Endocrine Abstracts

JOINT1880

Background: The inheritance mode of P450scc deficiency caused by CYP11A1 mutations remains unclear. It was previously considered an autosomal recessive disorder, but sporadic cases of heterozygous mutations have been reported.

Objective: To report a case of non-classic P450scc deficiency caused by a heterozygous mutation in CYP11A1 and review similar cases in the literature.

Patients and Methods: An 11-year-7-month-old female presented with a 1-year history of facial hair growth, deepening of the voice, and hyperpigmentation. She had a history of fatigue since childhood but no other obvious signs of adrenal insufficiency. Physical examination revealed Tanner stage 3 pubic hair, clitoromegaly, a urogenital sinus opening on the perineum, and scrotum bifid with no palpable testes. Laboratory tests showed elevated ACTH, LH 9.17 IU/l, FSH 16.81 IU/l, testosterone 10.2 nmol/l, and decreased levels of cortisol, 17α-hydroxyprogesterone, progesterone, dehydroepiandrosterone, and androstenedione. AMH was 2.55 ng/ml. INHB was 179.38 pg/ml. Karyotype analysis showed 46,XY. Ultrasound revealed normal adrenal glands, testes in pelvis, and no uterus or ovaries. She was the first child of non-consanguineous parents, with a normal birth history and healthy parents and a younger sister (46,XX). Whole exome sequencing was performed on the patient. Cases of CYP11A1 heterozygous mutations causing adrenal insufficiency (AI) with or without disorders of sex development (DSD) reported in PubMed and CNKI databases were reviewed.

Results: The patient was found to have a heterozygous mutation in the CYP11A1 gene (c.1379G>A, p.R460Q), which has been associated with P450scc dysfunction. Combined with her clinical manifestations and steroid hormone levels, the diagnosis of P450scc deficiency was confirmed. Her mother and younger sister also had the same mutation but were asymptomatic. A literature review identified 5 patients from 4 families. Family 1 had a spontaneous mutation (c.809_814dupGGGACG) presenting with AI and 46,XY DSD. Family 2 had a mutation (c.235G>A) with a 46,XY proband presenting with AI, while the father and sister with the same mutation also had AI. Family 3 had a mutation (c.431C>A) with a 46,XX proband presenting with AI, but the mother with the same mutation was asymptomatic. Family 4 had a mutation (c.1076C>T) with a proband presenting with AI and 46,XY DSD, while the mother and brother with the same mutation were asymptomatic.

Conclusion: Heterozygous mutations in CYP11A1 can cause P450scc deficiency. There is significant clinical variability among heterozygous mutation carriers, and family members with the same mutation may be asymptomatic.