CYP11B1 – Congenital Adrenal Hyperplasia due to 11-beta-hydroxylase deficiency

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder resulting from biallelic pathogenic variants in CYP11B1, which encodes the mitochondrial cytochrome P450 enzyme responsible for conversion of 11-deoxycortisol to cortisol. A series of three unrelated classic 11-beta-hydroxylase deficiency patients established the first splice donor site mutation (c.954+1G>A) and new nonsense (c.55C>T (p.Gln19Ter)) and missense alleles, confirming a mutational hotspot at codon 318 and suggesting founder effects in certain populations (PMID:9435454).

Further case reports expand the number of probands to at least eleven across geographically diverse families, including a misdiagnosed Taiwanese child with hypertension and hypokalemia (PMID:15549155), a Tunisian kindred homozygous for p.Gly379Val (PMID:33708317), and sibling pairs demonstrating segregation of T318= and R123G alleles (PMID:29858860). Segregation analysis in Jews of Moroccan ancestry (prevalence 1 in 5000–7000 births) revealed consistent homozygosity for p.Arg448His, highlighting a population-specific founder mutation (PMID:8481357).

The CYP11B1 variant spectrum comprises splice-site (c.954+1G>A; c.954+1G>C), nonsense (c.55C>T (p.Gln19Ter)), missense (c.953C>G (p.Thr318Arg)), frameshift and in-frame deletions. Recurrent alleles such as p.Thr318Arg and p.Gln356Ter are reported in multiple unrelated patients, supporting hot-spot and founder models. Genetic testing routinely detects these alleles in probands presenting with hypertension (HP:0000822), hypokalemia (HP:0002900) and virilization or precocious puberty (HP:0001250).

Phenotypically, patients exhibit cortisol deficiency, androgen excess with virilization, mineralocorticoid precursor accumulation leading to early-onset hypertension and hypokalemic episodes. Biochemical diagnosis is confirmed by elevated 11-deoxycortisol levels. Regular blood pressure monitoring and steroid profiling distinguish 11-beta-hydroxylase deficiency from 21-hydroxylase deficiency in ambiguous CAH cases.

Functional assays in COS-7 cells and yeast demonstrate that splice, nonsense and missense CYP11B1 alleles abolish steroid 11-beta-hydroxylase activity, consistent with loss-of-function pathogenesis (PMID:7903314; PMID:8506298). Exon skipping and truncation resulting from splice-site mutations further confirm haploinsufficiency. Glucocorticoid replacement reverses hypertension and biochemical abnormalities, providing rescue evidence.

Heterozygous carriers maintain sufficient enzyme function and do not display clinical or hormonal abnormalities (PMID:8530633), affirming the autosomal recessive inheritance. No studies have convincingly refuted the CYP11B1–11-beta-hydroxylase deficiency association.

Integration of genetic segregation, variant spectrum and concordant functional data fulfills ClinGen criteria for a Strong clinical validity. Genetic evidence is Moderate, based on ≥11 probands with diverse biallelic CYP11B1 mutations. Functional evidence is Moderate, with multiple in vitro assays demonstrating enzyme loss. Key take-home: CYP11B1 molecular analysis is essential for definitive diagnosis, clinical management and genetic counseling of 11-beta-hydroxylase deficiency.

References

• The Journal of clinical endocrinology and metabolism • 1998 • Novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency. PMID:9435454
• Journal of the Formosan Medical Association = Taiwan yi zhi • 2004 • Congenital adrenal hyperplasia with 11 beta-hydroxylase deficiency. PMID:15549155
• Hormones (Athens, Greece) • 2018 • Two rare forms of congenital adrenal hyperplasia, 11β hydroxylase deficiency and 17-hydroxylase/17,20-lyase deficiency, presenting with novel mutations PMID:29858860
• The Pan African medical journal • 2020 • Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency in a Tunisian family. PMID:33708317
• The Journal of steroid biochemistry and molecular biology • 1993 • Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. PMID:8481357
• Proceedings of the National Academy of Sciences of the United States of America • 1993 • Mutations in the CYP11B1 gene causing 11 beta-hydroxylase deficiency cluster in exons 6, 7, and 8. PMID:8506298
• The Journal of clinical endocrinology and metabolism • 1993 • A nonsense mutation (TGG [Trp116]-->TAG [Stop]) in CYP11B1 causes steroid 11 beta-hydroxylase deficiency. PMID:7903314
• The Journal of clinical endocrinology and metabolism • 1995 • Absence of steroid biosynthetic defects in heterozygote individuals for classic 11 beta-hydroxylase deficiency due to a R448H mutation in the CYP11B1 gene. PMID:8530633

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