Tetraploidy

Cytogenetic and autopsy findings of a nonmosaic tetraploid male neonate, alive until shortly after birth at 37 weeks' gestation, are described. Oligohydramnios, intrauterine growth retardation, cranial abnormalities, and Dandy-Walker malformation were noted prenatally. Autopsy findings included cleft lip and palate; overlapping fingers; low-set ears; simian creases; hypoplastic external genitalia with undescended testes; Dandy-Walker malformation; slightly dilated lateral and third ventricles; hypoplasia of the cerebrum, pons, medulla, pituitary gland, thymus, lung, adrenal gland, and kidney; large ventricular septal defect; and enteric cyst behind the urinary bladder. The placenta was hypoplastic and showed no remarkable abnormalities, except for mild syncytial knots. Chromosome analyses of amniotic fluid cells at 31 weeks' gestation and the umbilical cord blood cells at delivery revealed a 92,XXYY karyotype. G-, C-, Q-, and N-banding heteromorphic studies demonstrated duplication of paternal chromosomes 1, 3, and 15, and maternal chromosome 22. In addition, the results of an analysis with 16 CA repeat polymorphic markers were consistent with duplicated inheritance of 1 paternal and 1 maternal haploid sets to the tetraploid patient. Therefore, it is most likely that the tetraploidy was caused by a cytoplasmic cleavage failure at the first mitotic division.

Tetraploidy in humans is usually lethal, and fetuses found to have it are usually aborted at the first trimester and rarely proceed to birth. The incidence of tetraploidy is 2.0% to 3.2% in spontaneous abortions and 5% to 6% among abortuses with chromosomal abnormalities.1 Thirteen liveborn infants with nonmosaic tetraploidy have been described in the literature to date.2-5 Anatomical abnormalities most often reported in these infants include positional limb defects, craniofacial abnormalities, and urinary tract/kidney abnormalities.2 Nonmosaic tetraploidy may occur by (a) trispermic fertilization of a haploid ovum,6 (b) fertilization of a diploid ovum by a diploid sperm, (c) cytoplasmic cleavage failure at the first mitotic division of the fertilized ovum,7 or (d) fusion of 2 fertilized cells.7,8

We recently encountered a tetraploid male newborn. In this article, we report the autopsy findings together with the origin of the tetraploidy.

REPORT OF A CASE

The male newborn described was the first child of healthy and nonconsanguineous parents. The mother was 27 years old at the time of delivery. Ultrasound evaluation of the fetus at 26 weeks' gestation suggested oligohydramnios, intrauterine growth retardation, and some cranial abnormalities. Fetal magnetic resonance imaging revealed Dandy-Walker malformation, indicating a large cystic lesion (Figure 1, a). The baby was born at 37 weeks' gestation and died of respiratory failure shortly after birth. His birth weight was 1728 g (normal value with standard deviation score, 2462 ± 821 g), and his length was 42 cm (44.5 ± 7.0 cm).

AUTOPSY FINDINGS

Complete pathologic examinations of the neonate and the placenta were performed at autopsy. The following physical features were noted: cleft lip and palate, overlapping fingers, low-set ears, simian creases, obscure dermatoglyphics, and hypoplastic external genitalia. The brain weighed 210 g (298 ± 70 g). As the distended roof of the fourth ventricle formed a large cyst, and the lower part of the vermis cerebelli was defective, a diagnosis of Dandy-Walker malformation was made (Figure 1, b). The cerebrum, pons, and medulla were hypoplastic. The lateral and third ventricles were slightly dilated. The basilar artery was normal. Other pathologic findings included bilateral pulmonary hypoplasia (left: 4.1 g, right: 5.8 g, normal bilateral: 38.7 ± 22.9 g; lung/body weight ratio: 0.0057, normal: >0.012), bilateral hypoplasia of the adrenal glands (left: 0.2 g, right: 0.1 g, normal bilateral: 6.6 ± 3.3 g) and kidneys (left: 3 g, right: 2.2 g, normal bilateral: 23.3 ± 9.9 g), hypoplasia of the pituitary gland and thymus, large ventricular septal defect, enteric cyst located behind the urinary bladder, and undescended testes. The placenta was hypoplastic (295 g, normal: 420 ± 45 g) and showed no remarkable abnormalities, except for mild syncytial knots.

