Patients with
Disorders of Sex Development (DSD), especially those with
gonadal dysgenesis and hypovirilization are at risk of developing malignant type II
germ cell tumors/
cancer (GCC) (
seminoma/
dysgerminoma and nonseminoma), with either
carcinoma in situ (CIS) or
gonadoblastoma (GB) as precursor lesion. In 10-15% of
46,XY gonadal dysgenesis cases (i.e.,
Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of
DNA.
Frasier syndrome (FS) is characterized by
gonadal dysgenesis with a high risk for development of GB as well as
chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the
Wilms' tumor 1 gene (WT1). Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development. Embryonic germ cells residing in this unfavourable micro-environment have an increased risk for malignant transformation. Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as
hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY. Functional in vitro studies showed no convincing
protein malfunctioning. Laparoscopic examination revealed streak ovaries and a normal, but small, uterus. Pathological examination demonstrated bilateral GB and
dysgerminoma, confirmed by immunohistochemistry. Occurrence of a delayed progressive
kidney failure (focal segmental glomerular
sclerosis) triggered analysis of WT1, revealing a pathogenic splice-site mutation in intron 9. Analysis of the SRY gene in an additional five FS cases did not reveal any mutations. The case presented shows the importance of multi-gene based diagnosis of DSD patients, allowing early diagnosis and treatment, thus preventing putative development of an invasive
cancer.