A girl with 7 1,xXXXYkaryotype Maaswinkel-Mooij PD, van Zwieten P, Mollervanger P,van Noort E, Beverstock G. A girl with 71,XXXXY karyotype. Clin Genet 1992: 41: 96-99.

P. 0. Maatwinkel-Moolj'J, P. van Zwieten', P. Mollevanger', L van Nooff and 6. Beverstocp

A girl with a 7 1,XXXXY karyotype is described. Internal and external genitalia were female despite the presence of a Y-chromosome.

Departments of 'Clinical Genetics, 2Pediatrics and SCytogenetics. University Hospital Leiden, The Netherlands

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Key words in situ hybridiration sex chrome m e aneuploidy sex reversal triploidy

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Dr. F! l l MaaswinkeCMooij, Clinical Genetics Centre, University Hospital Leiden. PO Box 9600, NL-2300 RC Leiden, The Netherlands Received 4 March, revised 5 August, accepted for publication 8 September 1991

Triploidy is a relatively common form of chromosome abnormality among humans, occurring in some 1-3% of all recognized conceptuses (Boue et al. 1981). Gestation most frequently ends in spontaneous abortion. Very few triploid foetuses survive to term; those that do are delivered prematurely and die in the early postnatal period. Triploidy in combination with sex chromosome aneuploidy is rare; to our knowledge only four cases have been reported: 48,XXYY/71 ,XXXYY mosaicism in a boy (Schmid & Vischer 1967), 70,XXYY karyotype in a foetus (Meisner et al. 1987) and 68,XX karyotype in two first trimester abortions (Uchida & Freeman 1985). In this report we describe a liveborn girl with 71,XXXXY karyotype. Female internal and external genitalia were found, despite the presence of a Y-chromosome. Case history

This phenotypic girl was born at 34 weeks of pregnancy, the first child of healthy, unrelated parents, aged 27 and 25 years. Echoscopy at 15 weeks was consistent with a gestational age of 13.5 weeks. At 32 weeks, severe intrauterine growth retardation was noted. The mother's blood pressure was normal. No gross congenital malformations were seen on foetal echoscopy; amniotic fluid was sparse. Cordocentesis for chromosomal analysis was unsuccessful. Because of foetal distress, a caesarean section was performed. The baby was primarily intubated and ventilated. Apgar scores were 2, 6 and 9 at 1, 5 and 10 min, respectively. Birth weight was 700 g ( < < P2,3), and head circumference 26.6 98

Fig. 1. Postmortem view of the girl with 7I.XXXXY karyotype.

A girl with 71,XXXXY karyotype

cm ( < < < P2,3). Growth retardation was disproportional, with a large head relative to body size (Fig. 1). Physical examination revealed multiple congenital anomalies: incomplete ossification of the calvaria; small upturned nose with low nasal bridge; large poorly shaped ears with a low placed auricular canal; micrognathia and ocular hypertelorism, although the eyes appeared normal. Bilateral syndactyly of the third and fourth finger and clinodactyly of the fifth finger were present, with ulnar deviation of the fingers. The first and especially the second toes were remarkably long. External genitalia were female but no clitoris was seen; the vulvar opening was short with a long perineum. Echographic examination of the brain revealed some ventricular dilatation. Artificial ventilation was very difficult and several drains had to be inserted for pneumothorax and pneumomediastinum. The girl was oliguric and later anuric. She was hypotonic and did not respond to external stimuli. As soon as the results of the chromosome analysis were known, which showed a 71,XXXXYkaryotype, ventilation was disconnected and the baby succumbed immediately.

Postmortem examination revealed further abnormalities: bilateral atresia of the external meatus acous ticus; lung hypoplasia with abnormal lobulation; obstruction of the foramen ovale with hypertrophy of the left ventricle; aplasia of the gallbladder; malformation of the ileocaecal wing; a very low-placed right kidney; both kidneys were microscopically normal with a slight dilatation of the tubuli. Internal genitalia were female; only one ovary was found, with two Fallopian tubes and a normal uterus. The placenta weighed 120 g and appeared to be normal with three vessels in the umbilical cord. Material and methods Cytogenetics

Chromosome preparations were made according to standard techniques. The karyotype was 71,XXXXY(Fig. 2). A skin fibroblast culture confirmed this finding; there was no evidence of mosaicism. Discontinuous pulse labeling of the chromosomes with bromo-oxyuridine BUdR according to

\r

1

2

4

3

I

x .

-420

21

22

Y

Fig. 2. The 71,XXXXY karyotype.

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Maaswinkel-Mooij et al. the method of Dutrillaux et al. (1976) showed that three of the four X-chromosomes were inactive.

