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Hydrochlorothiazide Test as a Tool in the Diagnosis of Gitelman Syndrome in Chinese Patients.

ABSTRACT: Traditional clinical diagnostic criteria for Gitelman syndrome (GS) including hypomagnesemia and hypocalciuria have been challenged by reports of atypical manifestations recently, as well as the development of genetic testing. Hydrochlorothiazide (HCT) test is a diagnostic method different from the traditional biochemical parameters, which could evaluate the function of thiazide-sensitive sodium-chloride co-transporter (NCC) in vivo by a small dose of NCC inhibitor HCT. In this retrospective study, we compared the diagnostic significance of hypomagnesemia, hypocalciuria, and the reaction of HCT test, among Chinese patients with GS confirmed by genetic test. For patients who were clinically suspected of GS manifestations, SLC12A3 gene was sequenced to make genetic diagnosis. A total of 83 GS and 19 control patients were recruited, among which 37 underwent HCT test according to the standard process. Compared with the gold standard of genetic diagnosis, both the diagnostic sensitivity (93.10%) and specificity (100.00%) of the HCT test were much higher than those of hypomagnesemia and/or hypocalciuria. The area under the receiver operating characteristic (ROC) curve was 1.000 (95% CI 0.905-1.000) for HCT test, higher than the values using hypomagnesemia and/or hypocalciuria. The cost of HCT test was around $54, much lower than genetic diagnosis. In conclusion, besides traditional hypomagnesemia and hypocalciuria, HCT test could be a valuable tool in the clinical diagnosis of Chinese GS patients.

SUBMITTER: Peng X

PROVIDER: S-EPMC6165878 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Hydrochlorothiazide Test as a Tool in the Diagnosis of Gitelman Syndrome in Chinese Patients.

Peng Xiaoyan X Zhao Bingbin B Zhang Lei L Jiang Lanping L Yuan Tao T Wang Ying Y Wang Haiyun H Ma Jie J Li Naishi N Zheng Ke K Nie Min M Li Xuemei X Xing Xiaoping X Chen Limeng L

Frontiers in endocrinology 20180924

Traditional clinical diagnostic criteria for Gitelman syndrome (GS) including hypomagnesemia and hypocalciuria have been challenged by reports of atypical manifestations recently, as well as the development of genetic testing. Hydrochlorothiazide (HCT) test is a diagnostic method different from the traditional biochemical parameters, which could evaluate the function of thiazide-sensitive sodium-chloride co-transporter (NCC) <i>in vivo</i> by a small dose of NCC inhibitor HCT. In this retrospect ...[more]

PMID: 30319542

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Project description:Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.

Project description:BackgroundGitelman syndrome (GS) is an autosomal recessive disorder and mild variant of classic Bartter syndrome. The latter is caused by defects in the genes CLCNKB and/or CLCNKA (chloride voltage-gated channel Ka and Kb). Patients with GS usually have loss-of-function mutations in SLC12A3. No patient has been reported with compound heterozygous mutations in these genes. We report a girl with GS with a paternally inherited heterozygous mutation in SLC12A3, and maternally inherited heterozygous variants in both CLCNKB and CLCNKA.Case presentationIn this report, we reported a female patient (8 y and 10 mo) who had growth retardation (111.8 cm, - 1.62 standard deviation height for age) and normal blood pressure, with persistent hypokalemia, hypomagnesemia, hypocalciuria, hypochloremic alkalosis, and elevated levels of plasma renin and aldosterone. Her younger brother, father, and paternal grandmother all had histories of mild low levels of plasma potassium (3.0-3.5 mmol/L), which were rectified by potassium-rich foods. The genomic DNA of the patient, younger brother, parents, and grandparents were screened for gene variations and pedigree analysis using trio whole exome sequencing (WES). The candidate variants were validated by Sanger sequencing. Protein-protein interaction analysis utilized the following databases: Biogrid, MINT, HPRD, STRING, IntAct, iRefIndex, and ppiTrim. The trio WES screening showed that the patient has paternally inherited SLC12A3 p.N359K, and maternally inherited CLCNKB p.L94I. The paternal grandmother and younger brother are both carriers of SLC12A3 p.N359K. According to the STRING database, SLC12A3 and CLCNKB proteins may interact or coexpress with proteins associated with GS.ConclusionsBased on clinical phenotypes, genetic evidence of the pedigree, and previous reported studies, this case of GS indicates a digenetic inheritance of SLC12A3 and CLCNKB that resulted in renal tubular dysfunction perhaps, due to a genetic double-hit mechanism. The putative pathogenicity of the CLCNKB p.L94I variant requires confirmation.

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Hydrochlorothiazide Test as a Tool in the Diagnosis of Gitelman Syndrome in Chinese Patients.

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Hydrochlorothiazide Test as a Tool in the Diagnosis of Gitelman Syndrome in Chinese Patients.

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