title: A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma.
abstract: 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.
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Remko
authors.initials: R
authors.lastname: Hersmus
authors.forename: Bertie H C G M
authors.initials: BH
authors.lastname: de Leeuw
authors.forename: Hans
authors.initials: H
authors.lastname: Stoop
authors.forename: Pascal
authors.initials: P
authors.lastname: Bernard
authors.forename: Helena C
authors.initials: HC
authors.lastname: van Doorn
authors.forename: Hennie T
authors.initials: HT
authors.lastname: Brüggenwirth
authors.forename: Stenvert L S
authors.initials: SL
authors.lastname: Drop
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Harley
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D006061:Gonadal Dysgenesis, 46,XY / Q000150:complications* / Q000235:genetics*; D018238:Gonadoblastoma / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D006066:Gonads / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D051876:Sex-Determining Region Y Protein / Q000235:genetics*
chemical_list: C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein