{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:37:41Z","timestamp":1760060261184,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Purpose: This study investigates the role of CASR gene polymorphisms (A986S, R990G, Q1011E) in PHPT genetic susceptibility and its clinical variability. The aim is to evaluate the prevalence of these polymorphisms in patients with sporadic PHPT and their impact on clinical course, biochemistry, and histological features. Methods: 106 patients underwent clinical and anamnestic evaluations, focusing on major PHPT complications, as well as biochemical analyses of blood and urine. Genetic testing was conducted for CASR gene polymorphisms. Histological data were available for 68 patients who underwent parathyroidectomy. Results: The sample included 83 women and 23 men; mean age at diagnosis was 54.5 years. 55 patients carried CASR gene polymorphisms, while 51 were wild-type. Prevalence rates of polymorphisms were consistent with data for the Caucasian population, with A986S being the most common (31%). No significant associations were found between polymorphisms and increased levels of ionized calcium or other blood phospho-calcium metabolism parameters. However, 24-h urinary calcium levels were higher in patients with polymorphisms (p = 0.0185), particularly in those older than 50 years (p = 0.030) and with the A986S variant. Hypercalciuria was predictive of CASR polymorphism presence (OR = 2.76, p = 0.003). No significant association with PHPT complications, such as renal calculi or bone involvement, was confirmed. Histological data revealed no clear links between polymorphisms and more aggressive variants. Conclusions: CASR gene polymorphisms are associated with hypercalciuria but do not significantly influence age of onset or clinical phenotype in PHPT. Genetic analysis may be useful in selected cases to better understand individual clinical profiles.<\/jats:p>","DOI":"10.3390\/genes16080974","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T11:41:41Z","timestamp":1755603701000},"page":"974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CaSR Gene Polymorphisms and PHPT Phenotypes: What Else Can We Learn? A Single-Center Experience on a Cohort of Italian Patients"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9208-0632","authenticated-orcid":false,"given":"Michele","family":"Cannito","sequence":"first","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3628-0492","authenticated-orcid":false,"given":"Giacomo","family":"Voltan","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Carraro","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8520-5317","authenticated-orcid":false,"given":"Michela","family":"Ferrarese","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4615-5814","authenticated-orcid":false,"given":"Giacomo","family":"Contini","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Mogno","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7931-0084","authenticated-orcid":false,"given":"Loris","family":"Bertazza","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5821-2693","authenticated-orcid":false,"given":"Susi","family":"Barollo","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Torresan","sequence":"additional","affiliation":[{"name":"Endocrine Surgery Unit, Department of Medicine (DIMED), 35128 Padua, Italy"},{"name":"Endocrine Surgery Unit, Department of Surgical, Oncological and Gastroenterological Sciences DISCOG, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6057-4642","authenticated-orcid":false,"given":"Maurizio","family":"Iacobone","sequence":"additional","affiliation":[{"name":"Endocrine Surgery Unit, Department of Medicine (DIMED), 35128 Padua, Italy"},{"name":"Endocrine Surgery Unit, Department of Surgical, Oncological and Gastroenterological Sciences DISCOG, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Mian","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Camozzi","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine (DIMED), Via Ospedale Civile 105, 35128 Padua, Italy"},{"name":"Endocrinology Unit, University-Hospital of Padova, Via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jocd.2012.11.009","article-title":"Epidemiology of primary hyperparathyroidism","volume":"16","author":"Clarke","year":"2013","journal-title":"J. Clin. Densitom."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1210\/jc.2018-01225","article-title":"Primary Hyperparathyroidism","volume":"103","author":"Bilezikian","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1159\/000491039","article-title":"Parathyroid Carcinoma","volume":"51","author":"Cetani","year":"2019","journal-title":"Front. Horm. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1067\/msy.2001.118377","article-title":"Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years","volume":"130","author":"Lundgren","year":"2001","journal-title":"Surgery"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1136\/bmj.321.7261.598","article-title":"Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism","volume":"321","author":"Vestergaard","year":"2000","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1359\/jbmr.1999.14.10.1700","article-title":"Primary hyperparathyroidism and the risk of fracture: A population-based study","volume":"14","author":"Khosla","year":"1999","journal-title":"J. Bone Min. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.beem.2018.09.004","article-title":"Primary hyperparathyroidism","volume":"32","author":"Silva","year":"2018","journal-title":"Best. Pr. Res. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1111\/j.1582-4934.2007.00096.x","article-title":"Structure and function of the human calcium-sensing receptor: Insights from natural and engineered mutations and allosteric modulators","volume":"11","author":"Hu","year":"2007","journal-title":"J. Cell Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/10408360590886606","article-title":"The calcium-sensing receptor in normal physiology and pathophysiology: A review","volume":"42","author":"Brown","year":"2005","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.beem.2013.02.006","article-title":"Role of the calcium-sensing receptor in extracellular calcium homeostasis","volume":"27","author":"Brown","year":"2013","journal-title":"Best. Pr. Res. