A 46,XY Female DSD Patient with Bilateral Gonadoblastoma, a Novel SRY Missense Mutation Combined with a WT1 KTS Splice-Site Mutation

被引：24

作者：

Hersmus, Remko ^{[1
]}

van der Zwan, Yvonne G. ^{[1
,9
]}

Stoop, Hans ^{[1
]}

Bernard, Pascal ^{[2
]}

Sreenivasan, Rajini ^{[2
,3
]}

Oosterhuis, Wolter ^{[1
]}

Brueggenwirth, Hennie T. ^{[4
]}

de Boer, Suzan ^{[5
]}

White, Stefan ^{[5
]}

Wolffenbuttel, Katja P. ^{[6
]}

Alders, Marielle ^{[7
]}

McElreavy, Kenneth ^{[3
,8
]}

Drop, Stenvert L. S. ^{[9
]}

Harley, Vincent R. ^{[2
]}

Looijenga, Leendert H. J. ^{[1
]}

机构：

[1] Erasmus MC Univ, Med Ctr, Josephine Nefkens Inst, Daniel den Hoed Canc Ctr,Dept Pathol, Rotterdam, Netherlands

[2] Prince Henrys Inst Med Res, Mol Genet & Dev Div, Clayton, Vic, Australia

[3] Univ Melbourne, Dept Anat & Cell Biol, Melbourne, Vic, Australia

[4] Erasmus MC Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands

[5] Monash Inst Med Res, Ctr Reprod & Dev, Clayton, Vic, Australia

[6] Erasmus MC Univ, Med Ctr, Dept Pediat Urol, Rotterdam, Netherlands

[7] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands

[8] Inst Pasteur, Human Dev Genet Unit, Paris, France

[9] Erasmus MC Univ, Med Ctr, Dept Pediat Endocrinol, Sophia Childrens Hosp, Rotterdam, Netherlands

来源：

PLOS ONE | 2012年 / 7卷 / 07期

基金：

英国医学研究理事会;

关键词：

GERM-CELL TUMORS; TESTICULAR DYSGENESIS SYNDROME; MALE SEXUAL DEVELOPMENT; FRASIER-SYNDROME; NUCLEAR IMPORT; MOSAIC FATHER; SOX9; EXPRESSION; DISORDERS; DIFFERENTIATION;

D O I：

10.1371/journal.pone.0040858

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：8