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1.
Eur J Endocrinol ; 190(5): 347-353, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38652803

RESUMO

BACKGROUND AND OBJECTIVE: Apparent mineralocorticoid excess (AME) syndrome is an ultra-rare autosomal-recessive tubulopathy, caused by mutations in HSD11B2, leading to excessive activation of the kidney mineralocorticoid receptor, and characterized by early-onset low-renin hypertension, hypokalemia, and risk of chronic kidney disease (CKD). To date, most reports included few patients, and none described patients from Israel. We aimed to describe AME patients from Israel and to review the relevant literature. DESIGN: Retrospective cohort study. METHODS: Clinical, laboratory, and molecular data from patients' records were collected. RESULTS: Five patients presented at early childhood with normal estimated glomerular filtration rate (eGFR), while 2 patients presented during late childhood with CKD. Molecular analysis revealed 2 novel homozygous mutations in HSD11B2. All patients presented with severe hypertension and hypokalemia. While all patients developed nephrocalcinosis, only 1 showed hypercalciuria. All individuals were managed with potassium supplements, mineralocorticoid receptor antagonists, and various antihypertensive medications. One patient survived cardiac arrest secondary to severe hyperkalemia. At last follow-up, those 5 patients who presented early exhibited normal eGFR and near-normal blood pressure, but 2 have hypertension complications. The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation. CONCLUSIONS: In this 11-year follow-up report of 2 Israeli families with AME, patients who presented early maintained long-term normal kidney function, while those who presented late progressed to ESKD. Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment.


Assuntos
Síndrome de Excesso Aparente de Minerolocorticoides , Humanos , Israel/epidemiologia , Masculino , Feminino , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Estudos Retrospectivos , Criança , Pré-Escolar , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Adolescente , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Mutação , Hipertensão/epidemiologia , Hipopotassemia , Adulto
2.
Eur J Endocrinol ; 189(5): R11-R22, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37847213

RESUMO

Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions. Treatment options for these disorders depend on the distinct underlying pathophysiology, which involves specific pharmacological therapies or surgical adrenalectomy in some instances. This review article summarizes the current state of knowledge on the therapeutic management of congenital forms of endocrine hypertension, focusing on familial hyperaldosteronism (FH), congenital adrenal hyperplasia, apparent mineralocorticoid excess, and Liddle syndrome. We provide an overview of the genetic and molecular pathogenesis underlying each disorder, describe the clinical features, and discuss the various therapeutic approaches available and their risk of adverse effects, aiming to improve outcomes in patients with these rare and complex conditions.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperaldosteronismo , Hipertensão , Síndrome de Excesso Aparente de Minerolocorticoides , Humanos , Hipertensão/genética , Hipertensão/terapia , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/genética , Hiperaldosteronismo/terapia , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/terapia , Esteroides , Aldosterona
4.
Blood Press Monit ; 27(3): 208-211, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35044984

RESUMO

A genetic defect of 11 ß-hydroxysteroid dehydrogenase causes apparent mineralocorticoid excess syndrome. Since 50 days of life, our patient was hospitalized several times for various reasons including hypokalemia. At the age of 3.3 years, she was diagnosed with severe hypertension (160/120 mmHg). She also had left ventricular hypertrophy and hypertensive retinopathy and referred to our center. Her renal function and electrolytes were normal except for hypokalemia. She was on captopril treatment; nifedipine and propranolol were added. Plasma renin and aldosterone concentrations were 1.13 pg/ml (1-8.2 pg/ml) and 12.2 ng/dl (35-300 ng/dl), respectively. Severe hypertension, hypokalemia, low renin and aldosterone levels pointed to the diagnosis of apparent mineralocorticoid excess syndrome. Strict salt-restricted diet and potassium citrate were ordered. Genetic analysis of the HSD11B2 gene showed c.623G>A (p.Arg208His). Spironolactone was initiated. On follow-up, amiloride was added and her blood pressure was controlled. In patients with severe HSD11B2 mutation, combination therapy of spironolactone with amiloride could be effective in controlling blood pressure.


