A case of 46,XX testicular disorders of sex development due to an apparent synonymous variant in the WT1 gene: difficulties of differential diagnosis of intrauterine virililzation syndrome in a girl

Disorders of sex development (DSD) represent a group of congenital conditions in which there is a discrepancy between the chromosomal and (or) gonadal sex and the structure of the genitals. Within the DSD there is a subgroup of 46,XX testicular DSD (46,XX TDSD), which may be caused by the translocation of the SRY gene, and more rarely — due to other causes (SRY-negative forms). In this report, we present an observation of a patient with SRY-negative 46,XX TDSD, in whom the condition was initially regarded as a virile form of congenital adrenal hyperplasia, then as idiopathic intrauterine virilization in a girl. Due to the development of virilization at the age of 11, the presence of testicular tissue was suspected. Molecular genetic analysis (whole exome sequencing with Sanger validation) revealed a de novo variant in exon 9 of the WT1 gene (chr11:32413528T>C), which, according to predictions, did not lead to a change in the amino acid sequence (p.Thr479=, NM_024426.6), but disrupted splicing, resulting in a previously described in 46,XX TDSD a change in the C-terminal domain of WT1. After verification of the diagnosis, a gonadectomy was performed and estrogen replacement therapy was prescribed. Thus, we have described a patient with a rare form of 46,XX TDSD caused by a variant in the WT1 gene. The presented observation illustrates the difficulties of differential diagnosis of intrauterine virilization syndrome in female karyotype.

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