{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T15:59:03Z","timestamp":1788019143521,"version":"build-2784847793"},"reference-count":83,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Germline TSHR activating mutation\u2010associated hyperthyroidism (GTAMH) manifests as sporadic or familial forms. Studies have shown poor correlation between receptor activity and clinical manifestations, highlighting a knowledge gap in understanding genotype\u2013phenotype relationships.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>A classification based on age of symptom onset: infantile (<jats:italic>n<\/jats:italic>\u2009=\u200936), childhood (<jats:italic>n<\/jats:italic>\u2009=\u200933) and adulthood (&gt;\u200918 years, <jats:italic>n<\/jats:italic>\u2009=\u200913) was attempted by performing a systematic review of literature of GTAMH (<jats:italic>n<\/jats:italic>\u2009=\u200982 probands, including a 25\u2010year\u2010old woman with TSHR p.Ile640Val variant and subclinical hyperthyroidism managed at our centre). Patients were analysed for various parameters such as demographic, clinical, biochemical and genotype\u2013phenotype correlation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eighty\u2010two probands harbouring 47 different TSHR variants are reported. Probands with infantile\u2010onset were less often familial (19.4%, <jats:italic>p<\/jats:italic>\u2009=\u20090.00) than childhood (93.9%) and adult\u2010onset (84.6%) cases. Median serum free\u2010T3 and T4 were highest in infantile (3.1 and 3.4 XULN) followed by childhood (1.6 and 1.9 X\u2010ULN) and adult\u2010onset (1.2 and 0.8 X\u2010ULN) cases. All infant\/childhood onset probands had overt hyperthyroidism, whereas 1\/3 of adult\u2010onset cases were subclinical. Most (15\/18) recurrent variants were exclusive to infantile, childhood or adult\u2010onset disease groups, except for p.Ser505Asn, p.Asp619Gly and p.Asn670Ser. Including data for probands and genetically affected family members, there was a moderate correlation for the age at diagnosis (infancy, childhood or adulthood), among family members (<jats:italic>r<\/jats:italic>\u2009=\u20090.40, <jats:italic>p<\/jats:italic>\u2009=\u20090.00), and members of multiple families harbouring the same TSHR variants (<jats:italic>r<\/jats:italic>\u2009=\u20090.46, <jats:italic>p<\/jats:italic>\u2009=\u20090.00).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A phenotypic classification of GTAMH into infantile\u2010onset severe hyperthyroxinemia (mostly due to de novo variants), childhood\u2010onset overt hyperthyroidism or adulthood\u2010onset overt\/subclinical hyperthyroidism correlates with the genotype of TSHR variants, may guide patient management.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.15288","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T10:16:19Z","timestamp":1749118579000},"page":"119-128","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genotype\u2013Phenotype Correlation in Germline TSH Receptor Activating Mutation Associated Hyperthyroidism: A Systematic Review"],"prefix":"10.1111","volume":"103","author":[{"given":"Chethan","family":"Yamichannaiah","sequence":"first","affiliation":[{"name":"Department of Endocrinology Seth GS Medical College and KEM Hospital Parel Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba Samad","family":"Memon","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Seth GS Medical College and KEM Hospital Parel Mumbai 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