Assuntos
Hipertensão , Hipopotassemia , Síndrome de Excesso Aparente de Minerolocorticoides , Aldosterona , Amilorida , Pressão Sanguínea , Pré-Escolar , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipopotassemia/complicações , Hipopotassemia/etiologia , Síndrome de Excesso Aparente de Minerolocorticoides/complicações , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Renina , Espironolactona/uso terapêutico , Síndrome de Excesso Aparente de Minerolocorticoides
5.
Pflugers Arch ; 473(6): 897-910, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34028587

RESUMO

We discovered high Na+ and water content in the skin of newborn Sprague-Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2-/- animals exhibiting lower skin Na+ and water levels than controls at birth, they retained ~ 30% higher Na+ content in their pelts at the expense of K+ thereafter. Hsd11b2-/- neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na+ through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na+ imbalance in the Hsd11b2-/- neonate leads to excess Na+ storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na+ uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na+ plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney.


Assuntos
Pressão Sanguínea , Síndrome de Excesso Aparente de Minerolocorticoides/metabolismo , Pele/metabolismo , Sódio/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Animais , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley
6.
Endocrine ; 70(3): 607-615, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32816205

RESUMO

PURPOSE: Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) 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 11ßHSD2 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.


Assuntos
Hipertensão , Hipopotassemia , Síndrome de Excesso Aparente de Minerolocorticoides , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Adolescente , Humanos , Hipertensão/genética , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Mutação , Síndrome de Excesso Aparente de Minerolocorticoides
8.
J Transl Med ; 17(1): 392, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775784

RESUMO

BACKGROUND: The "nonclassic" apparent mineralocorticoid excess (NC-AME) has been identified in approximately 7% of general population. This phenotype is characterized by low plasma renin activity (PRA), high serum cortisol (F) to cortisone (E) ratio, low cortisone, high Fractional Excretion of potassium (FEK) and normal-elevated systolic blood pressure (SBP). An early detection and/or identification of novel biomarkers of this phenotype could avoid the progression or future complications leading to arterial hypertension. Isolation of extracellular vesicles, such as exosomes, in specific biofluids support the identification of tissue-specific RNA and miRNA, which may be useful as novel biomarkers. Our aim was to identify miRNAs within urinary exosomes associated to the NC-AME phenotype. METHODS: We perform a cross-sectional study in a primary care cohort of 127 Chilean subjects. We measured BP, serum cortisol, cortisone, aldosterone, PRA. According to the previous reported, a subgroup of subjects was classified as NC-AME (n = 10). Urinary exosomes were isolated and miRNA cargo was sequenced by Illumina-NextSeq-500. RESULTS: We found that NC-AME subjects had lower cortisone (p < 0.0001), higher F/E ratio (p < 0.0001), lower serum potassium (p = 0.009) and higher FEK 24 h (p = 0.03) than controls. We found miR-204-5p (fold-change = 0.115; p 0.001) and miR-192-5p (fold-change = 0.246; p 0.03) are both significantly downregulated in NC-AME. miR-192-5p expression was correlated with PRA (r = 0.45; p 0.028) and miR-204-5p expression with SBP (r = - 0.48, p 0.027) and F/E ratio (r = - 0.48; p 0.026). CONCLUSIONS: These findings could support a potential role of these miRNAs as regulators and novel biomarkers of the NC-AME phenotype.


Assuntos
Regulação para Baixo/genética , Exossomos/genética , MicroRNAs/genética , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Exossomos/ultraestrutura , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Síndrome de Excesso Aparente de Minerolocorticoides/urina , Reprodutibilidade dos Testes , Adulto Jovem , Síndrome de Excesso Aparente de Minerolocorticoides
9.
J Clin Endocrinol Metab ; 104(11): 5205-5216, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225872

