{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T16:44:19Z","timestamp":1777049059046,"version":"3.51.4"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Familial hypocalciuric hypercalcemia (FHH) is a disorder caused by abnormal sensing of calcium by the parathyroids and renal tubules and may mimic primary hyperparathyroidism (PHPT). Patients with FHH should not be subjected to unnecessary and potentially harmful parathyroid surgery. We sought to evaluate the clinical and biochemical presentation of FHH in our endocrine practice. This was a retrospective chart review done after Institutional Review Board approval. We describe 25 cases of likely FHH from our endocrine practice (20 FHH1, 1 FHH2, and 4 FHH3). The 24-h urinary calcium levels were often greater than 100\u00a0mg\/24\u00a0h and sometimes greater than 200\u00a0mg\/24\u00a0h. The calcium to creatinine clearance ratio (CCCR) was consistently &amp;lt;0.01 in 10 of 22 (45%). We also describe several variants of CASR and 1 variant of GNA11 that are probably pathogenic. Some patients, particularly FHH3 patients, have hypercalcemia severe enough to warrant treatment with a calcimimetic medication (cinacalcet). Traditional methods of excluding FHH using 24-h urinary calcium and CCCR are not adequate to distinguish FHH and PHPT. In addition to young age, family history of hypercalcemia and low CCCR, we believe molecular testing should be considered prior to surgery when hypercalcemia cannot be demonstrated to be acquired and in the case of persistent PHPT after surgery by an experienced parathyroid surgeon.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziag049","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:39:46Z","timestamp":1774355986000},"source":"Crossref","is-referenced-by-count":0,"title":["Clinical and molecular characterization of familial hypocalciuric hypercalcemia in an endocrine practice: a case series of 25 patients"],"prefix":"10.1093","volume":"10","author":[{"given":"Jack","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Medicine, Endocrinology and Molecular Medicine, Medical College of Wisconsin , Milwaukee, WI 53226 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracy S","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Medical College of Wisconsin , Milwaukee, WI 53226 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Donahue","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical College of Wisconsin , Milwaukee, WI 53226 ,","place":["United States"]},{"name":"IntrospectDNA, LLC , Milwaukee, WI 53212 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6266-1029","authenticated-orcid":false,"given":"Joseph L","family":"Shaker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Endocrinology and Molecular Medicine, Medical College of Wisconsin , Milwaukee, WI 53226 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"issue":"5","key":"2026042412012509800_ref1","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1210\/endrev\/bnad009","article-title":"Molecular and clinical spectrum of primary hyperparathyroidism","volume":"44","author":"Jha","year":"2023","journal-title":"Endocr Rev"},{"issue":"11","key":"2026042412012509800_ref2","doi-asserted-by":"publisher","first-page":"2293","DOI":"10.1002\/jbmr.4677","article-title":"International workshop on primary hyperparathyroidism evaluation and management of primary hyperparathyroidism: summary statement and guidelines from the fifth international workshop","volume":"37","author":"Bilezikian","year":"2022","journal-title":"J Bone Miner Res"},{"key":"2026042412012509800_ref3","first-page":"883","article-title":"Hereditary hypercalcemia and parathyroid hyperplasia without definite hyperparathyroidism","volume":"68","author":"Jackson","year":"1966","journal-title":"J Lab Clin Med"},{"issue":"6","key":"2026042412012509800_ref4","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1210\/jcem-47-6-1190","article-title":"Circulating parathyroid hormone activity: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism","volume":"47","author":"Marx","year":"1978","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026042412012509800_ref5","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1097\/00005792-198111000-00002","article-title":"The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds","volume":"60","author":"Marx","year":"1981","journal-title":"Medicine (Baltimore)"},{"issue":"2","key":"2026042412012509800_ref6","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1172\/jci111016","article-title":"Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism","volume":"72","author":"Attie","year":"1983","journal-title":"J Clin Invest"},{"issue":"5","key":"2026042412012509800_ref7","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1111\/j.1365-2265.2008.03259.x","article-title":"Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods","volume":"69","author":"Christensen","year":"2008","journal-title":"Clin Endocrinol"},{"issue":"7","key":"2026042412012509800_ref8","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1016\/0092-8674(93)90617-y","article-title":"Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism","volume":"75","author":"Pollak","year":"1993","journal-title":"Cell."