RESUMEN
Disorders of isolated mineralocorticoid deficiency, which cause potentially life-threatening salt-wasting crisis early in life, have been associated with gene variants of aldosterone biosynthesis or resistance; however, in some patients no such variants are found. WNT/ß-catenin signaling is crucial for differentiation and maintenance of the aldosterone-producing adrenal zona glomerulosa (zG). Herein, we describe a highly consanguineous family with multiple perinatal deaths and infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability and resulted in loss of Wnt/ß-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex-specific ablation of Lgr4, using Lgr4fl/fl mice mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG, and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling, which results in abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.
Asunto(s)
Hipoaldosteronismo , Receptores Acoplados a Proteínas G , Vía de Señalización Wnt , Animales , Humanos , Ratones , Aldosterona/metabolismo , beta Catenina/metabolismo , Hipoaldosteronismo/complicaciones , Hipoaldosteronismo/genética , Hipoaldosteronismo/patología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoAsunto(s)
Hipoaldosteronismo , Pérdida de Peso , Humanos , Hipoaldosteronismo/genética , Recién Nacido , MutaciónRESUMEN
CONTEXT: Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. OBJECTIVE: To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. DESIGN: Clinical and molecular study. SETTING: Tertiary academic Children's Hospital, Center for Rare Pediatric Endocrine Diseases. PATIENTS AND METHODS: Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. RESULTS: CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. CONCLUSION: Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene.
Asunto(s)
Citocromo P-450 CYP11B2/genética , Hipoaldosteronismo/genética , Enfermedad de Addison/diagnóstico , Enfermedad de Addison/genética , Estudios de Cohortes , Citocromo P-450 CYP11B2/deficiencia , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Grecia , Heterocigoto , Homocigoto , Humanos , Hipoaldosteronismo/congénito , Hipoaldosteronismo/diagnóstico , Lactante , Recién Nacido , Masculino , MutaciónRESUMEN
Corticosterone methyloxidase deficiency type 2 is an autosomal recessive disorder presenting with salt loss and failure to thrive in early childhood and is caused by inactivating mutations of the CYP11B2 gene. Herein, we describe four Turkish patients from two families who had clinical and hormonal features compatible with corticosterone methyloxidase deficiency and all had inherited novel CYP11B2 variants. All of the patients presented with vomiting, failure to thrive and severe dehydration, except one patient with only failure to thrive. Biochemical studies showed hyponatremia, hyperkalemia and acidosis. All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels. Three patients from the same family were found to harbor a novel homozygous variant c.1175T>C (p.Leu392Pro) and a known homozygous variant c.788T>A (p.Ile263Asn) in the CYP11B2 gene. The fourth patient had a novel homozygous variant c.666_667delCT (p.Phe223ProfsTer35) in the CYP11B2 gene which caused a frame shift, forming a stop codon. Corticosterone methyloxidase deficiency should be considered as a differential diagnosis in patients presenting with hyponatremia, hyperkalemia and growth retardation, and it should not be forgotten that this condition is life-threatening if untreated. Genetic analyses are helpful in diagnosis of the patients and their relatives. Family screening is important for an early diagnosis and treatment. In our cases, previously unreported novel variants were identified which are likely to be associated with the disease.
Asunto(s)
Citocromo P-450 CYP11B2/genética , Hipoaldosteronismo/genética , Preescolar , Femenino , Humanos , Hipoaldosteronismo/metabolismo , Hipoaldosteronismo/fisiopatología , Lactante , Masculino , LinajeRESUMEN
OBJECTIVE: Aldosterone synthase deficiency (ASD) is a rare, autosomal recessive inherited disease with an overall clinical phenotype of failure to thrive, vomiting, severe dehydration, hyperkalemia, and hyponatremia. Mutations in the CYP11B2 gene encoding aldosterone synthase are responsible for the occurrence of ASD. Defects in CYP11B2 gene have only been reported in a limited number of cases worldwide. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation is essential for the clinical management of offsprings. CASE PRESENTATION: We herein describe an unusual case of ASD type II in a neonate with faltering growth as a single presenting symptom. To our knowledge, this is the first Greek case of ASD type II reported with confirmed genetic analysis. Next generation sequencing of her DNA revealed the homozygous mutation p.T185I (ACC-ATC) (c.554C>T) (g.7757C>T) in exon 3 of the CYP11B2 gene in the neonate, inherited from both parents who were heterozygotes for the mutation. CONCLUSIONS: Physicians handling neonates with faltering growth, particularly in the initial six weeks of life, should be suspicious of mineralocorticoid insufficiency either as isolated hypoaldosteronism or in the context of congenital adrenal hyperplasia. Essential investigations should be performed and appropriate treatment should be administered promptly without awaiting for the hormonal profile results. Interpretation of the clinical picture and the hormonal profile will guide the analysis of candidate genes. Primary selective hypoaldosteronism is a rare, life threatening disease, but still with an unknown overall population impact. Thus, reporting cases with confirmed gene mutations is of major importance.
