{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:43:56Z","timestamp":1789447436004,"version":"build-2803163510"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2014,11,17]],"date-time":"2014-11-17T00:00:00Z","timestamp":1416182400000},"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":[[2015,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A\/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A\/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications. \u00a9 2014 American Society for Bone and Mineral Research \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2408","type":"journal-article","created":{"date-parts":[[2014,11,17]],"date-time":"2014-11-17T09:25:06Z","timestamp":1416216306000},"page":"906-912","source":"Crossref","is-referenced-by-count":33,"title":["TSH Elevations as the First Laboratory Evidence for Pseudohypoparathyroidism Type Ib (PHP-Ib)"],"prefix":"10.1093","volume":"30","author":[{"given":"Angelo","family":"Molinaro","sequence":"first","affiliation":[{"name":"Endocrinology UnitDepartment of Clinical and Experimental MedicineUniversity of PisaUniversity Hospital of PisaPisaItaly"},{"name":"Endocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonMA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dov","family":"Tiosano","sequence":"additional","affiliation":[{"name":"Division of Pediatric EndocrinologyMeyer Children's HospitalRambam Health Care CampusHaifaIsrael"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rieko","family":"Takatani","sequence":"additional","affiliation":[{"name":"Endocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonMA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dionisios","family":"Chrysis","sequence":"additional","affiliation":[{"name":"Department of PediatricsMedical SchoolUniversity of PatrasPatrasGreece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Russell","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology and DiabetesVanderbilt University School of MedicineNashvilleTN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolas","family":"Koscielniak","sequence":"additional","affiliation":[{"name":"Program in Occupational TherapyWashington University School of MedicineSt. LouisMO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Laure","family":"Kottler","sequence":"additional","affiliation":[{"name":"Reference Centre for Rare Disorders of Calcium and Phosphorus MetabolismDepartment of GeneticsCentre Hospitalier Universitaire de CaenCaenFrance"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Agretti","sequence":"additional","affiliation":[{"name":"Endocrinology UnitDepartment of Clinical and Experimental MedicineUniversity of PisaUniversity Hospital of PisaPisaItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"De Marco","sequence":"additional","affiliation":[{"name":"Endocrinology UnitDepartment of Clinical and Experimental MedicineUniversity of PisaUniversity Hospital of PisaPisaItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petteri","family":"Ahtiainen","sequence":"additional","affiliation":[{"name":"Department of EndocrinologyKuopio University HospitalKuopioFinland"},{"name":"Department of EndocrinologyCentral Finland Central HospitalJyv\u00e4skyl\u00e4Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Christov","sequence":"additional","affiliation":[{"name":"Endocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonMA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"M\u00e4kitie","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Institute of GeneticsHelsinkiFinland"},{"name":"Department of PediatricsHelsinki University Central Hospital and University of HelsinkiHelsinkiFinland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Tonacchera","sequence":"additional","affiliation":[{"name":"Endocrinology UnitDepartment of Clinical and Experimental MedicineUniversity of PisaUniversity Hospital of PisaPisaItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"J\u00fcppner","sequence":"additional","affiliation":[{"name":"Endocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonMA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,11,17]]},"reference":[{"key":"2024020319162083400_jbmr2408-bib-0001","first-page":"675","article-title":"Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting","volume":"22","author":"Weinstein","year":"2001","journal-title":"Endocr 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