{"title":"种系TSH受体激活突变相关甲亢的基因型-表型相关性：一项系统综述。","authors":"Chethan Yamichannaiah, Saba Samad Memon, Vijaya Sarathi, Anurag Ranjan Lila, Swati Ramteke Jadhav, Puja Thadani, Samiksha Chandrashekhar Hegishte, Rohit Barnabas, Manjiri Karlekar, Aditya Phadte, Anima Sharma, Tushar Bandgar","doi":"10.1111/cen.15288","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objective</h3>\n \n <p>Germline TSHR activating mutation-associated 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–phenotype relationships.</p>\n </section>\n \n <section>\n \n <h3> Design</h3>\n \n <p>A classification based on age of symptom onset: infantile (<i>n</i> = 36), childhood (<i>n</i> = 33) and adulthood (> 18 years, <i>n</i> = 13) was attempted by performing a systematic review of literature of GTAMH (<i>n</i> = 82 probands, including a 25-year-old 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–phenotype correlation.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Eighty-two probands harbouring 47 different TSHR variants are reported. Probands with infantile-onset were less often familial (19.4%, <i>p</i> = 0.00) than childhood (93.9%) and adult-onset (84.6%) cases. Median serum free-T3 and T4 were highest in infantile (3.1 and 3.4 XULN) followed by childhood (1.6 and 1.9 X-ULN) and adult-onset (1.2 and 0.8 X-ULN) cases. All infant/childhood onset probands had overt hyperthyroidism, whereas 1/3 of adult-onset cases were subclinical. Most (15/18) recurrent variants were exclusive to infantile, childhood or adult-onset 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 (<i>r</i> = 0.40, <i>p</i> = 0.00), and members of multiple families harbouring the same TSHR variants (<i>r</i> = 0.46, <i>p</i> = 0.00).</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>A phenotypic classification of GTAMH into infantile-onset severe hyperthyroxinemia (mostly due to de novo variants), childhood-onset overt hyperthyroidism or adulthood-onset overt/subclinical hyperthyroidism correlates with the genotype of TSHR variants, may guide patient management.</p>\n </section>\n </div>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":"103 2","pages":"119-128"},"PeriodicalIF":2.4000,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen.15288","citationCount":"0","resultStr":"{\"title\":\"Genotype–Phenotype Correlation in Germline TSH Receptor Activating Mutation Associated Hyperthyroidism: A Systematic Review\",\"authors\":\"Chethan Yamichannaiah, Saba Samad Memon, Vijaya Sarathi, Anurag Ranjan Lila, Swati Ramteke Jadhav, Puja Thadani, Samiksha Chandrashekhar Hegishte, Rohit Barnabas, Manjiri Karlekar, Aditya Phadte, Anima Sharma, Tushar Bandgar\",\"doi\":\"10.1111/cen.15288\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>Germline TSHR activating mutation-associated 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–phenotype relationships.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Design</h3>\\n \\n <p>A classification based on age of symptom onset: infantile (<i>n</i> = 36), childhood (<i>n</i> = 33) and adulthood (> 18 years, <i>n</i> = 13) was attempted by performing a systematic review of literature of GTAMH (<i>n</i> = 82 probands, including a 25-year-old 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–phenotype correlation.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Eighty-two probands harbouring 47 different TSHR variants are reported. Probands with infantile-onset were less often familial (19.4%, <i>p</i> = 0.00) than childhood (93.9%) and adult-onset (84.6%) cases. Median serum free-T3 and T4 were highest in infantile (3.1 and 3.4 XULN) followed by childhood (1.6 and 1.9 X-ULN) and adult-onset (1.2 and 0.8 X-ULN) cases. All infant/childhood onset probands had overt hyperthyroidism, whereas 1/3 of adult-onset cases were subclinical. Most (15/18) recurrent variants were exclusive to infantile, childhood or adult-onset 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 (<i>r</i> = 0.40, <i>p</i> = 0.00), and members of multiple families harbouring the same TSHR variants (<i>r</i> = 0.46, <i>p</i> = 0.00).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>A phenotypic classification of GTAMH into infantile-onset severe hyperthyroxinemia (mostly due to de novo variants), childhood-onset overt hyperthyroidism or adulthood-onset overt/subclinical hyperthyroidism correlates with the genotype of TSHR variants, may guide patient management.</p>\\n </section>\\n </div>\",\"PeriodicalId\":10346,\"journal\":{\"name\":\"Clinical Endocrinology\",\"volume\":\"103 2\",\"pages\":\"119-128\"},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2025-06-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cen.15288\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Endocrinology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cen.15288\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Endocrinology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cen.15288","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Genotype–Phenotype Correlation in Germline TSH Receptor Activating Mutation Associated Hyperthyroidism: A Systematic Review
Objective
Germline TSHR activating mutation-associated 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–phenotype relationships.
Design
A classification based on age of symptom onset: infantile (n = 36), childhood (n = 33) and adulthood (> 18 years, n = 13) was attempted by performing a systematic review of literature of GTAMH (n = 82 probands, including a 25-year-old 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–phenotype correlation.
Results
Eighty-two probands harbouring 47 different TSHR variants are reported. Probands with infantile-onset were less often familial (19.4%, p = 0.00) than childhood (93.9%) and adult-onset (84.6%) cases. Median serum free-T3 and T4 were highest in infantile (3.1 and 3.4 XULN) followed by childhood (1.6 and 1.9 X-ULN) and adult-onset (1.2 and 0.8 X-ULN) cases. All infant/childhood onset probands had overt hyperthyroidism, whereas 1/3 of adult-onset cases were subclinical. Most (15/18) recurrent variants were exclusive to infantile, childhood or adult-onset 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 (r = 0.40, p = 0.00), and members of multiple families harbouring the same TSHR variants (r = 0.46, p = 0.00).
Conclusion
A phenotypic classification of GTAMH into infantile-onset severe hyperthyroxinemia (mostly due to de novo variants), childhood-onset overt hyperthyroidism or adulthood-onset overt/subclinical hyperthyroidism correlates with the genotype of TSHR variants, may guide patient management.
期刊介绍：
Clinical Endocrinology publishes papers and reviews which focus on the clinical aspects of endocrinology, including the clinical application of molecular endocrinology. It does not publish papers relating directly to diabetes care and clinical management. It features reviews, original papers, commentaries, correspondence and Clinical Questions. Clinical Endocrinology is essential reading not only for those engaged in endocrinological research but also for those involved primarily in clinical practice.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
