXX or XXYY. No 92,XYYY or XXXY conceptus has been reported. The most frequent abnormalities were growth and developmental delay, hypoto-nia, craniofacial anomalies (short palpebral fissures, low-set malformed ears, high arched/cleft palate, micrognathia), and contracture/structural abnormalities of the limbs, hands, and feet. Cardiac defects were present in three cases. Urinary tract abnormalities, such as hypoplastic kidneys, have also been recorded. Most patients died before 1 years of age. One girl had survived to 22 months at the time of report (199).

Mosaic tetraploidy (diploid/tetraploid mixoploidy) has been reported in 12 liveborns (reviewed in ref. 200,201). Tetraploid cells were seen in peripheral blood lymphocytes, skin fibroblasts, and bone marrow cells. In one severely malformed patient who died at 2 days of age, tetraploid cells were found in 95% of bone marrow cells (202). In two females, aged 11 and 21 years, with severe intellectual handicaps and skin pigmentary dysplasia, tetraploid cells were found only in skin fibroblasts (201). In lymphocytes, the proportion of tetraploid cells decreases with age (203). Overall, clinical features are similar to but less severe than those in nonmosaic tetraploidy patients. In addition to the longer survivals mentioned above (201), survivals to 6 years at the time of reporting have also been recorded (204).

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