Patients with
disorders of sex development (DSD), especially those with
gonadal dysgenesis and hypovirilization, are at risk of developing the so-called type II
germ cell tumors (GCTs). Both
carcinoma in situ and
gonadoblastoma (GB) can be the precursor lesion, resulting in a seminomatous or non-seminomatous invasive
cancer. SRY mutations residing in the HMG domain are found in 10-15% of
46,XY gonadal dysgenesis cases. This domain contains two
nuclear localization signals (NLSs). In this study, we report a unique case of a phenotypical normal woman, diagnosed as a patient with
46,XY gonadal dysgenesis, with an NLS missense mutation, on the basis of the histological diagnosis of a unilateral GB. The normal role of SRY in gonadal development is the upregulation of SOX9 expression. The premalignant lesion of the initially removed gonad was positive for OCT3/4, TSPY and
stem cell factor in germ cells, and for FOXL2 in the stromal component (ie, granulosa cells), but not for SOX9. On the basis of these findings, prophylactical
gonadectomy of the other gonad was performed, also showing a GB lesion positive for both FOXL2 (ovary) and SOX9 (testis). The identified W70L mutation in the SRY gene resulted in a 50% reduction in the nuclear accumulation of the
mutant protein compared with wild type. This likely explains the diminished SOX9 expression, and therefore the lack of proper Sertoli cell differentiation during development. This case shows the value of the proper diagnosis of human GCTs in identification of patients with DSD, which allows subsequent early diagnosis and prevention of the development of an invasive
cancer, likely to be treated by
chemotherapy at young age.