RESUMO

CONTEXT: Six patients carrying heterozygous loss-of-function mutations of glucocorticoid (GC) receptor (GR) presented with hypercortisolism, associated with low kalemia, low plasma renin, and aldosterone levels, with or without hypertension, suggesting a pseudohypermineralocorticism whose mechanisms remain unclear. We hypothesize that an impaired activity of the 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2; encoded by the HSD11B2 gene), catalyzing cortisol (F) inactivation, may account for an inappropriate activation of a renal mineralocorticoid signaling pathway in these GC-resistant patients. OBJECTIVE: We aim at studying the GR-mediated regulation of HSD11B2. DESIGN: The HSD11B2 promoter was subcloned and luciferase reporter assays evaluated GR-dependent HSD11B2 regulation, and 11ß-HSD2 expression/activity was studied in human breast cancer MCF7 cells, endogenously expressing this enzyme. RESULTS: Transfection assays revealed that GR transactivated the long (2.1-kbp) HSD11B2 promoter construct, whereas a defective 501H GR mutant was unable to stimulate luciferase activity. GR-mediated transactivation of the HSD11B2 gene was inhibited by the GR antagonist RU486. A threefold increase in HSD11B2 mRNA levels was observed after dexamethasone (DXM) treatment of MCF7 cells, inhibited by RU486 or by actinomycin, supporting a GR-dependent transcription. Chromatin immunoprecipitation further demonstrated a DXM-dependent GR recruitment onto the HSD11B2 promoter. 11ß-HSD2 activity, evaluated by the cortisone/F ratio, quantified by liquid chromatography/tandem mass spectrometry, was 10-fold higher in the supernatant of DXM-treated cells than controls, consistent with a GR-dependent stimulation of 11ß-HSD2 catalytic activity. CONCLUSION: Collectively, we demonstrate that 11ß-HSD2 expression and activity are transcriptionally regulated by GR. In the context of GR haploinsufficiency, these findings provide evidence that defective GR signaling may account for apparent mineralocorticoid excess in GC-resistant patients.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Regulação da Expressão Gênica , Receptores de Glucocorticoides/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Dexametasona/administração & dosagem , Feminino , Células HEK293 , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/genética , Transdução de Sinais , Síndrome de Excesso Aparente de Minerolocorticoides
10.
J Clin Endocrinol Metab ; 104(2): 595-603, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239803

RESUMO

Context: Classical apparent mineralocorticoid excess (AME) is a rare recessive disorder, caused by severe 11ß-hydroxysteroid dehydrogenase type 2 enzyme (11ß-HSD2) deficiency. AME manifests as low-renin pediatric hypertension, hypokalemia and high cortisol/cortisone (F/E) ratio. Objective: To evaluate nonclassic AME (NC-AME) due to partial 11ß-HSD2 insufficiency and its association with hypertension, mineralocorticoid receptor (MR) activation, and inflammatory parameters. Design: Cross-sectional study. Setting: Primary care cohort. Participants: We recruited 127 adolescents and adults. Subjects with secondary hypertension were excluded. We measured clinical, biochemical, renal, vascular, and inflammatory variables. Sequencing of HSD11B2 gene was performed in all subjects. Main Outcome Measure: NC-AME. Results: Serum F/E ratio was positively associated with systolic blood pressure (BP), microalbuminuria, and high-sensitivity C-reactive protein (hs-CRP). Serum cortisone correlated with MR activation parameters even when adjusted for age, body mass index, and sex: lower cortisone with higher potassium excretion (partial r = -0.29, P = 0.002) and with lower plasma renin activity (PRA) (partial r = 0.29, P = 0.001). Consistently, we identified 9 in 127 subjects (7.1%) with high F/E ratios (first quartile) and low cortisone (last quartile), suggestive of NC-AME. These subjects had higher systolic BP, 141.4 ± 25.7 mm Hg vs 127.3 ± 18.1 mm Hg, P = 0.03; lower PRA, 0.36 ± 0.19 ng/L*s vs 0.64 ± 0.47 ng/L*s, P < 0.0001; and greater potassium excretion, microalbuminuria, hs-CRP, and plasminogen activator inhibitor. We only found in 2 out of 9 subjects with NC-AME heterozygous mutations in the HSD11B2 gene. Conclusions: These findings suggest a spectrum of partial 11ß-HSD2 insufficiency in a primary care cohort without the classic phenotype and genotype of AME. NC-AME may represent a phenotype of MR activation and cardiovascular risk, suggesting that these subjects could be treated with MR antagonists.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Fenótipo , Adolescente , Adulto , Biomarcadores/sangue , Chile , Cortisona/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Excesso Aparente de Minerolocorticoides/sangue , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Adulto Jovem
11.
Am J Hypertens ; 31(8): 910-918, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-29617893

