11β-Hydroxysteroid dehydrogenase type 2 in hypertension: comparison of phenotype and genotype analysis

Kosicka, Katarzyna; Cymerys, Maciej; Majchrzak‐Celińska, Aleksandra; Chuchracki, Marek; Główka, Franciszek

doi:10.1038/jhh.2012.67

Cited by 14 publications

(6 citation statements)

References 31 publications

(70 reference statements)

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“…3f), inhibiting binding to MR. Under conditions of impaired 11β-HSD2 function, cortisol which is present in 1000–2000 times higher concentrations compared to aldosterone, binds to MR, causing enhanced Na + − reabsorption which in turn leads to the expansion of intravascular fluid, causing hypertension [42]. Diagnosis of BS in the 6 month old patient described here was made based on hypokalemic metabolic alkalosis with low birth weight, failure to thrive and poor growth.…”

Section: Discussionmentioning

confidence: 99%

Mimicry and well known genetic friends: molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis

Najafi

Kordi-Tamandani

Behjati

et al. 2019

Orphanet J Rare Dis

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Background Bartter Syndrome is a rare, genetically heterogeneous, mainly autosomal recessively inherited condition characterized by hypochloremic hypokalemic metabolic alkalosis. Mutations in several genes encoding for ion channels localizing to the renal tubules including SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, MAGED2 and CASR have been identified as underlying molecular cause. No genetically defined cases have been described in the Iranian population to date. Like for other rare genetic disorders, implementation of Next Generation Sequencing (NGS) technologies has greatly facilitated genetic diagnostics and counseling over the last years. In this study, we describe the clinical, biochemical and genetic characteristics of patients from 15 Iranian families with a clinical diagnosis of Bartter Syndrome. Results Age range of patients included in this study was 3 months to 6 years and all patients showed hypokalemic metabolic alkalosis. 3 patients additionally displayed hypercalciuria, with evidence of nephrocalcinosis in one case. Screening by Whole Exome Sequencing (WES) and long range PCR revealed that 12/17 patients (70%) had a deletion of the entire CLCNKB gene that was previously identified as the most common cause of Bartter Syndrome in other populations. 4/17 individuals (approximately 25% of cases) were found to suffer in fact from pseudo-Bartter syndrome resulting from congenital chloride diarrhea due to a novel homozygous mutation in the SLC26A3 gene, Pendred syndrome due to a known homozygous mutation in SLC26A4 , Cystic Fibrosis (CF) due to a novel mutation in CFTR and apparent mineralocorticoid excess syndrome due to a novel homozygous loss of function mutation in HSD11B2 gene. 1 case (5%) remained unsolved. Conclusions Our findings demonstrate deletion of CLCNKB is the most common cause of Bartter syndrome in Iranian patients and we show that age of onset of clinical symptoms as well as clinical features amongst those patients are variable. Further, using WES we were able to prove that nearly 1/4 patients in fact suffered from Pseudo-Bartter Syndrome, reversing the initial clinical diagnosis with important impact on the subsequent treatment and clinical follow up pathway. Finally, we propose an algorithm for clinical differential diagnosis of Bartter Syndrome. Electronic supplementary material The online version of this article (10.1186/s13023-018-0981-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Mimicry and well known genetic friends: molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis

Najafi

Kordi-Tamandani

Behjati

et al. 2019

Orphanet J Rare Dis

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“…Severe hypertension and hypokalemic alkalosis are associated with endorgan damage in AME, especially affecting cardiovascular and nervous systems, kidneys, and retina [3]. Variability in biochemical parameters (the ratio of cortisol to cortisone) is related to the underlying genetic defect [31], so genetic testing is a precise and effective tool to detect HSD11B2 mutations [6,32]. Hence, our study also highlights the utility of next-generation sequencing for diagnosing AME even where enzymatic characterization is unavailable.…”

Section: Discussionmentioning

confidence: 71%

Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia

Peng

Yang

et al. 2020

Endocrine

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Purpose Apparent 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. Methods Next-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. Results Next-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). Conclusions We 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.

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“…Kosicka et al found no significant differences in UFF/UFE between hypertensives and controls. 39 However, the median of UFF/ UFE was higher in hypertensives (n = 79) than the controls (n = 70), but not significant. UFF/UFE exceeded the reference range, ≤0.6 in 15.9% of hypertensive subjects and 7.1% of normotensives.…”

Section: Disscussionmentioning

confidence: 74%

11-Beta Dehydrogenase Type 2 Activity Is Not Reduced in Treatment Resistant Hypertension

Ghazi

Dudenbostel

Hachem

et al. 2017

American Journal of Hypertension

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11β-Hydroxysteroid dehydrogenase type 2 in hypertension: comparison of phenotype and genotype analysis

Cited by 14 publications

References 31 publications

Mimicry and well known genetic friends: molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis

Mimicry and well known genetic friends: molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis

Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia

11-Beta Dehydrogenase Type 2 Activity Is Not Reduced in Treatment Resistant Hypertension

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