Endocrine Abstracts

JOINT3980

Introduction: CYP11A1 (P450scc) deficiency is a rare and complex disorder associated with primary adrenal insufficiency and 46,XY disorders of sex development (DSD).

Objective: This study delineates the clinical spectrum and genetic underpinnings of 46,XY sex reversal and adrenal insufficiency, using a detailed case presentation and comprehensive literature review.

Methods: We present a case of congenital adrenal hyperplasia (CAH) due to P450scc deficiency in a patient with complete 46,XY DSD. This case prompted a review of similar reported cases focusing on the onset of adrenal insufficiency (AI), clinical presentations, and gonadal management.

Results: Our index case involves a 4-year-old child, assigned female at birth, presenting with recurrent vomiting, hypoglycemia, fatigue, and hyperpigmentation of the lips and hand creases. Clinical examination revealed clitoromegaly. Laboratory tests indicated mild hyponatremia, low cortisol, elevated ACTH, diminished steroidogenesis across all pathways, low aldosterone, and elevated renin. Diagnosis of primary adrenal insufficiency was established, and treatment with hydrocortisone and fludrocortisone was initiated. Chromosomal analysis confirmed a 46,XY karyotype. Pelvic MRI showed no female internal genitalia and bilateral inguinal gonads. Whole exome sequencing revealed a homozygous variant in CYP11A1, confirming P450scc deficiency. The literature review included 25 cases, all demonstrating mutations in the CYP11A1 gene. The mean age at presentation of AI was 3.7 years, ranging from neonates to 18 years. The most common clinical presentations involved ambiguous genitalia or undervirilization (90%) and signs of adrenal crisis or insufficiency (50%). Genital appearances varied, with micropenis, cryptorchidism, and bifid scrotum being prevalent. Approximately 60% had non-palpable or undescended testes. Gonadal management typically involved surveillance or gonadectomy, based on malignancy risk and anatomical findings, with no established timing for surgery.

Conclusion: This case report and literature review underscore the heterogeneity in presentation and genetic variability of 46,XY sex reversal and adrenal insufficiency. Importantly, mutations in the CYP11A1 gene were present in all cases reviewed, highlighting the critical role of genetic analysis in diagnosis. Early genetic screening and multidisciplinary management are crucial for optimizing patient outcomes, suggesting a need for further research into tailored therapeutic approaches.