Asunto(s)
Citocromo P-450 CYP11B2/deficiencia , Citocromo P-450 CYP11B2/genética , Hipoaldosteronismo/diagnóstico , Femenino , Pruebas Genéticas , Grecia , Heterocigoto , Humanos , Hipoaldosteronismo/genética , Recién Nacido , Polimorfismo de Nucleótido SimpleRESUMEN
Background Aldosterone deficiency (hypoaldosteronism) or aldosterone resistance (pseudohypoaldosteronism) both result in defective aldosterone activity. Case presentation A 42-day-old man presented with failure to thrive, hyponatremia, high urine sodium output, severe hyperkalemia and high plasma renin activity and aldosterone levels. NR3C2, SCNN1A, B and G sequencing showed no variants. Exclusive sodium supplementation resulted in clinical stabilization and growth normalization. His younger sibling had similar clinical and laboratory features, except for low-normal aldosterone. Both patients showed compound heterozygous mutations in CYP11B2 (c.C554T/2802pbE1-E2del). The younger patient needed transient fludrocortisone treatment and higher sodium supplementation, recuperating his weight and a normal growth velocity, although below his brother's and target height (c.10th vs. c.50th). Conclusions On a suggestive clinical picture, high aldosterone plasma levels in early infancy do not rule out aldosterone insufficiency and might mislead differential diagnosis with pseudohypoaldosteronism. Therapeutic requests and growth impairment in hypoaldosteronism vary even with a common genetic background.
Asunto(s)
Aldosterona/sangre , Hipoaldosteronismo/diagnóstico , Seudohipoaldosteronismo/diagnóstico , Aldosterona/deficiencia , Niño , Desarrollo Infantil/fisiología , Preescolar , Citocromo P-450 CYP11B2/genética , Diagnóstico Diferencial , Estudios de Seguimiento , Gráficos de Crecimiento , Humanos , Hipoaldosteronismo/sangre , Hipoaldosteronismo/genética , Lactante , Masculino , Mutación , Seudohipoaldosteronismo/sangre , Seudohipoaldosteronismo/genética , Hermanos , EspañaRESUMEN
BACKGROUND: X-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1. Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease. CASE PRESENTATION: A 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC. CONCLUSIONS: AHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.
Asunto(s)
Receptor Nuclear Huérfano DAX-1/genética , Insuficiencia Corticosuprarrenal Familiar/genética , Hipoaldosteronismo/genética , Mutación , Insuficiencia Suprarrenal/etiología , Insuficiencia Suprarrenal/genética , Insuficiencia de Crecimiento/etiología , Insuficiencia de Crecimiento/genética , Humanos , Insuficiencia Corticosuprarrenal Familiar/complicaciones , Hipoaldosteronismo/etiología , Recién Nacido , MasculinoRESUMEN
Aldosterone synthase inhibitors (ASIs) should alleviate obesity-related cardiovascular and renal problems resulting partly from aldosterone excess, but their clinical use may have limitations. To improve knowledge for the use of ASIs, we investigated physiology in aldosterone synthase-knockout (ASKO) mice. On regular chow diet (CD), ASKO mice ate more and weighed less than WT mice, largely because they hyperventilated to eliminate acid as CO2. Replacing CD with high-fat diet (HFD) lessened the respiratory burden in ASKO mice, as did 12- to 15-hour fasting. The latter eliminated the genotype differences in respiratory workload and energy expenditure (EE). Thus, aldosterone deficiency burdened the organism more when the animals ate carbohydrate-rich chow than when they ate a HFD. Chronic HFD exposure further promoted hyperinsulinemia in ASKO mice that contributed to visceral fat accumulation accompanied by reduced lipolysis, thermogenic reprogramming, and the absence of weight-gain-related EE increases. Intracerebroventricular aldosterone supplementation in ASKO mice attenuated the HFD-induced hyperinsulinemia, but did not affect EE, suggesting that the presence of aldosterone increased the body's energetic efficiency, thus counteracting the EE-increasing effect of low insulin. ASIs may therefore cause acid-overload-induced respiratory burden and promote obesity. Their use in patients with preexisting renal and cardiopulmonary diseases might be contraindicated.
