Three sisters with XY gonadal dysgenesis and sex reversal - a new variant? W. Just¹, A. Sinkus², L. Andriuskeviciute², L. Jurkeniene², C. Geerkens¹, I. Reisert³, W. Vogel¹, A. Baumstark¹. 1) Dept Medical Genetics, Univ Ulm, Ulm, Germany; 2) Dept Biology, Kaunas Medical Academy, Kaunas, Lithuania; 3) Dept Anatomy and Cell Biology, Univ Ulm, Ulm, Germany.

   Gonadal dysgenesis in females with an XY karyotype may be the consequence of mutations in SRY. Since the discovery of SRY, mutations in other genes and deletions of defined chromosomal regions have been reported which also may lead to XY sex reversal.
   We report on a family with three sisters, all XY females. Histological examination of their gonads showed only ovarian tissues. It consisted of hypoplastic ovarian stroma with degenerated primary and secondary follicles. No testicular structures were apparent. The presence of SRY was confirmed by PCR. A sequence analysis of the coding region did not reveal any mutation. Loss of heterozygosity was studied for markers in distal 9p, a region where deletions also contribute to gonadal dysgenesis. From the marker analyses it was apparent that all sisters had two alleles and all inherited the same allele from their father. This may indicate a mutation in a gene (DMT1?) from this chromosomal region.
   Since the pedigree suggests an X-chromosomal mode of inheritance, we studied the dosage of genes from Xp21 - the DSS region (dosage-sensitive sex reversal). By quantitative Southern blot a double dosage of the DAX1 gene from this interval was excluded. With a total of 28 microsatellite markers from the X chromosome we screened for co-segregation of the disorder with these markers. They had in common a 15.65 Mb interval ranging from DXS1202 (Xp21.3-p21.2) to DXS1003 (Xp11.3) including the DSS region.
   Genetic studies on mutations/deletions of WT1 and SOX9 were not considered, because the sisters did not show symptoms of Campomelic dysplasia (SOX9) or kidney cancer (WT1).
   We conclude that mutations rather than dosage differences in a gene(s) from distal 9p or from a region around DSS may be responsible for the XY sex reversal.