HSD11B2 – Apparent Mineralocorticoid Excess

Apparent Mineralocorticoid Excess (AME) is an autosomal recessive disorder caused by biallelic loss-of-function variants in the HSD11B2 gene (HGNC:5209), which encodes 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). This enzyme inactivates cortisol to cortisone in renal epithelial cells, preventing inappropriate activation of the mineralocorticoid receptor by glucocorticoids. Deficiency of 11β-HSD2 leads to sodium retention, hypokalemia, metabolic alkalosis, low renin, suppressed aldosterone, and early-onset, salt-dependent hypertension.

Genetic studies have identified at least 101 patients from over 40 unrelated families harbouring 54 distinct pathogenic HSD11B2 variants ([PMID:32816205]). Segregation analyses in multiple consanguineous kindreds demonstrated AME in 19 additional affected relatives beyond index cases. Both homozygous and compound heterozygous configurations consistently result in enzymatic deficiency and the AME phenotype.

The variant spectrum comprises missense substitutions (e.g., c.1009C>T (p.Arg337Cys)), deletions (e.g., c.895_897del (p.Tyr299del)), small insertions, splice-site changes, and premature stop codons. The R337C mutation was first reported in an Iranian family and remains a recurrent founder allele ([PMID:7593456]). Compound heterozygous R208H/ΔY338 was described in a Japanese patient, illustrating diverse ethnic founder effects ([PMID:9398712]).

Functional assays of mutant 11β-HSD2 confirm a loss-of-function mechanism. R337C exhibits a ten-fold increase in Km and is inactive in cell-free preparations, with reduced stability in intact cells ([PMID:7593456]; [PMID:8733000]). R208H abolishes enzyme activity in transfected cells ([PMID:9398712]). Variants such as p.Pro227Leu and p.Tyr299del show partial residual activity and elevated Km, correlating with milder phenotypes ([PMID:9707624]; [PMID:15126515]).

Pathogenic HSD11B2 variants elicit mineralocorticoid receptor overstimulation by cortisol, driving the classic AME clinical triad of juvenile low-renin hypertension, hypokalemia, and metabolic alkalosis. Carriers of single pathogenic alleles may exhibit salt sensitivity or mild essential hypertension, suggesting dosage effects in heterozygosity ([PMID:10760070]).

No studies have conclusively refuted the HSD11B2–AME relationship. Promoter polymorphisms can modulate salt sensitivity but do not cause classical AME ([PMID:17551100]).

Collectively, the genetic and functional evidence meets ClinGen criteria for a Definitive gene-disease association. Genetic testing of HSD11B2 informs early diagnosis, enables targeted use of mineralocorticoid receptor antagonists and low-dose glucocorticoids, and prevents irreversible end-organ damage. Key Take-Home: Biallelic pathogenic HSD11B2 variants definitively cause AME, and their detection directly guides precision therapy.

References

• The Journal of clinical endocrinology and metabolism • 1995 • The R337C mutation generates a high Km 11 beta-hydroxysteroid dehydrogenase type II enzyme in a family with apparent mineralocorticoid excess. PMID:7593456
• The Journal of clinical endocrinology and metabolism • 1997 • A new compound heterozygous mutation in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. PMID:9398712
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • A genetic defect resulting in mild low-renin hypertension. PMID:9707624
• Kidney international • 2000 • Role of the 11beta-hydroxysteroid dehydrogenase type 2 in blood pressure regulation. PMID:10760070
• Pediatric nephrology (Berlin, Germany) • 2000 • Nephrocalcinosis and renal cysts associated with apparent mineralocorticoid excess syndrome. PMID:11095013
• The Journal of clinical endocrinology and metabolism • 2004 • In vitro expression studies of a novel mutation delta299 in a patient affected with apparent mineralocorticoid excess. PMID:15126515
• Endocrine • 2020 • Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia. PMID:32816205
• Hypertension research : official publication of the Japanese Society of Hypertension • 2006 • Genetic variations of HSD11B2 in hypertensive patients and in the general population, six rare missense/frameshift mutations. PMID:16778331
• FASEB journal : official publication of the Federation of American Societies for Experimental Biology • 2007 • Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity. PMID:17551100
• The Journal of clinical endocrinology and metabolism • 2022 • Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. PMID:36329487

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