CHROMOSOME AND POLYMORPHIC MARKER STUDIES

Amniocentesis and subsequent G-banding chromosome analysis were performed at 31 weeks' gestation for prenatal karyotyping of the fetus. Fluorescence in situ hybridization analysis was performed on noncultured amniotic fluid cells using a probe for chromosome 18 (D18Z1CEP, Vysis, Inc, Abbott Park, Ill), because trisomy 18 was first suspected from the ultrasound findings. G-, C-, Q-, and N-banding chromosome analyses were performed again at delivery on cultured lymphocytes from umbilical cord blood and from the parents' peripheral blood lymphocytes. Parent-child transmission of alleles was studied at 16 CA repeat marker loci on chromosomes 1-3, 9-13, 15-17, 19, 20, 22, and X by the method describee previously.9

RESULTS AND COMMENT

All 48 cultured amniotic fluid cells and all 20 cord blood lymphocytes had a 92,XXYY karyotype. Fluorescence in situ hybridization analysis using D18Z1CEP showed 4 signals in most of the cells we analyzed (Figure 2, a). From these findings, the neonate was diagnosed as nonmosaic tetraploid, although the placenta and other fetal tissues were not karyotypically analyzed. The G-, C-, N-, and Q-banding heteromorphism analysis demonstrated that the neonate inherited in duplicate 1 paternal homologous member for chromosomes 1, 3, and 15, and 1 maternal chromosome 22 (Figure 2, b through g). The results of CA repeat marker analysis were consistent with duplicated inheritance of 1 each of maternal and paternal alleles at all 16 loci examined in the patient (Table). Thus, a lack of evidence for the inheritance of both members of any parental homologs to the patient ruled out both trispermy and the fertilization of diploid ovum by diploid sperm, and indicated that the tetraploidy was composed of a duplicated diploid genome, that is, duplication of 1 each of paternally derived and maternally derived haploid sets of chromosomes. It is most likely that the nonmosaic tetraploidy of the neonate was caused by a cytoplasmic cleavage failure at the first mitotic division.

Many pathologic findings of tetraploidy have been reported.2,4 The abnormalities frequently reported included positional limb defects and craniofacial abnormalities.2 The tetraploid newborn we describe here did not have limb defects but presented with craniofacial anomalies, such as Dandy-Walker malformation and cleft lip and palate. Among our findings, Dandy-Walker malformation, bilateral pulmonary hypoplasia, and enteric cyst are unique to tetraploidy and merit attention. Although Dandy-Walker malformation has frequently been reported in chromosome abnormalities,10,11 it has not previously been described in tetraploidy. Bilateral pulmonary hypoplasia is associated with various chromosome abnormalities and oligohydramnios, and may have been the cause of death in this newborn. Hypoplasia of other organs, such as the adrenal glands, kidney, pituitary gland, and thymus, may also be attributed to tetraploidy. It has been suggested that some anomalies observed in triploids and tetraploids overlap with those in 13- and 18-trisomics. This observation may support a hypothesis that the ratio between different chromatin portions and/or a balance between chromosomes is more important in determining the phenotype than the absolute chromosome numbers.12 Alternatively, the phenotypic similarity may be attributed to a selection bias for these trisomies by which individuals tend to survive until birth. The placenta in the present tetraploid neonate appeared hypoplastic and had mild syncytial knots, but did not show molar changes. This may reflect no excess of paternally derived haploid sets, such as those by trispermy, supporting the somatic origin of the present tetraploidy. Tetraploids with trispermy may show swollen chorionic villus, such as hydatidiform mole in dispermic triploid fetuses.6,13

In conclusion, we have described a male newborn with nonmosaic tetraploidy due to a cytoplasmic cleavage failure at the first mitosis. Since tetraploidy frequently occurs as an artifact of in vitro cell culture,2,14 it is necessary to confirm its nonmosaicism in noncultured cells by various techniques, such as flow cytometry,2 comparative genomic hybridization,15 or fluorescence in situ hybridization, as in the present case.