},{"issue":"9","key":"2026042412012509800_ref9","doi-asserted-by":"publisher","first-page":"2594","DOI":"10.1210\/jcem.80.9.7673400","article-title":"Familial hypocalciuric hypercalcemia associated with mutations in the human Ca(2+)-sensing receptor gene","volume":"80","author":"Aida","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2026042412012509800_ref10","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1056\/NEJM198202043060502","article-title":"An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds","volume":"306","author":"Marx","year":"1982","journal-title":"N Engl J Med"},{"issue":"6","key":"2026042412012509800_ref11","doi-asserted-by":"publisher","first-page":"2683","DOI":"10.1172\/JCI118335","article-title":"Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism","volume":"96","author":"Pearce","year":"1995","journal-title":"J Clin Invest"},{"issue":"3","key":"2026042412012509800_ref12","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1172\/JCI117062","article-title":"Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, effects of mutant gene dosage on phenotype","volume":"93","author":"Pollak","year":"1994","journal-title":"J Clin Invest"},{"issue":"6","key":"2026042412012509800_ref13","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1097\/MED.0b013e32834c3c7c","article-title":"Familial hypocalciuric hypercalcaemia: a review","volume":"18","author":"Christensen","year":"2011","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"issue":"26","key":"2026042412012509800_ref14","doi-asserted-by":"publisher","first-page":"2476","DOI":"10.1056\/NEJMoa1300253","article-title":"Mutations affecting g-protein subunit 11 in hypercalcemia and hypocalcemia","volume":"368","author":"Nesbit","year":"2013","journal-title":"N Engl J Med"},{"issue":"1","key":"2026042412012509800_ref15","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/ng.2492","article-title":"Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3","volume":"45","author":"Nesbit","year":"2013","journal-title":"Nat Genet"},{"issue":"5","key":"2026042412012509800_ref16","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.beem.2018.05.004","article-title":"Familial hypocalciuric hypercalcemia and related disorders","volume":"32","author":"Lee","year":"2018","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026042412012509800_ref17","doi-asserted-by":"publisher","first-page":"150016","DOI":"10.1530\/EDM-15-0016","article-title":"Familial hypocalciuric hypercalcemia with a de novo heterozygous mutation of calcium-sensing receptor","volume":"2015","author":"Taki","year":"2015","journal-title":"Endocrinol Diabetes Metab Case Rep"},{"issue":"1","key":"2026042412012509800_ref18","doi-asserted-by":"publisher","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":"11","key":"2026042412012509800_ref19","doi-asserted-by":"publisher","first-page":"988","DOI":"10.4158\/EP-2018-0350","article-title":"Calcium-creatinine clearance ratio is not helpful in differentiating primary hyperparathyroidism from familial hypercalcemic hypocalciuria: a study of 1000 patients","volume":"24","author":"Moore","year":"2018","journal-title":"Endocr Pract"},{"issue":"D1","key":"2026042412012509800_ref20","doi-asserted-by":"publisher","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2013","journal-title":"Nucleic Acids Res"},{"issue":"7616","key":"2026042412012509800_ref21","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"issue":"6664","key":"2026042412012509800_ref22","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction of alphamissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"issue":"4","key":"2026042412012509800_ref23","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1093\/clinchem\/hvad008","article-title":"Persistent hypercalcemia: choose your testing strategy carefully","volume":"69","author":"Sharag-Eldin","year":"2023","journal-title":"Clin Chem"},{"issue":"2","key":"2026042412012509800_ref24","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1210\/clinem\/dgae769","article-title":"CASRdb: a publicly accessible comprehensive database for disease-associated calcium-sensing receptor variants","volume":"110","author":"Charoenngam","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2026042412012509800_ref25","doi-asserted-by":"publisher","first-page":"351","DOI":"10.7326\/0003-4819-92-3-351","article-title":"Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration","volume":"92","author":"Marx","year":"1980","journal-title":"Ann Intern Med"},{"issue":"11","key":"2026042412012509800_ref26","doi-asserted-by":"publisher","first-page":"4373","DOI":"10.1210\/jc.2007-0322","article-title":"Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population","volume":"92","author":"Nissen","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2026042412012509800_ref27","doi-asserted-by":"publisher","first-page":"108840","DOI":"10.1016\/j.surg.2024.07.077","article-title":"Is biochemical screening enough to guide calcium-sensing receptor gene mutational analysis when diagnosing familial hypocalciuric hypercalcemia? A retrospective study","volume":"177","author":"Flaris","year":"2025","journal-title":"Surgery"},{"issue":"11","key":"2026042412012509800_ref28","doi-asserted-by":"publisher","first-page":"3933","DOI":"10.1210\/jc.2017-01606","article-title":"Calcimimetic use in familial hypocalciuric hypercalcemia-a perspective in endocrinology","volume":"102","author":"Marx","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2026042412012509800_ref29","doi-asserted-by":"publisher","first-page":"2185","DOI":"10.1210\/jc.2015-3442","article-title":"Familial hypocalciuric hypercalcemia types 1 and 3 and primary hyperparathyroidism: similarities and differences","volume":"101","author":"Vargas-Poussou","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2026042412012509800_ref30","doi-asserted-by":"publisher","first-page":"458","DOI":"10.3389\/fphys.2016.00458","article-title":"Autosomal dominant hypocalcemia (hypoparathyroidism) types 1 and 2","volume":"7","author":"Roszko","year":"2016","journal-title":"Front Physiol"},{"issue":"6","key":"2026042412012509800_ref31","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1016\/j.ajhg.2020.04.006","article-title":"Familial hypocalciuric hypercalcemia type 1 and