title: Prevalence of thyrotropin receptor germline mutations and clinical courses in 89 hyperthyroid patients with diffuse goiter and negative anti-thyrotropin receptor antibodies.
abstract: BACKGROUND
  We studied the frequency of thyrotropin (TSH) receptor mutations in hyperthyroid patients with diffuse goiter and negative TSH receptor antibodies (TRAb), and the clinical pictures of the hyperthyroid patients in the presence and absence of mutations.
  
  
  METHODS
  From 2003 through 2012, 89 hyperthyroid patients with diffuse goiter and negative TRAb based on a second- or third-generation assay underwent sequence analysis of the TSH receptor gene from peripheral leukocytes. The outcome of hyperthyroidism in patients with a TSH receptor mutation and their affected family members was compared with that in patients without any mutation after a 1-10-year follow-up.
  
  
  RESULTS
  Germline mutations of the TSH receptor occurred in 4 of the 89 patients (4.5%), including 3 definitive constitutively activating mutations (L512Q, E575K, and D617Y). The main difference in the clinical outcome of hyperthyroidism was that no patients with a TSH receptor mutation achieved euthyroidism throughout the follow-up, while 23.5% of patients without any mutation entered remission. The progression from subclinical to overt hyperthyroidism was not significantly different between patients with or without a mutation. Meanwhile, 10.3% of TRAb-negative patients without any TSH receptor mutation developed TRAb-positive Graves' hyperthyroidism during the follow-up.
  
  
  CONCLUSIONS
  The prevalence of nonautoimmune hyperthyroidism with TSH receptor mutations is lower than that of latent Graves' disease in TRAb-negative patients with hyperthyroidism. However, all affected patients with a TSH receptor mutation showed persistent hyperthyroidism regardless of subclinical or overt hyperthyroidism throughout the follow-up.
authors.affiliation: 1 Center for Excellence in Thyroid Care, Kuma Hospital , Kobe, Japan .
authors.forename: Eijun
authors.initials: E
authors.lastname: Nishihara
authors.forename: Shuji
authors.initials: S
authors.lastname: Fukata
authors.forename: Akira
authors.initials: A
authors.lastname: Hishinuma
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amino
authors.forename: Akira
authors.initials: A
authors.lastname: Miyauchi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D013956:Antithyroid Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006042:Goiter / Q000209:etiology* / Q000517:prevention & control; D006801:Humans; D006980:Hyperthyroidism / Q000151:congenital* / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D007564:Japan; D008297:Male; D008875:Middle Aged; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013961:Thyroid Gland / Q000000981:diagnostic imaging* / Q000187:drug effects; D014463:Ultrasonography; D055815:Young Adult
chemical_list: D013956:Antithyroid Agents; D011989:Receptors, Thyrotropin