title: A 46,XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation.
abstract: 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.
authors: Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands.
authors: Remko
authors: R
authors: Hersmus
authors: Yvonne G
authors: YG
authors: van der Zwan
authors: Hans
authors: H
authors: Stoop
authors: Pascal
authors: P
authors: Bernard
authors: Rajini
authors: R
authors: Sreenivasan
authors: J Wolter
authors: JW
authors: Oosterhuis
authors: Hennie T
authors: HT
authors: Brüggenwirth
authors: Suzan
authors: S
authors: de Boer
authors: Stefan
authors: S
authors: White
authors: Katja P
authors: KP
authors: Wolffenbuttel
authors: Marielle
authors: M
authors: Alders
authors: Kenneth
authors: K
authors: McElreavy
authors: Stenvert L S
authors: SL
authors: Drop
authors: Vincent R
authors: VR
authors: Harley
authors: Leendert H J
authors: LH
authors: Looijenga
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D052159:Frasier Syndrome / Q000235:genetics; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics* / Q000473:pathology; D018238:Gonadoblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D051876:Sex-Determining Region Y Protein / Q000235:genetics*; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
chemical_list: D022821:RNA Splice Sites; D051876:Sex-Determining Region Y Protein; D025721:WT1 Proteins