Asunto(s)
Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Hiperinsulinismo/genética , Obesidad/genética , Adipocitos/citología , Animales , Citocromo P-450 CYP11B2/efectos de los fármacos , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Metabolismo Energético , Heces , Femenino , Hipoaldosteronismo/genética , Insulina/sangre , Resistencia a la Insulina/genética , Lipólisis , Locomoción , Masculino , Ratones , Ratones Noqueados , Pletismografía , TermogénesisRESUMEN
BACKGROUND AND AIM: Hypoaldosteronism is associated with either insufficient aldosterone production or aldosterone resistance (pseudohypoaldosteronism). Patients with aldosterone defects typically present with similar symptoms and findings, which include failure to thrive, vomiting, hyponatremia, hyperkalemia and metabolic acidosis. Accurate diagnosis of these clinical conditions therefore can be challenging. Molecular genetic analyses can help to greatly clarify this complexity. The aim of this study was to obtain an overview of the clinical and genetic characteristics of patients with aldosterone defects due to biosynthesis defects or aldosterone resistance. DESIGN AND PATIENTS: We investigated the clinical and molecular genetic features of 8 consecutive patients with a clinical picture of aldosterone defects seen in our clinics during the period of May 2015 through October 2017. We screened CYP11B2 for aldosterone synthesis defects and NR3C2 and the three EnaC subunits (SCNN1A, SCNN1B and SCNN1G) for aldosterone resistance. RESULTS: We found 4 novel and 2 previously reported mutations in the genes CYP11B2, NR3C2, SCNN1A and SCNN1G in 9 affected individuals from 7 unrelated families. CONCLUSION: Molecular genetic investigations can help confidently diagnose these conditions and clarify the pathogenicity of aldosterone defects. This study may expand the clinical and genetic correlations of defects in aldosterone synthesis or resistance.
Asunto(s)
Aldosterona/uso terapéutico , Hipoaldosteronismo/tratamiento farmacológico , Hipoaldosteronismo/genética , Hiponatremia/genética , Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Canales Epiteliales de Sodio/genética , Femenino , Pruebas Genéticas , Humanos , Lactante , Recién Nacido , Masculino , Mutación/genética , Receptores de Mineralocorticoides/genéticaRESUMEN
Isolated aldosterone synthase deficiency may result in life-threatening salt-wasting and failure to thrive. The condition involves hyperkalemia accompanying hyponatremia. Two types of aldosterone synthase deficiency may be observed depending on hormone levels: corticosterone methyl oxidase type 1 (CMO 1) and CMO 2. Herein, we describe a Turkish infant patient with aldosterone synthase deficiency who presented with failure to thrive and salt wasting but with normal potassium levels. Urinary steroid characteristics were compatible with CMO I deficiency. Diagnosis of aldosterone synthase deficiency was confirmed by mutational analysis of the CYP11B2 gene which identified the patient as homozygous for two mutations: c.788T>A (p.Ile263Asn) and c.1157T>C (p.Val386Ala). Family genetic study revealed that the mother was heterozygous for c.788T>A and homozygous for c.1157T>C and the father was heterozygous for both c.788T>A and c.1157T>C. To the best of our knowledge, this is only the second Turkish case with a confirmed molecular basis of type 1 aldosterone synthase deficiency. This case is also significant in showing that spot urinary steroid analysis can assist with the diagnosis and that hyperkalemia is not necessarily part of the disease.
Asunto(s)
Citocromo P-450 CYP11B2/deficiencia , Hipoaldosteronismo/genética , Mutación , Potasio/metabolismo , Corticosterona/orina , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/orina , Análisis Mutacional de ADN , Humanos , Hipoaldosteronismo/orina , Lactante , Masculino , Potasio/sangreRESUMEN
The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure control, fluid, and electrolyte balance in humans. Chronic activation of mineralocorticoid production leads to dysregulation of the cardiovascular system and to hypertension. The key mineralocorticoid is aldosterone. Hyperaldosteronism causes sodium and fluid retention in the kidney. Combined with the actions of angiotensin II, chronic elevation in aldosterone leads to detrimental effects in the vasculature, heart, and brain. The adverse effects of excess aldosterone are heavily dependent on increased dietary salt intake as has been demonstrated in animal models and in humans. Hypertension develops due to complex genetic influences combined with environmental factors. In the last two decades, primary aldosteronism has been found to occur in 5% to 13% of subjects with hypertension. In addition, patients with hyperaldosteronism have more end organ manifestations such as left ventricular hypertrophy and have significant cardiovascular complications including higher rates of heart failure and atrial fibrillation compared to similarly matched patients with essential hypertension. The pathophysiology, diagnosis, and treatment of primary aldosteronism will be extensively reviewed. There are many pitfalls in the diagnosis and confirmation of the disorder that will be discussed. Other rare forms of hyper- and hypo-aldosteronism and unusual disorders of hypertension will also be reviewed in this article.