In sifuhybridisation The X-chromosome centromere-specific probe pBamX5 (Willard et al. 1983) was labelled by standard nick translation with biotin-1 1-UTP (Sigma, U.S.A.). The unstained chromosome preparations were treated according to the procedure previously described by Beverstock et al. (1990). Four positive, X-chromosome specific signals were seen not only in all metaphases but also in almost all interphase nuclei. Discussion

Triploidy is the most frequent chromosome aberration in first trimester spontaneous abortion (Schintel 1984). It is not infrequently found in premature and stillborn infants, occurring in 1 in 60 000 liveborns. Triploidy with autosome aneuploidy seems rather common in first trimester abortions; it was described by Uchida & Freeman (1985) in 8 triploids out of a sample of 105 triploids found among a consecutive series of early spontaneous abortions. However, the combination of triploidy with sex chromosome aneuploidy is less frequent. In the report of Uchida & Freeman ( 1985) two foetuses with 68,XX were found in their series of first trimester abortions. Furthermore, a boy with mental retardation and multiple congenital anomalies with 48,XXYY/7 1,XXXYY diploidtriploid mosaicism was reported by Schmid & Vischer (1967), and a 70,XXYY karyotype in a foetus was discovered as a result of elevated levels of alpha-foetoprotein in maternal serum (Meisner et al. 1987). Our patient is the first liveborn child with non-mosaic triploidy and sex chromosome aneuploidy. Phenotypically, our patient showed many features seen in regular triploidy. However, there were some striking differences: namely the long first and second toes, the atretic auditory canals and the abnormal ileocaecal wing. The low-placed right kidney might be related to the abnormal embryogenesis of the internal genitalia. Despite the presence of a Y-chromosome, confirmed by QFQ-banding, our patient had female internal and external genitalia. Patients with 69,XXY triploidy show varying degrees of ambiguous external genitalia with hyperplasia of Leydig cells as a common finding in testicular histology (Schinzel 1984). Patients with a 49,XXXXY karyotype have male external genitalia with a small penis, small or undescended testes and a small or hypoplastic scrotum (Sarto et al. 1987).The patient 98

with 48,XXYY/71,XXXYY mosaicism showed normal male genitalia (Schmid & Vischer 1967). The external genitalia in the 70,XXYY foetus were female, while the internal genitalia were male (Meisner et al. 1987). Due to the genetic imbalance in our patient, with three sets of autosomes in the presence of four X-chromosomes (of which only one was active) and one Y-chromosome, the male phenotype was completely suppressed; female development, however, was also disturbed since no clitoris and only one ovary were found. Diandry is the most frequent cause of triploidy, with dispermy being more common than fertilisation by a diploid sperm (Boue et al. 1988). Fertilisation from a diploid ovum, arising from the fusion of the second polar body with one of the daughter nuclei of the first or second zygotic division, by a haploid sperm, has also been demonstrated (Uchida & Freeman 1985). There are three possible explanations for the presence of the supernumerary sex chromosomes in our patient. Firstly, if dispermy was the cause of the triploidy, a haploid ovum could have been fertilised simultaneously by a normal haploid X-bearing sperm cell together with an XXY sperm cell, resulting from non-disjunction at the first and second meiotic division of paternal spermatogenesis, Secondly, a non-disjunction in the first meiotic division of female oogenesis could have resulted in a haploid gamete with two X chromosomes. After fusion of the second polar body with one of the daughter nuclei of the first zygotic division, a diploid XXXX ovum is formed. After fertilisation with a haploid Y-bearing sperm cell, the triploid XXXXY karyotype is completed. Lastly, there is the possibility that a diploid ovum is fertilised by a haploid XXY gamete, as a result of a meiotic error in both the father and the mother.

References Beverstock GC, Ploem JE, Wessels HW, Keur Dvd, Mollevanger P. Trisomy 13 and myelodysplastic syndrome. Cancer Genet Cytogenet 1990: 48: 179-182. Boue A, Couillon P, Boue A. Mechanisms of triploidy. Clin Genet 1981: 19: 493. Dutrillaux B, Couturier J, Richter C-L, Viegas-Peguignot E. Sequence of DNA replication in 277 R- and Q-bands of human chromosomes using BUdR treatment. Chromosoma 1976: 58: 51-61. Meisner LF, Louie LR, Arya S, Gilbert EF. Triploidy with an extra sex chromosome (70,XXYY) and elevated alphafoetoprotein levels. BD:OAS 1987: 23: 333-339. Sarto GE, Otto PG, Kuhn EM, Therman E. What causes the abnormal phenotype in an 49,XXXXY male? Hum Genet 1987: 76: 1-4. Schinzel A. Triploidy and triploidy mosaicism. In: Catalogue of unbalanced chromosome aberrations in man, Schinzel A

A girl with 71,XXXXY karyotype ed. Berlin, New York: Walter De Gruyter & CO., 1984: 747-753. Schmid W, Vischer D. A malformed boy with double aneuploidy and diploid-triploid mosaicism 48XXYY /7 I XXXYY. Cytogenetics 1967: 6: 145-155.

Uchida IA, Freeman VCP. Triploidy and chromosomes. Am J Obstet Gynecol 1985: 151: 65-69. Willard HF, Smith KD, Sutherland J. Isolation and characterisation of a major tandem repeat family from the human Xchromosome. Nucl Acids Res 1983: 11: 2017-2033.

A girl with 71,XXXXY karyotype.

A girl with a 71,XXXXY karyotype is described. Internal and external genitalia were female despite the presence of a Y-chromosome...
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