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1126\/scisignal.2002208","article-title":"Agonist-driven maturation and plasma membrane insertion of calcium-sensing receptors dynamically control signal amplitude","volume":"4","author":"Grant","year":"2011","journal-title":"Sci. Signal"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5883","DOI":"10.1210\/endo.140.12.7190","article-title":"Expression and signal transduction of calcium-sensing receptors in cartilage and bone","volume":"140","author":"Chang","year":"1999","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41574-021-00477-2","article-title":"Hormonal regulation of biomineralization","volume":"17","author":"Arnold","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.1172\/JCI57407","article-title":"PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor","volume":"122","author":"Loupy","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1152\/ajpendo.00315.2009","article-title":"The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion","volume":"297","author":"Kantham","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1152\/ajprenal.00249.2003","article-title":"Calcium-sensing receptor regulation of PTH-inhibitable proximal tubule phosphate transport","volume":"285","author":"Ba","year":"2003","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1093\/hmg\/dds105","article-title":"Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: Evidence for clustering of extracellular domain mutations at calcium-binding sites","volume":"21","author":"Hannan","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1210\/jcem.81.4.8636323","article-title":"Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains","volume":"81","author":"Heath","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1006\/mgme.2000.3126","article-title":"Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene","volume":"72","author":"Cole","year":"2001","journal-title":"Mol. Genet. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1530\/eje.0.1440257","article-title":"Calcium sensing receptor gene polymorphism, circulating calcium concentrations and bone mineral density in healthy adolescent girls","volume":"144","author":"Lorentzon","year":"2001","journal-title":"Eur. J. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1530\/eje.0.1450421","article-title":"Frequency of the calcium-sensing receptor variant A986S in patients with primary hyperparathyroidism","volume":"145","author":"Miedlich","year":"2001","journal-title":"Eur. J. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1046\/j.1365-2265.2001.01318.x","article-title":"Association of polymorphic alleles of the calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism","volume":"55","author":"Yamauchi","year":"2001","journal-title":"Clin. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S8756-3282(02)00741-X","article-title":"Lack of association between calcium-sensing receptor gene \u2018A986S\u2019 polymorphism and bone mineral density in Hungarian postmenopausal women","volume":"30","author":"Speer","year":"2002","journal-title":"Bone"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1097\/01.ASN.0000030077.72157.D2","article-title":"Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients","volume":"13","author":"Vezzoli","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1530\/eje.0.1480603","article-title":"Calcium-sensing receptor gene polymorphism is not associated with bone mineral density in Italian postmenopausal women","volume":"148","author":"Cetani","year":"2003","journal-title":"Eur. J. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1007\/BF03345085","article-title":"Calcium-sensing receptor gene polymorphisms in primary hyperparathyroidism","volume":"25","author":"Cetani","year":"2002","journal-title":"J. Endocrinol. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s00223-002-0066-1","article-title":"Calcium-sensing receptor gene polymorphism A986S does not predict serum calcium level, bone mineral density, calcaneal ultrasound indices, or fracture rate in a large cohort of elderly women","volume":"74","author":"Bollerslev","year":"2004","journal-title":"Calcif. Tissue Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5634","DOI":"10.1210\/jc.2004-0129","article-title":"Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor","volume":"89","author":"Scillitani","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1530\/eje.1.02286","article-title":"R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in patients with primary hyperparathyroidism","volume":"155","author":"Corbetta","year":"2006","journal-title":"Eur. J. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1210\/jc.2006-0857","article-title":"Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor","volume":"92","author":"Scillitani","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/sj.ki.5002156","article-title":"R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria","volume":"71","author":"Vezzoli","year":"2007","journal-title":"Kidney Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1530\/EJE-13-0441","article-title":"Clinical phenotypes of Chinese primary hyperparathyroidism patients are associated with the calcium-sensing receptor gene R990G polymorphism","volume":"169","author":"Han","year":"2013","journal-title":"Eur. J. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1530\/EJE-14-0343","article-title":"Factors associated with vertebral fracture risk in patients with primary hyperparathyroidism","volume":"171","author":"Battista","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_35","first-page":"163","article-title":"Clinical Expression of Calcium Sensing Receptor Polymorphism (A986S) in Normocalcemic and Asymptomatic Hyperparathyroidism","volume":"48","author":"Romero","year":"2016","journal-title":"Horm. Metab. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/sj.ejcn.1601278","article-title":"Validation of a food frequency questionnaire for nutritional calcium intake assessment in Italian women","volume":"56","author":"Montomoli","year":"2002","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_37","unstructured":"Voltan, G., and Ceccato, F. (2025, May 15). CASR Gene Polymorphisms in Primary Hyperparathyroidism: Genetic Susceptibility and Clinical Variability [Dataset]. Available online: https:\/\/researchdata.cab.unipd.it\/1566\/."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1002\/jbmr.4677","article-title":"Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop","volume":"37","author":"Bilezikian","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/cen.14254","article-title":"Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort","volume":"93","author":"Mariathasan","year":"2020","journal-title":"Clin. Endocrinol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:30:27Z","timestamp":1760034627000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,19]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080974"],"URL":"https:\/\/doi.org\/10.3390\/genes16080974","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,8,19]]}}}