Asunto(s)
Hiperaldosteronismo , Hipoaldosteronismo , Mineralocorticoides/metabolismo , Aldosterona/metabolismo , Animales , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/fisiopatología , Hiperaldosteronismo/terapia , Hipoaldosteronismo/diagnóstico , Hipoaldosteronismo/genética , Hipoaldosteronismo/metabolismo , Hipoaldosteronismo/terapia , Sistema Renina-Angiotensina/fisiologíaRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to describe the renin-angiotensin-aldosterone system and its regulatory control of sodium, potassium, chloride, hydrogen ion, and water homeostasis through its effects on the expression and activity of distal renal tubular cotransporter proteins and to discuss the gene mutations encoding these structures that disturb the function of this system. RECENT FINDINGS: Primary hypoaldosteronism may be the result of acquired or congenital errors in renal juxtaglomerular function (the source of renin), angiotensin generation or activity, or aldosterone synthesis. Secondary hypoaldosteronism (pseudohypoaldosteronism) occurs as a consequence of mutations in genes encoding the mineralocorticoid receptor (MR), the three subunits of the aldosterone-responsive, amiloride-sensitive nonvoltage-gated sodium channel encoded by SCNN1A, SCNN1B, and SCNN1G, the gene that regulates posttranslational phosphorylation (encoded by WNK4) of the thiazide-sensitive sodium chloride cotransporter encoded by SLC12A3, and those that regulate phosphorylation and ubiquitination of cofactors encoded by WNK1, KLH3, and CUL3 that affect WNK4 function. SUMMARY: Acquired disorders of renal function as well as mutations in many genes may adversely affect aldosterone-mediated mineral homeostasis.
Asunto(s)
Aldosterona/biosíntesis , Hipoaldosteronismo/genética , Hipoaldosteronismo/fisiopatología , Sistema Renina-Angiotensina , Sodio/metabolismo , Aldosterona/metabolismo , Humanos , Mutación , Potasio/metabolismo , Receptores de Mineralocorticoides/metabolismoRESUMEN
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.
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Hiperpotasemia/genética , Hipopotasemia/genética , Potasio/metabolismo , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/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 Exceso Aparente de Mineralocorticoides/diagnóstico , Síndrome de Exceso Aparente de Mineralocorticoides/genética , Síndrome de Exceso Aparente de Mineralocorticoides/terapia , Seudohipoaldosteronismo/diagnóstico , Seudohipoaldosteronismo/genética , Seudohipoaldosteronismo/terapiaRESUMEN
Isolated hypoaldosteronism is a rare and occasionally life-threatening cause of salt wasting in infancy. A 2-month-old Japanese boy of unrelated parents was examined for failure to thrive and poor weight gain. Laboratory findings were hyponatremia, hyperkalemia, high plasma renin and low aldosterone levels. Spot urine analysis by gas chromatography-mass spectrometry (GC-MS) showed that urinary excretion of corticosterone metabolites was elevated. Whereas excretion of 18-hydroxycortricosterone metabolites was within the normal range, excretion of aldosterone metabolites was undetectable. The patient was therefore suspected to have aldosterone synthase deficiency type 1. Sequence analysis of CYP11B2, the gene encoding aldosterone synthase (CYP11B2), showed that the patient was a compound heterozygote for c.168G>A, p.W56X in exon 1 and c.1149C>T, p.R384X in exon 7. p.W56X was inherited from his mother and p.R384X was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activity was speculated to cause his condition. To our knowledge, this is the first Japanese patient in which the molecular basis of aldosterone synthase deficiency type 1 has been clarified. This case also indicates that spot urinary steroid analysis is useful for diagnosis.
