Abstract
PurposeApparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) caused by mutations in HSD11B2. The purpose of this study was to identify novel compound heterozygous HSD11B2 mutations in a Chinese pedigree with AME and conduct a systematic review evaluating the AME clinical features associated with HSD11B2 mutations.MethodsNext-generation sequencing was performed in the proband, and Sanger sequencing was used to identify candidate variants in family members, 100 hypertensives, and 100 healthy controls. A predicted structure of 11βHSD2 was constructed by in silico modeling. A systematic review was used to identify cases of HSD11B2-related AME. Data for genotyping and clinical characterizations and complications were extracted.ResultsNext-generation sequencing showed novel compound heterozygous mutations (c.343_348del and c.1099_1101del) in the proband with early-onset hypertension and hypokalemia. Sanger sequencing verified the monoallelic form of the same mutations in five other relatives but not in 100 hypertensives or 100 healthy subjects. In silico structural modeling showed that compound mutations may simultaneously perturb the substrate and coenzyme binding pocket. A systematic review of 101 AME patients with 54 HSD11B2 mutations revealed early-onset hypertension, hypokalemia and homozygous mutations as common features. The homozygous HSD11B2 mutations correlated with low birth weight (r = 0.285, P = 0.02).ConclusionsWe report novel compound heterozygous HSD11B2 mutations in a Chinese teenager with early-onset hypertension, and enriched genotypic and phenotypic spectrums in AME. Genetic testing helps early diagnosis and treatment for AME patients, which may avoid target organ damage.
Highlights
IntroductionThe biochemical and hormonal features of Apparent mineralocorticoid excess (AME) were first described in 1977 by New et al [1], the first causative mutation in HSD11B2 was not discovered until 1995 in a consanguineous Iranian family with AME [2]
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Apparent mineralocorticoid excess (AME, OMIM #218030) is an ultrarare autosomal recessive form of monogenic hypertension
This study aimed to identify novel compound heterozygous mutations in HSD11B2 in a Chinese family with AME
Summary
The biochemical and hormonal features of AME were first described in 1977 by New et al [1], the first causative mutation in HSD11B2 was not discovered until 1995 in a consanguineous Iranian family with AME [2]. AME is characterized by juvenile hypertension, hypokalemia, hypernatremia, low plasma renin activity and Endocrine (2020) 70:607–615 aldosterone concentration, metabolic alkalosis, and responsiveness to spironolactone [6]. It has a spectrum of phenotypes ranging from life-threatening hypertension in infancy to a milder form of the disease in adults [7]. Because of the broad diversity and overlapping clinical features, precise diagnosis of AME is highly reliant on genetic evidence [8]
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