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      A Spanish Founder Mutation in the Chloride Channel Gene, CLCNKB, as a Cause of Atypical Bartter Syndrome in Adult Age

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          Abstract

          Background: Mutations in the chloride channel gene, CLCNKB, usually cause classic Bartter syndrome (cBS) or a mixed Bartter-Gitelman phenotype in the first years of life. Methods: We report an adult woman with atypical BS caused by a homozygous missense mutation, A204T, in the CLCNKB gene, which has previously been described as the apparently unique cause of cBS in Spain. Results: The evaluation of this patient revealed an overlap of phenotypic features ranging from severe biochemical and systemic disturbances typical of cBS to scarce symptoms and diagnosis in the adult age typical of Gitelman syndrome. The tubular disease caused a dramatic effect on mental, growth and puberal development leading to low IQ, final short stature and abnormal ovarian function. Furthermore, low serum PTH concentrations with concomitant nephrocalcinosis and normocalcaemia were observed. Both ovarian function and serum PTH levels were normalized after treatment with cyclooxygenase inhibitors. Conclusions: The present report confirms a weak genotype-phenotype correlation in patients with CLCNKB mutations and supports the founder effect of the A204T mutation in Spain. In our country, the genetic diagnosis of adult patients with hereditary hypokalaemic tubulopathies should include a screening of A204T mutation in the CLCNKB gene.

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          Most cited references 13

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          A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes.

          Gitelman syndrome (GS) and Bartter syndrome (BS) are hereditary hypokalemic tubulopathies with distinct phenotypic features. GS has been considered a genetically homogeneous disorder caused by mutation in the gene encoding the NaCl cotransporter (TSC) of the distal convoluted tubule. In contrast, BS is caused by mutations in the genes encoding either the Na-K-2Cl cotransporter (NKCC2), the K+ channel (ROMK) or the Cl- channel (ClC-Kb) of the thick ascending limb. The purpose of this study was to examine the clinical, biochemical and genetic characteristics of a very large inbred Bedouin kindred in Northern Israel with hereditary hypokalemic tubulopathy. Twelve family members affected with hypokalemic tubulopathy, as well as 26 close relatives were clinically and biochemically evaluated. All study participants underwent genetic linkage analysis. Mutation analysis was performed in affected individuals. Evaluation of affected family members (age range 3 to 36 years) revealed phenotypic features of both GS and classic Bartter syndrome (CBS). Features typical of GS included late age of presentation (>15 years) in 7 patients (58%), normal growth in 9 (75%), hypomagnesemia (SMg 5%) in 6 (50%) and hypocalciuria (urinary calcium/creatinine mmol/mmol 0.55) in 4 (33%) and nephrolithiasis in 1 (8%). Linkage analysis in affected patients excluded the TSC gene, SLC12A3, as the mutated gene, but demonstrated linkage to the Cl- channel gene, CLCNKB, on chromosome 1p36. Mutation analysis by direct sequencing revealed a novel homozygous missense mutation, arginine 438 to histidine (R438H), in exon 13 of CLCNKB in all patients. A restriction fragment length polymorphism (RFLP) analysis has been developed to aid in genotyping of family members. Our findings demonstrate intrafamilial heterogeneity, namely the presence of GS and CBS phenotypes, in a kindred with the CLCNKB R438H mutation. We conclude that GS can be caused by a mutation in a gene other than SLC12A3. The exact role of the CLCNKB R438H mutation in the pathogenesis of the electrolyte and mineral abnormalities in GS and CBS remains to be established.
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            Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis

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              Bartter syndrome: benefits and side effects of long-term treatment.

              The present study reports clinical and laboratory data of patients with Bartter syndrome at diagnosis and follow-up with emphasis on the long-term benefits and side effects of the pharmacological therapy, which includes indomethacin and potassium supplementation. We followed 12 children, 6 boys, with a median age at diagnosis of 24.5 months (range 7-137 months) and at the end of the study 157.5 months (range 26.0-224.0 months). All children presented with polyuria and polydipsia, dehydration, and metabolic and electrolyte disturbances with failure to thrive. However, at study entry 5 of 12 patients also had hypophosphatemia, which disappeared after a mean time of 50+/-22.4 months, 3 of 12 had nephrocalcinosis, and 2 of 12 had typical renal cysts. Despite treatment, hypokalemia was persistent in some patients. During long-term follow-up we observed recovery of growth velocity and adequate metabolic and electrolyte balance. However, we noticed renal and gastrointestinal complications: 2 patients had a perforated gastric ulcer, 1 had a gastric ulcer, and gastritis was detected in 3 children. A decreased glomerular filtration rate was observed in 2 patients during follow-up. Our data emphasize the need for regular surveillance of renal function and gastrointestinal endoscopy in these patients. As an alternative to indomethacin, we present our satisfactory preliminary results with rofecoxib.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2006
                February 2006
                23 February 2006
                : 65
                : 2
                : 62-68
                Affiliations
                aUnit of Endocrinology and Nutrition, Fundación Hospital Alcorcón, Madrid, Spain; bDepartment of Pediatrics, Philipps University, Marburg, Germany, and cUniversity Children’s Hospital, Bern, Switzerland
                Article
                90601 Horm Res 2006;65:62–68
                10.1159/000090601
                16391491
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Tables: 3, References: 21, Pages: 7
                Categories
                Novel Insights from Clinical Experience

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