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45,X/47,XX,+18 constitutional mosaicism: clinical presentation and evidence for a somatic origin of the aneuploid cell lines
  1. Istituto di Genetica Medica, Facoltà di Medicina e Chirurgia “A Gemelli”, Università Cattolica del S Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
  2. Laboratorio di Citogenetica, Servizio di Anatomia ed Istologia Patologica, Azienda Ospedaliera S Giovanni-Addolorata, Rome, Italy
    1. Istituto di Genetica Medica, Facoltà di Medicina e Chirurgia “A Gemelli”, Università Cattolica del S Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
    2. Laboratorio di Citogenetica, Servizio di Anatomia ed Istologia Patologica, Azienda Ospedaliera S Giovanni-Addolorata, Rome, Italy

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      Editor—Constitutional mosaicism for two distinct chromosome aneuploidies is a rare cytogenetic abnormality. Usually in such cases, an autosomal aneuploidy is associated with a gonosomal aneuploidy. Little is known about the sequence of errors leading to such complex conditions. The only available studies addressing this issue concern three mosaic autosomal/gonosomal cases involving chromosome 8 (two cases) and chromosome 21 (one case), in all of which chimerism could be ruled out.1 2 A mitotic origin was inferred for both mosaic trisomy 8 cases,1 whereas the initial error in the trisomy 21 mosaic most likely occurred at meiosis.2

      So far, trisomy 18 combined with monosomy X has been observed in three cases.3-5 We have recently observed a fourth patient with mosaic monosomy X/trisomy 18. We report the clinical and cytogenetic characteristics and the results of molecular analysis, which was undertaken in order to determine the origin of the aneuploid cell lines.

      The female proband was the second child of healthy, unrelated parents. There was no family history of congenital anomalies or chromosome disorders. The father was 32 and the mother 34 years old at the time of her birth. She was born at term after an uneventful pregnancy and her birth weight was 3600 g. Psychomotor development was slightly delayed and she attended school up to the age of 14 years. Menarche occurred at 11 years, with regular menses up to 15 years. Thereafter, menses became progressively less frequent, until secondary amenorrhoea developed at 18 years of age.

      The patient was referred for clinical and cytogenetic evaluation at the age of 23 years 2 months because of secondary amenorrhoea, mild mental retardation, and minor congenital anomalies. On clinical examination, height was 150.5 cm (3rd centile), weight 76 kg (>97th centile), and occipitofrontal circumference (OFC) 56 cm (50th centile). The face was asymmetrical, with a narrow nose and prominent nasal root and columella (fig 1). The ears were large and low set, with folded helices and large lobes (fig 1). The mouth was small, with a thin vermilion border and highly arched palate. There was bilateral cubitus valgus, brachydactyly, left Dubois sign, and abundance of white lines on both palms. Dermatoglyphics were (right)t, abcd,LUWWWW and (left) t, abcd,LUAAWW. There were bilateral genua valga, flat feet, and asymmetry of the lower limbs, the right being 2 cm shorter than the left. Several naevi were present on the face, trunk, and limbs. The patient had been treated for dorsal scoliosis. Pelvic ultrasound showed hypoplasia of the uterus and gonads, with normal kidneys. Brain magnetic resonance imaging showed a partially empty sella with pituitary hypoplasia.

      Figure 1

      (A) Front and (B) lateral view of the proband aged 23 years 2 months. (Photographs reproduced with permission.)

      A cytogenetic investigation performed on peripheral blood lymphocytes showed the presence of a mosaic chromosome constitution, 45,X/47,XX,+18. Out of a total of 200 metaphases scored, 25% were 45,X and 75% were 47,XX,+18. The distribution of the two cell lines was found to be reversed in skin fibroblasts; the 45,X and 47,XX,+18 karyotypes were found in 77% and 23% of the cells, respectively. Trisomy 18 was confirmed by fluorescence in situ hybridisation with a chromosome 18 specific painting probe (Oncor, Gaithesburg, MD). Parental chromosomes were normal.

