{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T18:07:45Z","timestamp":1783706865896,"version":"3.55.0"},"reference-count":40,"publisher":"The Endocrine Society","issue":"4","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,24]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p>Bartter syndrome (BS) is a group of rare autosomal-recessive tubulopathies characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Type 2 BS results from a defect in the renal outer medullary potassium channel encoded by the KCNJ1 gene. Type 2 BS presents with polyhydramnios, intrauterine growth retardation, prematurity, failure to thrive, polyuria, hypercalciuria, and life-threatening episodes of dehydration. Hypocalcemia is a very rare presenting symptom of BS, with only a few published cases reporting it as the initial manifestation of type 2 BS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To describe a child who presented with hypocalcemic seizure at the age of 2.3 years that was first related to vitamin D deficiency and high-phosphate soft drink consumption.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing (WES) was used to evaluate the biochemical abnormalities of the proband.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a previously described homozygous missense mutation c.212C&amp;gt;T, p.T71M in the KCNJ1 gene associated with type 2 BS. Six additional family members with the same mutation and diagnosed clinically with BS are also reported, 2 presenting with hypocalcemia associated with vitamin D deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This report expands the clinical spectrum associated with KCNJ1 mutations and emphasizes the role of WES in unsolved cases of hypocalcemia when genetic disease is suspected. It also highlights the hazardous effects of phosphate-containing soft drinks on calcium metabolism.<\/jats:p><\/jats:sec>","DOI":"10.1210\/clinem\/dgab821","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T11:30:30Z","timestamp":1636457430000},"page":"e1679-e1688","source":"Crossref","is-referenced-by-count":5,"title":["Hypocalcemia as the Initial Presentation of Type 2 Bartter Syndrome: A Family Report"],"prefix":"10.1210","volume":"107","author":[{"given":"Shira","family":"London","sequence":"first","affiliation":[{"name":"Pediatric Endocrine Institute, Ha\u2019Emek Medical Center, Afula, Israel"},{"name":"Armon Child Health Center, Clalit Health Services, Haifa, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Levine","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, Center for Bone Health, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2265-6727","authenticated-orcid":false,"given":"Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronen","family":"Spiegel","sequence":"additional","affiliation":[{"name":"Pediatric Ward B, Ha\u2019Emek Medical Center, Afula, Israel"},{"name":"The Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asaf","family":"Lebel","sequence":"additional","affiliation":[{"name":"The Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel"},{"name":"Pediatric Nephrology Unit, Ha\u2019Emek Medical Center, Afula, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rephael","family":"Halevy","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Unit, Ha\u2019Emek Medical Center, Afula, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5241-3419","authenticated-orcid":false,"given":"Yardena","family":"Tenenbaum-Rakover","sequence":"additional","affiliation":[{"name":"Pediatric Endocrine Institute, Ha\u2019Emek Medical Center, Afula, Israel"},{"name":"The Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"2022032516101835600_CIT0001","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1159\/000380997","article-title":"A practical approach to hypocalcaemia in children.","volume-title":"Calcium and bone disorders in children and adolescents","author":"Shaw","year":"2015","edition":"2"},{"issue":"7656","key":"2022032516101835600_CIT0002","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1136\/bmj.39582.589433.BE","article-title":"Diagnosis and management of hypocalcaemia","volume":"336","author":"Cooper","year":"2008","journal-title":"BMJ."},{"issue":"3","key":"2022032516101835600_CIT0003","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1681\/ASN.V93516","article-title":"Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. 1962","volume":"9","author":"Bartter","year":"1998","journal-title":"J Am Soc Nephrol."},{"key":"2022032516101835600_CIT0004","doi-asserted-by":"crossref","first-page":"396209","DOI":"10.4061\/2011\/396209","article-title":"Primary molecular disorders and secondary biological adaptations in Bartter syndrome","volume":"2011","author":"Desch\u00eanes","year":"2011","journal-title":"Int J Nephrol."},{"issue":"9","key":"2022032516101835600_CIT0005","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2147\/IJNRD.S155397","article-title":"Bartter syndrome: causes, diagnosis, and treatment","volume":"11","author":"Cunha","year":"2018","journal-title":"Int J Nephrol Renovasc Dis."},{"key":"2022032516101835600_CIT0006","doi-asserted-by":"crossref","first-page":"857136","DOI":"10.1155\/2012\/857136","article-title":"Antenatal Bartter syndrome: a review","volume":"2012","author":"Bhat","year":"2012","journal-title":"Int J Pediatr."