Abstract
Context: We report herein a remarkable family in which the mother of a woman with 46,XY complete gonadal dysgenesis was found to have a 46,XY karyotype in peripheral lymphocytes, mosaicism in cultured skin fibroblasts (80% 46,XY and 20% 45,X) and a predominantly 46,XY karyotype in the ovary (93% 46,XY and 6% 45,X).
Patients: A 46,XY mother who developed as a normal woman underwent spontaneous puberty, reached menarche, menstruated regularly, experienced two unassisted pregnancies, and gave birth to a 46,XY daughter with complete gonadal dysgenesis.
Results: Evaluation of the Y chromosome in the daughter and both parents revealed that the daughter inherited her Y chromosome from her father. Molecular analysis of the genes SOX9, SF1, DMRT1, DMRT3, TSPYL, BPESC1, DHH, WNT4, SRY, and DAX1 revealed normal male coding sequences in both the mother and daughter. An extensive family pedigree across four generations revealed multiple other family members with ambiguous genitalia and infertility in both phenotypic males and females, and the mode of inheritance of the phenotype was strongly suggestive of X-linkage.
Conclusions: The range of phenotypes observed in this unique family suggests that there may be transmission of a mutation in a novel sex-determining gene or in a gene that predisposes to chromosomal mosaicism.
Normal sexual differentiation in 46,XY individuals relies on a complex cascade of numerous genes, many of which have yet to be identified (1,2,3,4,5,6,7,8,9,10,11). Defects in these genes can cause disorders of sexual development of varying severity. The external genitalia and Müllerian structures are typically female in women with complete 46,XY gonadal dysgenesis in association with streak gonads bilaterally. Because the gonads are dysgenetic and nonfunctional, spontaneous pubertal development seldom occurs in these women (12), and successful pregnancy is even more unusual; unassisted pregnancy is unheard of (1). There have been a few instances of fertility in 46,XX/46,XY true hermaphrodites (13), but no reports of fertility in a 46,XY woman. Pregnancy in Turner syndrome is reported to be possible in about 2% of cases, although it is rare for unassisted pregnancy to occur in nonmosaic Turner patients possessing only a 45,X line (14).
Herein we report the extraordinary case of a fertile woman with normal ovaries and a predominantly 46,XY ovarian karyotype, who gave birth to a 46,XY female with complete gonadal dysgenesis. The karyotype of this phenotypically normal mother was 46,XY in blood, 80% 46,XY and 20% 45,X in cultured skin fibroblasts, and 93% 46,XY, 6% 45,X, and <1% 46,XX in the ovary. The family pedigree on the mother’s side was notable for the presence of seven individuals over four generations with either sexual ambiguity, infertility, or failure to menstruate, including one individual with documented 45,X/45,XY mixed gonadal dysgenesis. Both the mother and the 46,XY daughter were screened for mutations in a number of genes known to be involved in mammalian testis determination. In all genes screened (see below), the open reading frame was found to be normal. This suggests that a mutation in a novel sex-determination gene or a gene that predisposes to chromosomal mosaicism may be responsible for the phenotype in this family.