Abstract
Disclosure: P. Sharma: None. Introduction: 46 XX complete gonadal dysgenesis is characterized by primary amenorrhea and lack of spontaneous pubertal development due to lack of ovarian development in individuals with 46XX karyotype. Recent literature supports a role for BRCA gene mutation in the causation of complete gonadal dysgenesis. We report a case of a 64 year old female with 46 XX complete gonadal dysgenesis who was found to have a BRCA2 gene mutation at a later age. Clinical Case: A 64 year old female presented for a consultation for complete gonadal dysgenesis. At 15 years of age, she was evaluated for primary amenorrhea and lack of puberty. Evaluation showed absent ovaries with small fallopian tubes and uterus. Karyotyping showed 46XX karyotype. Patient was diagnosed with 46 XX complete gonadal dysgenesis and treated with estradiol and progesterone, following which she underwent puberty. At 50 years of age, she underwent total hysterectomy with bilateral salphingo-oopherectomy due to cervical carcinoma in situ. Surgical pathology showed uterus and fallopian tubes, but no ovarian material was identified. At 61 years of age, patient underwent genetic testing due to family history of BRCA mutation positive breast cancer and was found to have BRCA2 c.6944_6947del heterozygous mutation, associated with autosomal dominant hereditary breast and ovarian cancer syndrome and autosomal recessive Fanconi anemia. Since BRCA2 has a role in ovarian development and function, we believe that BRCA2 mutation played a critical role in this patient’s gonadal dysgenesis. Conclusion: The BRCA2 gene is a genome stability gene which helps with DNA repair. Ovarian development depends on normal repair of double stranded DNA breaks during meiosis. Therefore, mutations of DNA repair genes such as BRCA2 may affect ovarian development and function. BRCA1/2 mutations have been associated with decreased ovarian reserve and premature ovarian failure. Animal model studies in drosophila models have confirmed severe gonadal dysgenesis in flies without Dmbrca2 (the drosophilia orthologue of BRCA2) and small gonads in Zebrafish without BRCA2 gene. Patients with Fanconi anemia due to BRCA2 mutations have hypoplastic gonads (male) and premature ovarian failure (females). There is a case report of two sisters with 46 XX complete gonadal dysgenesis caused by BRCA2 mutation. In 2019, a patient with 46 XY gonadal dysgenesis (Swyer Syndrome) was found to have BRCA2 mutation. While more clinical studies are needed to establish a causal relationship, we suggest that BRCA2 mutations are associated with complete gonadal dysgenesis. Therefore, once a diagnosis of complete gonadal dysgenesis is confirmed, gene testing for BRCA2 mutation should be pursued. Presentation: Monday, July 14, 2025