      In order to determine the mechanisms underlying mosaic aneuploidy, genomic DNA extracted from peripheral blood leucocytes and skin fibroblasts was subjected to 30 rounds of PCR amplification in the presence of α32P-dCTP, followed by electrophoresis on denaturing polyacrylamide gels. The average genetic distance between the informative chromosome 18 loci investigated was 13.5 cM according to the integrated Genethon and CHLC maps. The parental origin of the missing X chromosome was determined by visual comparison of band intensities within and between individual electrophoretic lanes.

      The proband’s DNA displayed both a paternal and a maternal allele at X chromosome loci DXS1003, ALAS2, DXS983, DXS984, and DXS454 (fig 2). However, the latter showed consistently reduced intensity compared to the former on visual inspection of the autoradiograms. This difference was more pronounced in DNA extracted from skin fibroblasts, where the majority of the cells were monosomic for the X chromosome, than in leucocyte DNA, where the XX hyperdiploid line predominated. Based upon these data, it was concluded that the zygote initially possessed both a paternally and a maternally derived X chromosome, and subsequently lost the maternal copy at an early stage of development.

      Figure 2

      Typing of X chromosome and chromosome 18 microsatellite polymorphisms. The locus investigated is indicated below each autoradiogram. F=father, Dl=daughter, lymphocyte DNA, Df=daughter, skin fibroblast DNA; M=mother.

      A single paternal and a single maternal allele were observed in the proband’s DNA at the following informative loci on chromosome 18: D18S59, D18S476, D18S63, D18S464, D18S542, D18S453, D18S56, D18S468, D18S450, D18S483, D18S543, and D18S844 (fig 2). Although double crossovers between two adjacent markers might have occurred, the likelihood of such events is very low, in view of the spacing of the loci investigated. Therefore, it was concluded that the trisomic cell line most likely originated in a somatic cell at the postzygotic stage.

      The clinical manifestations observed in our proband can be attributed to the combined effects of mosaic monosomy X and trisomy 18. The phenotype of the three previously reported cases with a similar chromosome constitution is highly variable, ranging from multiple malformations with early mortality5 to normal intelligence with predominance of Turner stigmata.3 4 In our proband clinical manifestations attributable to trisomy 18, such as mild mental retardation, small mouth with thin lips, arches on the fingertips, and partially empty sella, were more pronounced compared to two of the previous patients who had a lower proportion of trisomic cells both in blood and in skin fibroblasts3 4 (table1).

      Table 1

      Clinical and cytogenetic findings in X0/+18 mosaicism

      However, it must be noted that, owing to lack of information on the distribution of the aneuploid cell lines in additional tissues and at different stages of development, clear cut correlations between phenotypic expression and cytogenetic findings cannot always be established. Thus, the severe trisomy 18 manifestations observed in a 45,X/47,XY,+18 patient who had a relatively low proportion of trisomic cells in both lymphocytes and fibroblasts5 (table 1) may be related to the presence of a higher fraction of trisomic cells in other tissues. Also, the percentage of trisomic cells in peripheral blood is not always associated with more severe manifestations in mosaic trisomy 18 cases, as shown by the finding of trisomy 18 in 100% of lymphocytes and 8% of skin fibroblasts in a girl with normal intelligence and mild dysmorphism.6

      The results of microsatellite typing suggest that both aneuploidies originated as independent somatic events at an early developmental stage. Since no euploid mitoses were found, the first error, involving chromosome 18, might have occurred at the first zygotic division, giving rise to a trisomic and to a non-viable monosomic cell. Thereafter, the trisomic line should have lost chromosomes X and 18, either simultaneously or at subsequent stages. Alternatively, two independent errors, involving chromosome 18 and the X chromosome, might have occurred separately in the two cells after normal completion of the first zygotic division.

      Theoretically, mixoploid chromosome constitutions may arise by combined meiotic/mitotic errors or by a series of mitotic errors. The latter sequence of events seems to be more common, since it has been reported in three out of four cases, including the present one, in which DNA studies were performed.1 2 It remains to be established whether the concomitance of several independent mitotic errors is determined by chance events or by an underlying chromosome instability, related to disturbance of the mechanisms which control correct chromosome segregation at mitosis. The latter hypothesis might also explain why the observed frequencies of double aneuploidies seem to be higher than those expected based on the prevalences of the single aberrations.7


      The authors are indebted to Laura Alesi and Maurizio Graziosi for expert technical assistance.


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