{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T01:21:44Z","timestamp":1768353704544,"version":"3.49.0"},"reference-count":22,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T00:00:00Z","timestamp":1583712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust Investigator","award":["106995\/Z\/15\/Z"],"award-info":[{"award-number":["106995\/Z\/15\/Z"]}]},{"name":"National Institute for Health Research Senior Investigator","award":["NF-SI-0514-10091"],"award-info":[{"award-number":["NF-SI-0514-10091"]}]},{"name":"National Institute for Health Research Oxford Biomedical Research Centre"},{"name":"Horizon 2020 Programme of the European Union","award":["675228"],"award-info":[{"award-number":["675228"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>The objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol\/L (6.28 mg\/dL); normal, 2.0 to 2.8 mmol\/L (8.0-11.2 mg\/dL) and parathyroid hormone of 2.2 pmol\/L; normal 1.0 to 9.3 pmol\/L, and required treatment with intravenous calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modeling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilization and mitogen-activated protein kinase responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Thus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa111","type":"journal-article","created":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T12:17:21Z","timestamp":1583756241000},"page":"1393-1400","source":"Crossref","is-referenced-by-count":8,"title":["Neonatal Hypocalcemic Seizures in Offspring of a 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