References

1. Kaufman MH. New insights into triploidy and tetraploidy, from an analysis of model systems for these conditions. Hum Reprod. 1991;6:8-16.

2. Coe SJ, Kapur R, Luthardt F, Rabinovitch P, Kramer D. Prenatal diagnosis of tetraploidy: a case report. Am J Med Genet. 1993;45:378-382.

3. Sagot P, Nomballais MF, David A, et al. Prenatal diagnosis of tetraploidy. Fetal Diagn Ther. 1993;8:182-186.

4. Teyssier M, Gaucherand P, Buenerd A. Prenatal diagnosis of a tetraploid fetus. Prenat Diagn. 1997;17:474-478.

5. Meiner A, Holland H, Reichenbach H, Horn LC, Faber R, Froster UG. Tetraploidy in a growth-retarded fetus with a thick placenta. Prenat Diagn. 1998;18:864-865.

6. Sheppard DM, Fisher RA, Lawler SD, Povey S. Tetraploid conceptus with three paternal contributions. Hum Genet. 1982;62:371-374.

7. Kajii T, Niikawa N. Origin of triploidy and tetraploidy in man: 11 cases with chromosome markers. Cytogenet Cell Genet. 1977;18:109-125.

8. Meulenbroek GH, Geraedts JP. Parental origin of chromosome abnormalities in spontaneous abortions. Hum Genet. 1982;62:129-133.

9. Miyoshi O, Kondoh T, Taneda H, Otsuka K, Matsumoto T, Niikawa N. 47,XX,UPD(7)mat, +r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS) gene from a 7p13-q11 region. J Med Genet. 1999;36:326-329.

10. Murru P, Coscia A, Martano C, et al. Complex cerebral malformation including Dandy-Walker in a newborn with trisomy 9 mosaicism. Radiol Med (Torino). 2002;103:261-263.

11. Myles TD, Burd L, Font G, McCorquodale MM, McCorquodale DJ. Dandy-Walker malformation in a fetus with pentasomy X (49,XXXXX) prenatally diagnosed by fluorescence in situ hybridization technique. Fetal Diagn Ther. 1995;10:333-336.

12. Golbus MS, Bachman R, Wiltse S, Hall BD. Tetraploidy in a liveborn infant. J Med Genet. 1976;13:329-332.

13. Surti U, Szulman AE, Wagner K, Leppert M, O'Brien SJ. Tetraploid partial hydatidiform moles: two cases with a triple paternal contribution and a 92,XXXY karyotype. Hum Genet. 1986;72:15-21.

14. Kohn G, Robinson A. Tetraploidy in cells cultured from amniotic fluid. Lancet. 1970;2:778-779.

15. Daniely M, Barkai G, Goldman B, Aviram-Goldring A. Detection of numerical chromosome aberrations by comparative genomic hybridization. Prenat Diagn. 1999;19:100-104.

Yasuhiro Nakamura, MD; Michiyo Takaira, CT; Etsuko Sato, CT; Katuichi Kawano, MD; Osamu Miyoshi, MD; Norio Niikawa, MD

Accepted for publication August 1, 2003.

From the Departments of Clinical Laboratories (Dr Nakamura, Ms Takaira, and Ms Sato) and Obstetrics (Dr Kawano), St Mary's Hospital, Kurume, Japan; the Department of Neuropsychiatry, Mie University School of Medicine, Tsu, Japan (Dr Miyoshi); and the Department of Human Genetics, Nagasaki University School of Medicine, Nagasaki, lapan (Dr Niikawa).

Reprints: Yasuhiro Nakamura, MD, Department of Clinical Laboratories, St Mary's Hospital, Tsubukuhon-machi 422, Kurume, Japan, 830-8543 (e-mail: naka@st-mary-med.or.jp).

Copyright College of American Pathologists Dec 2003
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