A case of a parthenogenetic 46,XX/46,XY chimera presenting ambiguous genitalia

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Abstract

Sex-chromosome discordant chimerism (XX/XY chimerism) is a rare chromosomal disorder in humans. We report a boy with ambiguous genitalia and hypospadias, showing 46,XY[26]/46,XX[4] in peripheral blood cells. To clarify the mechanism of how this chimerism took place, we carried out whole-genome genotyping using a SNP array and microsatellite analysis. The B-allele frequency of the SNP array showed a mixture of three and five allele combinations, which excluded mosaicism but not chimerism, and suggested the fusion of two embryos or a shared parental haplotype between the two parental cells. All microsatellite markers showed a single maternal allele. From these results, we concluded that this XX/XY chimera is composed of two different paternal alleles and a single duplicated maternal genome. This XX/XY chimera likely arose from a diploid maternal cell that was formed via endoduplication of the maternal genome just before fertilization, being fertilized with both X and Y sperm.

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Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis.

Laura Conlin, Brian D Thiel, Carsten Bönnemann … (2010)

Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1-3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.

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Androgenetic/biparental mosaicism causes placental mesenchymal dysplasia.

James McFadden, K. Rao, Timothy Robinson … (2006)

Placental mesenchymal dysplasia (PMD) is a distinct syndrome of unknown aetiology that is associated with significant fetal morbidity and mortality. Intrauterine growth restriction is common, yet, paradoxically, many of the associated fetuses/newborns have been diagnosed with Beckwith-Wiedemann syndrome (BWS). We report two cases of PMD with high levels of androgenetic (complete paternal uniparental isodisomy) cells in the placenta and document, in one case, a likely androgenetic contribution to the fetus as well. The same haploid paternal complement found in the androgenetic cells was present in coexisting biparental cells, suggesting origin from a single fertilisation event. Preferential allocation of the normal cells into the trophoblast explains the absence of trophoblast overgrowth, a key feature of this syndrome. Interestingly, the distribution of androgenetic cells appears to differ from that reported for artificially created androgenetic mouse chimeras. Androgenetic mosaicism for the first time provides an aetiology for PMD, and may be a novel mechanism for BWS and unexplained intrauterine growth restriction.

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Chimera and other fertilization errors.

M Vekemans, C Turleau, V Malan (2006)

The finding of a mixture of 46,XX and 46,XY cells in an individual has been rarely reported in literature. It usually results in individuals with ambiguous genitalia. Approximately 10% of true human hermaphrodites show this type of karyotype. However, the underlying mechanisms are poorly understood. It may be the result of mosaicism or chimerism. By definition, a chimera is produced by the fusion of two different zygotes in a single embryo, while a mosaic contains genetically different cells issued from a single zygote. Several mechanisms are involved in the production of chimera. Stricto sensu, chimerism occurs from the post-zygotic fusion of two distinct embryos leading to a tetragametic chimera. In addition, there are other entities, which are also referred to as chimera: parthenogenetic chimera and chimera resulting from fertilization of the second polar body. Furthermore, a particular type of chimera called 'androgenetic chimera' recently described in fetuses with placental mesenchymal dysplasia and in rare patients with Beckwith-Wiedemann syndrome is discussed. Strategies to study mechanisms leading to the production of chimera and mosaics are also proposed.