ESPE Abstracts (2014) 82 FC6.4

Familial 46,XY Complete Female External Sex Development and Primary Amenorrhea Along with Hidden Gonad Tumors, Secondary to a Novel p.met64val SRY Gene Mutation

Elisa Vaiania, Carmen Malosettib, Roxana Marinoa, Pablo Ramireza, Natalia Perez Garridoa, Esperanza Berensztaina, Florencia Da Cola, Marcela Baileza, Josefina Salaa, Laura Galluzzoa, Mercedes Maceirasa, Juan Manuel Lazzatia, Marco Rivarolaa & Alicia Belgoroskya


aHospital de Pediatria Garrahan, Buenos Aires, Argentina; bHospital de Niños de San Justo, Buenos Aires, Argentina


Background: The SRY protein is a transcription factor that contains a high mobility group (HMG) homeobox domain which possesses sequence-specific DNA binding activity and regulates other genes involved in male sex determination pathway. The majority of the identified mutations occurred within the HMG-box motif. There are few reports of pedigrees with familial transmission.

Objective and Hypotheses: To describe a paternally transmitted novel SRY mutation within the HMG-box (p.Met64Val) in two 46,XY sisters aged 16 (P1) and 14 (P2) years old, referred because of primary amenorrhea without sexual ambiguity.

Method: Direct DNA sequencing and in silico tools were used to identify SRY gene mutations and to predict the pathogenicity. Hormonal, pelvic ultrasound (PU), and Histopathological studies were also carried out.

Results: In silico prediction models indicated that the substitution p.Met64Val probably affects protein function. Breast development was Tanner II and IV, PU revealed Mullerian structures and two gonads resembling ovaries in P1 and P2 respectively. In P2, a complex 3.7 cm long cyst was found in left ovary. In P1 and P2 endocrine studies revealed high levels of LH (22.6; 24.7 mUI/ml) and FSH (61.7; 73.8 mUI/ml), normal AMH (30.7; 21.6 pmol/l), low E2 (<9; 33.6 pg/ml), and undetectable testosterone, AFP and βhCG respectively. Histopathological examination of gonads revealed: P1: left dysgenetic gonad without evidence of tumor, and right gonadoblastoma. In P2: left gonadal dysgerminoma, and gonadoblastoma in both.

Conclusion: Complete penetrance and/or somatic mosaicism are two hypotheses that may explain a normal phenotype in a father carrying this novel SRY mutation transmitted to 46, XY daughters. 46 XY dysgenetic gonads have a high risk of developing germ cells tumors. Acyclic sexual development can occur due to estrogen synthesis by gonad tumor or dysgentic cells. Mutations in human SRY associated with somatic sex reversal provide a model for a genetic switch in organogenesis.