autosomal-dominant hypocalcemia type 1: prevalence in a large healthcare population","volume":"106","author":"Dershem","year":"2020","journal-title":"Am J Hum Genet"},{"issue":"3","key":"2026042412012509800_ref32","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1210\/jc.2012-4022","article-title":"Incidence and prevalence of primary hyperparathyroidism in a racially mixed population","volume":"98","author":"Yeh","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2026042412012509800_ref33","doi-asserted-by":"publisher","first-page":"e1117","DOI":"10.1210\/clinem\/dgad201","article-title":"Stable incidence and increasing prevalence of primary hyperparathyroidism in a population-based study in Scotland","volume":"108","author":"Soto-Pedre","year":"2023","journal-title":"J Clin Endocrniol Metab"},{"issue":"10","key":"2026042412012509800_ref34","doi-asserted-by":"publisher","first-page":"3570","DOI":"10.1210\/jc.2014-1414","article-title":"Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the fourth international workshop","volume":"99","author":"Eastell","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026042412012509800_ref35","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1097\/CCO.0b013e32833fc9a9","article-title":"The growing role for genetic counseling in endocrinology","volume":"23","author":"Matloff","year":"2011","journal-title":"Curr Opin Oncol"},{"issue":"4","key":"2026042412012509800_ref36","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1056\/NEJMoa040008","article-title":"Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor","volume":"351","author":"Pallais","year":"2004","journal-title":"N Engl J Med"},{"issue":"13","key":"2026042412012509800_ref37","doi-asserted-by":"publisher","first-page":"5443","DOI":"10.1073\/pnas.0701290104","article-title":"An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations","volume":"104","author":"Makita","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"2026042412012509800_ref38","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1210\/jc.2010-1739","article-title":"Autoimmune hypocalciuric hypercalcemia unresponsive to glucocorticoid therapy in a patient with blocking autoantibodies against the calcium-sensing receptor","volume":"96","author":"Pallais","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026042412012509800_ref39","doi-asserted-by":"publisher","first-page":"K1","DOI":"10.1530\/EJE-17-0172","article-title":"Glucocorticoid-responsive lymphocytic parathyroiditis and hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor: a case report and literature review","volume":"177","author":"Song","year":"2017","journal-title":"Eur J Endocrinol"},{"issue":"7","key":"2026042412012509800_ref40","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.1210\/clinem\/dgaa219","article-title":"Autoimmune hypercalcemia due to autoantibodies against the calcium-sensing receptor","volume":"105","author":"Mi\u00f1ambres","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"20","key":"2026042412012509800_ref41","doi-asserted-by":"publisher","first-page":"e156742","DOI":"10.1172\/jci.insight.156742","article-title":"Successful prednisolone or calcimimetic treatment of acquired hypocalciuric hypercalcemia caused by biased allosteric CaSR autoantibodies","volume":"7","author":"Makita","year":"2022","journal-title":"JCI Insight"},{"issue":"8","key":"2026042412012509800_ref42","doi-asserted-by":"publisher","first-page":"e237036","DOI":"10.1136\/bcr-2020-237036","article-title":"Double jeopardy: a patient's tale of two concurrent hypercalcaemic syndromes","volume":"13","author":"Sharma","year":"2020","journal-title":"BMJ Case Rep"},{"issue":"3","key":"2026042412012509800_ref43","doi-asserted-by":"publisher","first-page":"412","DOI":"10.4158\/EP11272.RA","article-title":"Primary hyperparathyroidism and familial hypocalciuric hypercalcemia: relationships and clinical implications","volume":"18","author":"Eldeiry","year":"2012","journal-title":"Endocr Pract"},{"issue":"1","key":"2026042412012509800_ref44","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1530\/EJE-09-0257","article-title":"Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager","volume":"161","author":"Brachet","year":"2009","journal-title":"Eur J Endocrinol"},{"issue":"4","key":"2026042412012509800_ref45","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1007\/s00774-012-0399-4","article-title":"Primary hyperparathyroidism in a patient with familial hypocalciuric hypercalcaemia due to a novel mutation in the calcium-sensing receptor gene","volume":"31","author":"Egan","year":"2013","journal-title":"J Bone Miner Metab"},{"issue":"10","key":"2026042412012509800_ref46","doi-asserted-by":"publisher","first-page":"e46980","DOI":"10.7759\/cureus.46980","article-title":"Coexistence of a calcium-sensing receptor mutation and primary hyperparathyroidism","volume":"15","author":"Russell","year":"2023","journal-title":"Cureus"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmrplus\/advance-article-pdf\/doi\/10.1093\/jbmrpl\/ziag049\/67551022\/ziag049.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/10\/5\/ziag049\/67551022\/ziag049.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/10\/5\/ziag049\/67551022\/ziag049.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T16:01:34Z","timestamp":1777046494000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/doi\/10.1093\/jbmrpl\/ziag049\/8541704"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,26]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,4,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmrpl\/ziag049","relation":{},"ISSN":["2473-4039"],"issn-type":[{"value":"2473-4039","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,3,26]]},"article-number":"ziag049"}}