},{"issue":"3","key":"2022032516101835600_CIT0007","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0002-9343(01)01086-5","article-title":"Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies","volume":"112","author":"Peters","year":"2002","journal-title":"Am J Med."},{"issue":"1","key":"2022032516101835600_CIT0008","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13023-017-0570-z","article-title":"Diseases associated with calcium-sensing receptor","volume":"12","author":"Vahe","year":"2017","journal-title":"Orphanet J Rare Dis."},{"issue":"4","key":"2022032516101835600_CIT0009","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3345\/kjp.2015.58.4.148","article-title":"Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C","volume":"58","author":"Choi","year":"2015","journal-title":"Korean J Pediatr"},{"key":"2022032516101835600_CIT0010","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.cca.2020.10.002","article-title":"Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2","volume":"511","author":"Zuo","year":"2020","journal-title":"Clin Chim Acta."},{"issue":"6","key":"2022032516101835600_CIT0011","doi-asserted-by":"crossref","first-page":"e00160","DOI":"10.1002\/phy2.160","article-title":"Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter\u2019s syndrome and a functional analysis of their pathogenicity","volume":"1","author":"Srivastava","year":"2013","journal-title":"Physiol Rep."},{"issue":"14","key":"2022032516101835600_CIT0012","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics."},{"issue":"5","key":"2022032516101835600_CIT0013","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat Genet"},{"issue":"11","key":"2022032516101835600_CIT0014","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1210\/jc.2009-1535","article-title":"Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3\/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis","volume":"94","author":"Tencza","year":"2009","journal-title":"J Clin Endocrinol Metab."},{"issue":"3","key":"2022032516101835600_CIT0015","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1046\/j.1523-1755.2003.00153.x","article-title":"Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome\/antenatal Bartter syndrome","volume":"64","author":"Peters","year":"2003","journal-title":"Kidney Int."},{"issue":"2","key":"2022032516101835600_CIT0016","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1210\/jcem-61-2-285","article-title":"Dissociation between the effects of endogenous parathyroid hormone on adenosine 3\u2019,5\u2019-monophosphate generation and phosphate reabsorption in hypocalcemia due to vitamin D depletion: an acquired disorder resembling pseudohypoparathyroidism type II","volume":"61","author":"Rao","year":"1985","journal-title":"J Clin Endocrinol Metab."},{"issue":"4","key":"2022032516101835600_CIT0017","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.ecl.2018.07.011","article-title":"Pseudohypoparathyroidism","volume":"47","author":"Linglart","year":"2018","journal-title":"Endocrinol Metab Clin North Am."},{"issue":"34","key":"2022032516101835600_CIT0018","doi-asserted-by":"crossref","first-page":"e16738","DOI":"10.1097\/MD.0000000000016738","article-title":"A novel compound heterozygous KCNJ1 gene mutation presenting as late-onset Bartter syndrome: Case report","volume":"98","author":"Li","year":"2019","journal-title":"Medicine (Baltimore)."},{"issue":"1","key":"2022032516101835600_CIT0019","first-page":"6","article-title":"Alteraciones en el metabolismo del calcio y fosfato secundarias a la ingestion de refrescos fosforados","volume":"52","author":"Mazariegos-Ramos","year":"1995","journal-title":"Bol Me\u0301d Hosp Infant Me\u0301x"},{"issue":"6","key":"2022032516101835600_CIT0020","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/S0022-3476(95)70215-6","article-title":"Consumption of soft drinks with phosphoric acid as a risk factor for the development of hypocalcemia in children: a case-control study","volume":"126","author":"Mazariegos-Ramos","year":"1995","journal-title":"J Pediatr."},{"issue":"3","key":"2022032516101835600_CIT0021","first-page":"185","article-title":"Acute effects of soft drink intake on calcium and phosphate metabolism in immature and adult rats","volume":"50","author":"Amato","year":"1998","journal-title":"Rev Invest Clin."},{"issue":"5","key":"2022032516101835600_CIT0022","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1742-7843.2007.00053.x","article-title":"Evaluation of the effect of cola drinks on bone mineral density and associated factors","volume":"100","author":"Ogur","year":"2007","journal-title":"Basic Clin Pharmacol Toxicol."},{"issue":"4","key":"2022032516101835600_CIT0023","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S0188-4409(00)00090-4","article-title":"Cola beverage consumption induces bone mineralization reduction in ovariectomized rats","volume":"31","author":"Garc\u00eda-Contreras","year":"2000","journal-title":"Arch Med Res."},{"issue":"3","key":"2022032516101835600_CIT0024","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1007\/s13730-020-00464-y","article-title":"Isolated nephrocalcinosis due to compound heterozygous mutations in renal outer medullary potassium channel","volume":"9","author":"Khandelwal","year":"2020","journal-title":"CEN Case Rep."},{"issue":"7","key":"2022032516101835600_CIT0025","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1007\/s00467-016-3337-1","article-title":"Accentuated hyperparathyroidism in type II Bartter syndrome","volume":"31","author":"Landau","year":"2016","journal-title":"Pediatr Nephrol."