CYP11A1 – 46,XY Disorder of Sex Development with Adrenal Insufficiency

The autosomal recessive disorder congenital adrenal insufficiency with 46,XY sex reversal due to CYP11A1 deficiency is characterized by deficient cholesterol side‐chain cleavage by P450scc, encoded by CYP11A1, leading to cortisol and androgen biosynthesis failure (PMID:19116240). Patients present with primary adrenal insufficiency (HP:0000846) manifesting as hyperpigmentation (HP:0000953) and 46,XY DSD such as hypospadias (HP:0000047) and cryptorchidism (HP:0000028). Inheritance is autosomal recessive with homozygous and compound heterozygous variants segregating in multiple families.

Initial reports described a novel homozygous L222P mutation (c.665T>C (p.Leu222Pro)) in a 46,XY patient with late‐onset adrenal failure and midshaft hypospadias, showing residual P450scc activity of ~7% (PMID:19116240). Two siblings compound heterozygous for frameshift c.835del (p.Ile279fs) and c.806C>T (p.Ala269Val) retained ~11% activity and presented with a nonclassic lipoid CAH phenotype (PMID:21159840). Another family harbored compound heterozygous c.1315C>T (p.Arg439Ter) and c.1396C>T (p.Arg466Trp) in two siblings with early adrenal insufficiency and hyperpigmentation (PMID:36593618).

A larger series of seven patients from Bedouin kindreds revealed compound heterozygosity for c.694C>T (p.Arg232Ter) and c.644T>C (p.Phe215Ser), with residual activity of 2.5%, and additional novel null and hypomorphic variants including c.806C>T (p.Ala269Val), demonstrating a broad clinical spectrum without adrenal hyperplasia (PMID:23337730). A 46,XY patient homozygous for c.1076C>T (p.Ala359Val) presented at 1 yr 9 mo with complete sex reversal and corpus callosum agenesis, retaining ~11% activity (PMID:16705068). Compound heterozygous L141W (c.422T>G) and V415E (c.1244T>A) retained 38% and 0% activity, respectively, correlating with severe DSD and early‐onset adrenal failure (PMID:18182448).

Additional reports include two brothers with isolated adrenal insufficiency carrying c.1351C>T (p.Arg451Trp), preserving ~30% activity and normal genitalia (PMID:21880796), and a patient compound heterozygous for c.1078C>T (p.Arg360Trp) and c.1213C>T (p.Arg405Ter) with penoscrotal hypospadias and delayed adrenal crisis (PMID:22968487). Site‐directed mutagenesis of key lysine and arginine residues confirmed critical roles in adrenodoxin binding and enzymatic activity (PMID:11173513, PMID:12081479).

Mechanistically, pathogenic CYP11A1 variants result in loss‐of‐function causing haploinsufficiency under stress. Functional assays in HEK293 and COS‐1 cells demonstrate concordant reductions in pregnenolone synthesis across missense alleles (2.5–38% residual activity) and null alleles (0% activity) (PMID:19116240, PMID:23337730, PMID:18182448). Animal models and cellular rescue experiments further validate that reduced P450scc activity recapitulates adrenal and gonadal phenotypes.

Together, genetic and experimental data support a Strong gene‐disease association. Autosomal recessive inheritance, co‐segregation in at least 6 families, and consistent in vitro loss‐of‐function provide high clinical validity. Key take‐home: CYP11A1 sequencing should be implemented in 46,XY DSD with adrenal insufficiency to enable precise diagnosis and guide hormone replacement strategies.

References

• The Journal of clinical endocrinology and metabolism • 2009 • A novel homozygous mutation in CYP11A1 gene is associated with late-onset adrenal insufficiency and hypospadias in a 46,XY patient. PMID:19116240
• The Journal of clinical endocrinology and metabolism • 2011 • Partial defect in the cholesterol side-chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia. PMID:21159840
• BMJ case reports • 2022 • Two siblings with non-classic P450scc deficiency resulted from a novel mutation in CYP11A1 gene misdiagnosed as familial glucocorticoid deficiency. PMID:36593618
• The Journal of clinical endocrinology and metabolism • 2013 • Varied clinical presentations of seven patients with mutations in CYP11A1 encoding the cholesterol side-chain cleavage enzyme, P450scc. PMID:23337730
• The Journal of clinical endocrinology and metabolism • 2008 • Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. PMID:18182448
• Frontiers in endocrinology • 2011 • A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). PMID:21880796
• European journal of endocrinology • 2012 • Delayed diagnosis of adrenal insufficiency in a patient with severe penoscrotal hypospadias due to two novel P450 side-change cleavage enzyme (CYP11A1) mutations (p.R360W; p.R405X). PMID:22968487
• Biochemistry. Biokhimiia • 2000 • Site-directed mutagenesis of cytochrome P450scc (CYP11A1). Effect of lysine residue substitution on its structural and functional properties. PMID:11173513
• Biochemistry • 2002 • Probing the interaction of bovine cytochrome P450scc (CYP11A1) with adrenodoxin: evaluating site-directed mutations by molecular modeling. PMID:12081479

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