RESUMO

BACKGROUND: Pathogenic variations in HSD11B2 gene triggers the apparent mineralocorticoid excess syndrome (AME). There is scarce information regarding the phenotypes of subjects carrying heterozygous pathogenic variants in HSD11B2 gene. We investigated if serum cortisol/cortisone (F/E) ratio and cortisone are useful for identifying partial 11ßHSD2 deficiency in those heterozygous subjects. METHODS: We studied two patients diagnosed with AME and their families carrying either D223N or R213C mutation. We also evaluated 32 healthy control subjects (13 children and 19 adults) to obtain normal references ranges for all measured variables. Case 1: A boy carrying D223N mutation in HSD11B2 gene and Case 2: A girl carrying R213C mutation. We assessed serum F/E ratio and cortisone by HPLC-MS/MS, aldosterone, plasma-renin-activity(PRA), electrolytes, and HSD11B2 genetic analyses. RESULTS: The normal values (median [interquartile range]) in children for serum F/E and cortisone (µg/dl) were 2.56 [2.21-3.69] and 2.54 [2.35-2.88], and in adults were 4.42 [3.70-4.90] and 2.23 [1.92-2.57], respectively. Case 1 showed a very high serum F/E 28.8 and low cortisone 0.46 µg/dl. His mother and sister were normotensives and heterozygous for D223N mutation with high F/E (13.2 and 6.0, respectively) and low cortisone (2.0 and 2.2, respectively). Case 2 showed a very high serum F/E 175 and suppressed cortisone 0.11 µg/dl. Her parents and sister were heterozygous for the R213C mutation with normal phenotype, but high F/E and low cortisone. Heterozygous subjects showed normal aldosterone, PRA, but lower fractional excretion of sodium and urinary Na/K ratio than controls. CONCLUSION: Serum F/E ratio and cortisone allow to identify partial 11ßHSD2 deficiencies, as occurs in heterozygous subjects, who would be susceptible to develop arterial hypertension.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Cortisona/sangue , Hidrocortisona/sangue , Síndrome de Excesso Aparente de Minerolocorticoides/sangue , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Síndrome de Excesso Aparente de Minerolocorticoides/enzimologia , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Mutação , Natriurese/genética , Linhagem , Fenótipo , Valor Preditivo dos Testes
12.
Proc Natl Acad Sci U S A ; 114(52): E11248-E11256, 2017 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-29229831

RESUMO

Mutations in 11ß-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the HSD11B2 gene result either in severe AME or a milder phenotype (type 2 AME). To date, ∼40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of CYP21A2, the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known HSD11B2 missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Genótipo , Síndrome de Excesso Aparente de Minerolocorticoides , Mutação de Sentido Incorreto , Multimerização Proteica/genética , Adolescente , Criança , Pré-Escolar , Simulação por Computador , Estabilidade Enzimática , Feminino , Humanos , Lactente , Masculino , Síndrome de Excesso Aparente de Minerolocorticoides/enzimologia , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/patologia
13.
J Steroid Biochem Mol Biol ; 165(Pt A): 145-150, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26892095

RESUMO

Apparent mineralocorticoid excess (AME) is a genetic disorder causing severe hypertension, hypokalemia, and hyporeninemic hypoaldosteronism owing to deficient 11 beta-hydroxysteroid dehydrogenase type-2 (11ßHSD2) enzyme activity. The 11ßHSD2 enzyme confers mineralocorticoid receptor specificity for aldosterone by converting cortisol to its inactive metabolite, cortisone and inactivating the cortisol-mineralocorticoid receptor complex. The 20year follow-up of a consanguineous Iranian family with three sibs affected with AME shows the successes and pitfalls of medical therapy with spironolactone. The three sibs, (female, male, female) were diagnosed at the ages of 14, 11, and 4 years, respectively. At diagnosis, hypertensive retinopathy and left ventricular hypertrophy were present in the eldest female and retinopathy was noted in the male sib. Spironolactone treatment resulted in decreased blood pressure and rise in serum potassium levels. The older female, age 36, developed reduced left ventricular function with mitral and tricuspid regurgitation and renal failure after her second pregnancy. She was treated with renal transplantation resulting in cure of AME with decreased blood pressure and weaning from antihypertensives. Her younger sibs, age 34 and 26, do not have end organ damage. Early and vigilant treatment improves morbidity in patients with AME. Mineralocorticoid receptor antagonists normalize blood pressure, correct hypokalemia and reduce hypertensive end-organ damage in patients with AME. Low dose dexamethasone can be considered, though the response may be variable. Future directions of therapy include selective mineralocorticoid antagonists.


Assuntos
11-beta-Hidroxiesteroide Desidrogenases/deficiência , 11-beta-Hidroxiesteroide Desidrogenases/genética , Hipertensão/genética , Hipertensão/terapia , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/terapia , Adolescente , Adulto , Pressão Sanguínea , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Saúde da Família , Feminino , Humanos , Hipertensão/metabolismo , Irã (Geográfico) , Transplante de Rim , Masculino , Síndrome de Excesso Aparente de Minerolocorticoides/metabolismo , Mineralocorticoides/metabolismo , Mutação , Linhagem , Polimorfismo Genético , Gravidez , Insuficiência Renal/genética , Insuficiência Renal/terapia , Renina/metabolismo , Espironolactona/química , Espironolactona/uso terapêutico , Síndrome de Excesso Aparente de Minerolocorticoides
14.
Ann N Y Acad Sci ; 1376(1): 65-71, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27526338