},{"issue":"7-8","key":"2022032516101835600_CIT0026","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1515\/jpem-2014-0188","article-title":"Antenatal Bartter syndrome presenting as hyperparathyroidism with hypercalcemia and hypercalciuria: a case report and review","volume":"28","author":"Gross","year":"2015","journal-title":"J Pediatr Endocrinol Metab."},{"issue":"4","key":"2022032516101835600_CIT0027","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1007\/s10157-011-0431-3","article-title":"A novel compound heterozygous ROMK mutation presenting as late onset Bartter syndrome associated with nephrocalcinosis and elevated 1,25(OH)(2) vitamin D levels","volume":"15","author":"Sharma","year":"2011","journal-title":"Clin Exp Nephrol."},{"issue":"3","key":"2022032516101835600_CIT0028","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0022-3476(89)80838-8","article-title":"Hypercalciuria with Bartter syndrome: evidence for an abnormality of vitamin D metabolism","volume":"115","author":"Restrepo de Rovetto","year":"1989","journal-title":"J Pediatr"},{"issue":"1","key":"2022032516101835600_CIT0029","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1042\/bj2160237","article-title":"Stimulatory effect of prostaglandin E2 on 1 alpha,25-dihydroxyvitamin D3 synthesis in rats","volume":"216","author":"Yamada","year":"1983","journal-title":"Biochem J."},{"issue":"3","key":"2022032516101835600_CIT0030","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1067\/mpd.2003.100","article-title":"Transient neonatal hyperkalemia in the antenatal (ROMK defective) Bartter syndrome","volume":"142","author":"Finer","year":"2003","journal-title":"J Pediatr."},{"issue":"17","key":"2022032516101835600_CIT0031","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1007\/s00018-006-6011-0","article-title":"Potassium-related inherited tubulopathies","volume":"63","author":"Landau","year":"2006","journal-title":"Cell Mol Life Sci."},{"issue":"6966","key":"2022032516101835600_CIT0032","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nature02196","article-title":"TRP channels as cellular sensors","volume":"426","author":"Clapham","year":"2003","journal-title":"Nature."},{"issue":"3","key":"2022032516101835600_CIT0033","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/gb-2011-12-3-218","article-title":"The transient receptor potential family of ion channels","volume":"12","author":"Nilius","year":"2011","journal-title":"Genome Biol."},{"issue":"23","key":"2022032516101835600_CIT0034","doi-asserted-by":"crossref","first-page":"22540","DOI":"10.1074\/jbc.M503092200","article-title":"Alternative splicing switches the divalent cation selectivity of TRPM3 channels","volume":"280","author":"Oberwinkler","year":"2005","journal-title":"J Biol Chem."},{"issue":"23","key":"2022032516101835600_CIT0035","doi-asserted-by":"crossref","first-page":"20890","DOI":"10.1074\/jbc.M211232200","article-title":"Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3)","volume":"278","author":"Lee","year":"2003","journal-title":"J Biol Chem."},{"issue":"8","key":"2022032516101835600_CIT0036","doi-asserted-by":"crossref","first-page":"e104000","DOI":"10.1371\/journal.pone.0104000","article-title":"Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma","volume":"9","author":"Bennett","year":"2014","journal-title":"PLoS One."},{"issue":"5","key":"2022032516101835600_CIT0037","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/jhg.2009.30","article-title":"Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syndrome","volume":"54","author":"Kuniba","year":"2009","journal-title":"J Hum Genet"},{"issue":"2","key":"2022032516101835600_CIT0038","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1007\/s11689-011-9076-5","article-title":"A family with autism and rare copy number variants disrupting the Duchenne\/Becker muscular dystrophy gene DMD and TRPM3","volume":"3","author":"Pagnamenta","year":"2011","journal-title":"J Neurodev Disord."},{"issue":"9","key":"2022032516101835600_CIT0039","doi-asserted-by":"crossref","first-page":"612","DOI":"10.18632\/aging.100191","article-title":"Joint influence of small-effect genetic variants on human longevity","volume":"2","author":"Yashin","year":"2010","journal-title":"Aging (Albany NY)."},{"key":"2022032516101835600_CIT0040","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1186\/1752-0509-5-S2-S13","article-title":"A methodology for multivariate phenotype-based genome-wide association studies to mine pleiotropic genes","volume":"5","author":"Park","year":"2011","journal-title":"BMC Syst Biol."}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgab821\/41724663\/dgab821.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/107\/4\/e1679\/42994675\/dgab821.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/107\/4\/e1679\/42994675\/dgab821.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,14]],"date-time":"2023-01-14T19:18:18Z","timestamp":1673723898000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/107\/4\/e1679\/6423848"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,9]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,11,9]]},"published-print":{"date-parts":[[2022,3,24]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgab821","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,4,1]]},"published":{"date-parts":[[2021,11,9]]}}}