Asunto(s)
Citocromo P-450 CYP11B2/genética , Hipoaldosteronismo/genética , Alelos , Pueblo Asiatico/genética , Citocromo P-450 CYP11B2/deficiencia , Humanos , Lactante , Masculino , MutaciónRESUMEN
Maternally-inherited diabetes with deafness (MIDD) is a rare form of monogenic diabetes that results, in most cases, from an A-to-G transition at position 3243 of mitochondrial DNA (m.3243A>G) in the mitochondrial-encoded tRNA leucine (UUA/G) gene. As the name suggests, this condition is characterized by maternally-inherited diabetes and bilateral neurosensory hearing impairment. A characteristic of mitochondrial cytopathies is the progressive multisystemic involvement with the development of more symptoms during the course of the disease. We report here the case of a patient with MIDD who developed hyporeninemic hypoaldosteronism. Arq Bras Endocrinol Metab. 2012;56(8):574-7.
O diabetes mitocondrial (MIDD) é uma forma rara de diabetes monogênico resultante, na maioria dos casos, da mutação mitocondrial A3243G. Essa condição é caracterizada por diabetes de transmissão materna e disacusia neurossensorial. Uma característica das mitocondriopatias é o envolvimento progressivo de outros órgãos ou sistemas, levando ao aparecimento de diversos sintomas durante o curso da doença. Este relato descreve o caso de um paciente com MIDD que, durante o período de acompanhamento, apresentou hipoaldosteronismo hiporreninêmico. Arq Bras Endocrinol Metab. 2012;56(8):574-7.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , ADN Mitocondrial/genética , Sordera/genética , /genética , Hipoaldosteronismo/genética , Mutación Puntual/genética , LinajeRESUMEN
Neonatal salt-wasting syndromes are rare but potentially serious conditions. Isolated hypoaldosteronism is an autosomal recessive inherited disorder of terminal aldosterone synthesis, leading to selective aldosterone deficiency. Two different biochemical forms of this disease have been described, called aldosterone synthase deficiency or corticosterone methyl oxydase, types I and II. In type I, there is no aldosterone synthase activity and the 18 hydroxycorticosterone (18 OHB) level is low, whereas in type II, a residual activity of aldosterone synthase persists and 18 OHB is overproduced. We report on four patients with isolated hypoaldosteronism. In 2 of them, who were recently diagnosed with aldosterone synthase deficit, we discuss the symptoms and treatment. The 2 other patients are now adults. We discuss the long-term outcome, the quality of adult life, aldosterone synthase deficits, as well as the pathophysiology and molecular analysis.
Asunto(s)
Hipoaldosteronismo/diagnóstico , Hiponatremia/diagnóstico , Hipovolemia/diagnóstico , Adulto , Consanguinidad , Citocromo P-450 CYP11B2/deficiencia , Citocromo P-450 CYP11B2/genética , Análisis Mutacional de ADN , Enfermedades en Gemelos/diagnóstico , Enfermedades en Gemelos/tratamiento farmacológico , Enfermedades en Gemelos/genética , Enfermedades en Gemelos/fisiopatología , Relación Dosis-Respuesta a Droga , Emigrantes e Inmigrantes , Femenino , Fludrocortisona/administración & dosificación , Estudios de Seguimiento , Tamización de Portadores Genéticos , Alemania , Homocigoto , Humanos , Hipoaldosteronismo/tratamiento farmacológico , Hipoaldosteronismo/genética , Hipoaldosteronismo/fisiopatología , Lactante , Recién Nacido , Masculino , Calidad de Vida , Sodio en la Dieta/administración & dosificación , Turquía/etnologíaRESUMEN
UNLABELLED: Isolated aldosterone synthase deficiency can be the source of life-threatening salt wasting and failure to thrive in infancy. We studied an infant with failure to thrive and persistent hyponatremia despite oral sodium supplementation. Initial analyses revealed highly elevated plasma renin but normal values of plasma aldosterone. The biochemical diagnosis of corticosterone methyl oxidase deficiency type II was established by multisteroid analysis, revealing a pathognomonic pattern with a highly elevated ratio of 18-OH-corticosterone to aldosterone. This reflects an enzymatic defect in the aldosterone synthase that is responsible for the terminal steps in the aldosterone biosynthesis. Molecular genetic analysis supported the diagnosis revealing homozygosity for a pathogenic c.554C>T (p.T185I) variation in exon 3 of the CYP11B2 gene encoding aldosterone synthase. Homozygosity for two other polymorphic variations c.504C>T (p.F168F) and c.518A>G (p.K173R) were identified as well. Treatment with fludrocortisone resulted in catch-up growth. Discontinuation of treatment at the age of 9 years was later possible without any clinical or biochemical deterioration. CONCLUSIONS: Isolated deficiency in aldosterone biosynthesis should be considered in neonates and infants with failure to thrive and salt wasting. Normal levels of plasma aldosterone compared with highly elevated levels of plasma renin indicate an impaired aldosterone biosynthesis and suggest the disorder. Recognition of its existence is important as fludrocortisone replacement therapy effectively normalizes sodium balance and growth.