RESUMO

Apparent mineralocorticoid excess (AME) is a rare autosomal recessive genetic disorder causing severe hypertension in childhood due to a deficiency of 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), which is encoded by HSD11B2. Without treatment, chronic hypertension leads to early development of end-organ damage. Approximately 40 causative mutations in HSD11B2 have been identified in ∼100 AME patients worldwide. We have studied the clinical presentation, biochemical parameters, and molecular genetics in six patients from a consanguineous Omani family with AME. DNA sequence analysis of affected members of this family revealed homozygous c.799A>G mutations within exon 4 of HSD11B2, corresponding to a p.T267A mutation of 11ßHSD2. The structural change and predicted consequences owing to the p.T267A mutation have been modeled in silico. We conclude that this novel mutation is responsible for AME in this family.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Síndrome de Excesso Aparente de Minerolocorticoides/enzimologia , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Mutação/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/química , Sequência de Aminoácidos , Sequência de Bases , Pré-Escolar , Simulação por Computador , Análise Mutacional de DNA , Família , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Moleculares , Omã , Síndrome de Excesso Aparente de Minerolocorticoides
15.
Circulation ; 133(14): 1360-70, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-26951843

RESUMO

BACKGROUND: The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss-of-function mutations in the gene encoding 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11ßHSD2 is also expressed in the brain. However, the central contribution to Apparent Mineralocorticoid Excess and other hypertensive states is often overlooked and is unresolved. We therefore used a Cre-Lox strategy to generate 11ßHSD2 brain-specific knockout (Hsd11b2.BKO) mice, measuring blood pressure and salt appetite in adults. METHODS AND RESULTS: Basal blood pressure, electrolytes, and circulating corticosteroids were unaffected in Hsd11b2.BKO mice. When offered saline to drink, Hsd11b2.BKO mice consumed 3 times more sodium than controls and became hypertensive. Salt appetite was inhibited by spironolactone. Control mice fed the same daily sodium intake remained normotensive, showing the intrinsic salt resistance of the background strain. Dexamethasone suppressed endogenous glucocorticoid and abolished the salt-induced blood pressure differential between genotypes. Salt sensitivity in Hsd11b2.BKO mice was not caused by impaired renal sodium excretion or volume expansion; pressor responses to phenylephrine were enhanced and baroreflexes impaired in these animals. CONCLUSIONS: Reduced 11ßHSD2 activity in the brain does not intrinsically cause hypertension, but it promotes a hunger for salt and a transition from salt resistance to salt sensitivity. Our data suggest that 11ßHSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway. Therefore, central mineralocorticoid receptor antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Fissura/fisiologia , Hipertensão/genética , Síndrome de Excesso Aparente de Minerolocorticoides/fisiopatologia , Proteínas do Tecido Nervoso/deficiência , Receptores de Mineralocorticoides/fisiologia , Cloreto de Sódio na Dieta/toxicidade , Núcleo Solitário/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/fisiologia , Animais , Barorreflexo/efeitos dos fármacos , Corticosterona/sangue , Dexametasona/farmacologia , Comportamento de Ingestão de Líquido , Genes Sintéticos , Hipertensão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Excesso Aparente de Minerolocorticoides/tratamento farmacológico , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Néfrons/fisiopatologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Nestina/genética , Neurônios/fisiologia , Potássio/urina , RNA Mensageiro/biossíntese , Reflexo Anormal , Núcleo Solitário/fisiopatologia , Espironolactona/farmacologia
16.
Best Pract Res Clin Endocrinol Metab ; 29(4): 633-45, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26303089

RESUMO

Aldosterone plays an essential role in the maintenance of fluid and electrolyte homeostasis in the distal nephron. Monogenic forms of mineralocorticoid hypertension result from genetic defects leading to excessive production of aldosterone (or other mineralocorticoids) from the adrenal cortex or to illegitimate mineralocorticoid effects in the kidney. They are characterized in the majority of cases by early onset, severe or resistant hypertension and associated with suppressed renin levels. Depending on their causes, these diseases are distinguished at the clinical and biochemical level and differently affect aldosterone levels and kalemia. The diagnosis is confirmed by genetic testing, which allows in many cases targeted treatment to prevent severe cardiovascular consequences of high blood pressure or aldosterone excess. In this review we describe the different forms of inherited mineralocorticoid hypertension, providing an overview of their clinical and biochemical features, their underlying genetic defects and specific therapeutic options.


