CYP11B2 – Corticosterone Methyl Oxidase Type II Deficiency

Corticosterone methyl oxidase type II (CMO II) deficiency is a rare autosomal recessive disorder of aldosterone biosynthesis characterized by an elevated serum 18-hydroxycorticosterone to aldosterone ratio and salt wasting in early infancy. The condition presents with failure to thrive, recurrent dehydration, hyponatraemia and hyperkalaemia due to impaired 18-oxidation of 18-hydroxycorticosterone by aldosterone synthase, encoded by the CYP11B2 gene.

A case report described a male infant with recurrent dehydration and severe failure to thrive within the first 3 months of life, mild hyponatraemia (serum Na+ 127–132 mEq/l), and hyperkalaemia (serum K+ 5.3–5.9 mEq/l). Biochemical screening revealed an elevated plasma renin activity to aldosterone ratio and an increased 18-hydroxycorticosterone to aldosterone ratio, confirming CMO II deficiency; mineralocorticoid replacement normalized growth and renin levels ([PMID:1601005]).

Molecular analysis in seven Iranian-Jewish kindreds identified two missense variants in CYP11B2: c.541C>T (p.Arg181Trp) and c.1157T>C (p.Val386Ala). All affected individuals were homozygous for both mutations, while eight asymptomatic relatives were homozygous for p.Arg181Trp alone and three for p.Val386Ala alone, confirming autosomal recessive inheritance and complete segregation across seven families ([PMID:1594605]).

The variant spectrum in CMO II deficiency is limited to missense alleles affecting the 18-oxidase function. The recurrent founder alleles p.Arg181Trp and p.Val386Ala both impair 18-oxidase activity, with p.Arg181Trp abolishing oxidation completely and p.Val386Ala causing a moderate reduction in 18-hydroxylase efficiency.

Functional assays in transfected cells demonstrated that the p.Arg181Trp substitution abolishes 18-oxidase activity while preserving 11β-hydroxylase function, and p.Val386Ala induces a partial but consistent decrease in 18-hydroxylase output, consistent with the leaky nature of CMO II deficiency ([PMID:1594605]). These concordant functional data support a loss-of-function mechanism.

Integration of genetic and experimental findings yields a strong clinical validity for CYP11B2 in CMO II deficiency, with eight probands across seven families, clear autosomal recessive segregation, and consistent functional impairment of aldosterone synthase activity. Genetic testing for the c.541C>T (p.Arg181Trp) variant facilitates early diagnosis and management of life-threatening salt-wasting in infancy.

References

• European journal of pediatrics • 1992 • Corticosterone methyl oxidase type II deficiency: a cause of failure to thrive and recurrent dehydration in early infancy. PMID:1601005
• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. PMID:1594605

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