Asunto(s)
Citocromo P-450 CYP11B2/genética , Homocigoto , Hipoaldosteronismo/genética , Mutación Puntual , Citocromo P-450 CYP11B2/deficiencia , Femenino , Marcadores Genéticos , Humanos , Hipoaldosteronismo/diagnóstico , LactanteRESUMEN
UNLABELLED: Aldosterone synthase (P450c11AS) deficiency is a rare autosomal recessive disorder, presenting with severe salt-losing in early infancy. It is caused by inactivating mutations of the CYP11B2 gene. Here, we describe three unrelated Asian patients who have clinical and hormonal features compatible with aldosterone synthase deficiency and identify their CYP11B2 mutations. Patient 1 was a Thai female infant. Patient 2 was an Indian boy, and patient 3 was a Thai male infant. All subjects presented at the age of 1-2 months with diarrhea, failure to thrive, and severe dehydration. Their plasma electrolytes showed hyponatremia, hyperkalemia, and acidosis. All patients had normal cortisol response and had elevated plasma renin activity with low aldosterone levels. The entire coding regions of the CYP11B2 gene were amplified by polymerase chain reaction and sequenced. Patient 1 was homozygous for a previously described mutation, p.T318M. Patient 2 was homozygous for a novel c.666delC mutation inherited from both parents resulting in p.223F>Sfsx295. No CYP11B2 mutation was detected in patient 3. CONCLUSIONS: We report the first CYP11B2 defects in Southeast Asian families responsible for aldosterone synthase deficiency and identified a novel CYP11B2 mutation. However, the affected gene(s) responsible for primary hypoaldosteronism other than CYP11B2 remain to be determined.
Asunto(s)
Citocromo P-450 CYP11B2/deficiencia , Citocromo P-450 CYP11B2/genética , Hipoaldosteronismo/genética , Secuencia de Bases/genética , Femenino , Humanos , Hipoaldosteronismo/fisiopatología , Lactante , Masculino , Mutación , Reacción en Cadena de la PolimerasaRESUMEN
Aldosterone synthase deficiency (ASD) type II was diagnosed in a 3 week old boy with severe dehydration. Elevated plasma renin activity, low-normal aldosterone, increased levels for 18-OH corticosterone (18-OHB) and 18-OH-deoxycorticosterone were measured. Sequencing revealed a homozygous mutation for c554C > T in exon 3 (p.T185I) (CYP11B2). Hypospadias has so far not been reported in ASD.
Asunto(s)
Citocromo P-450 CYP11B2/deficiencia , Hipoaldosteronismo/genética , Hipospadias/diagnóstico , Citocromo P-450 CYP11B2/genética , Humanos , Hipoaldosteronismo/sangre , Hipoaldosteronismo/diagnóstico , Hipospadias/enzimología , Recién Nacido , Masculino , Mutación MissenseRESUMEN
An infant with a clinical phenotype of early onset hypoaldosteronism has been screened for mutation analysis of the Cyp11b2 gene encoding aldosterone synthase enzyme. We have described a novel nonsense mutation in exon 3 (c.508C>T) that gave rise to a shorter protein (Q170X) and two known concurrent missense mutations (c.594A>C in exon 3 and c.1157T>C in exon 7) that led to substitution of glutamic acid for aspartic acid at amino acid position 198 (E198D) and of valine for alanine at amino acid position 386 (V386A). The father, who carried E198D plus V386A mutations, showed a fractional sodium excretion of 1.25% that was unmodified by dietary salt restriction, suggesting a mild haploinsufficiency. We examined by in silico analysis the effect of the mutations on the secondary and tertiary structures of aldosterone synthase to explain the inefficient enzymatic activity. The Q170X mutation produced a truncated protein, which was consequently associated with a loss of catalytic activity. As predicted by JPred web system and Dock 6.3 software, the concurrent expression of E198D and V386A mutations induced a significant secondary structure rearrangement and a shift of the heme group and the 18-hydroxycorticosterone substrate from their optimal placement.