Assuntos
Hiperaldosteronismo/genética , Hipertensão/etiologia , Síndrome de Liddle/genética , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/metabolismo , Síndrome de Liddle/diagnóstico , Síndrome de Liddle/metabolismo , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Síndrome de Excesso Aparente de Minerolocorticoides/metabolismo , Mutação
17.
J Clin Endocrinol Metab ; 100(9): E1234-41, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26126204

RESUMO

CONTEXT: Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disease resulting from mutations within the hydroxysteroid (11ß-dehydrogenase2 [HSD11B2]) gene causing a prominent mineralocorticoid receptor activation by cortisol and hypokalemic low renin hypertension as the main clinical feature. OBJECTIVE: The objective of the study was to characterize AME for possible novel HSD11B2 mutations and to define the role of HSD11B2 promoter methylation in the phenotypic expression of the disease. SUBJECTS: Two proband brothers and 10 relatives participated in the study. METHODS: Peripheral blood mononuclear cell DNA was used for HSD11B2 exon sequencing, and a new predicted structure of 11ß-hydroxysteroid dehydrogenase type 2 was generated by an in silico three-dimensional modeling. Promoter methylation was determined by bisulfite pyrosequencing. Urinary tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone ratio, a surrogate marker of 11ß-hydroxysteroid dehydrogenase type 2 activity, was measured by gas chromatography-mass spectrometry. RESULTS: A novel homozygous variant at HSD11B2 exon 3 site (c.C662G) resulting in an alanine-to-glycine change at position 221 was discovered by sequencing the DNA of the probands. A monoallelic mutation was found in the DNA of the parents and other four relatives. In silico three-dimensional modeling showed that the Ala221Gly substitution could perturb a hydrophobic interaction by reducing the enzymatic affinity for the substrate. The HSD11B2 promoter methylation of normotensive heterozygous relatives was similar to that of wild types, whereas the hypertensive heterozygous subjects showed higher methylation than wild types, consistently with a transcriptional repressive effect of promoter hypermethylation. CONCLUSIONS: A novel HSD11B2 functional mutation accounting for an Ala221Gly substitution causes AME. The hypertension phenotype is also epigenetically modulated by HSD11B2 methylation in subjects heterozygous for the mutation.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Metilação de DNA , Epigênese Genética , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Mutação , Regiões Promotoras Genéticas , Adolescente , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Síndrome de Excesso Aparente de Minerolocorticoides
18.
Semin Nephrol ; 33(3): 300-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23953807

RESUMO

Hereditary disorders of potassium homeostasis are an interesting group of disorders, affecting people from the newborn period to adults of all ages. The clinical presentation varies from severe hypotension at birth to uncontrolled hypertension in adults, often associated with abnormal potassium values, although many patients may have a normal serum potassium concentration despite being affected by the genetic disorder. A basic understanding of these disorders and their underlying mechanisms has significant clinical implications, especially in the few patients with subtle clinical signs and symptoms. We present a summary of these disorders, with emphasis on the clinical presentation and genetic mechanisms of these disorders.


Assuntos
Hiperpotassemia/genética , Hipopotassemia/genética , Potássio/metabolismo , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/terapia , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Síndrome de Bartter/terapia , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/genética , Síndrome de Gitelman/terapia , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/genética , Hiperaldosteronismo/terapia , Hipoaldosteronismo/diagnóstico , Hipoaldosteronismo/genética , Hipoaldosteronismo/terapia , Síndrome de Liddle/diagnóstico , Síndrome de Liddle/genética , Síndrome de Liddle/terapia , Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/terapia , Pseudo-Hipoaldosteronismo/diagnóstico , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/terapia
19.
Indian Pediatr ; 50(4): 416-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23665601

RESUMO

Apparent mineralocorticoid excess (AME) syndrome is a rare autosomal recessive disorder due to the deficiency of 11b hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2). Mutations in this gene affect the enzymatic activity resulting to an excess of cortisol, which causes its inappropriate access to mineralocorticoid receptor leading to inherited hypertension.This is a potentially fatal but treatable disorder. We present clinical and molecular studies on two sisters diagnosed as AME.


Assuntos
Síndrome de Excesso Aparente de Minerolocorticoides/diagnóstico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Consanguinidade , Feminino , Humanos , Lactente , Síndrome de Excesso Aparente de Minerolocorticoides/enzimologia , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Mutação
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