CARATTERIZZAZIONE FUNZIONALE DEI MUTANTI DEL RECETTORE PER LA TIREOTROPINA (TSH)

Context: Heterozygous mutations in the TSH receptor gene (TSHR) are associated with partial TSH resistance, characterized by isolated nonautoimmune hyperthyrotropinemia (NAHT). The prevalence and management of this condition is controversial. Objective: Our objective was to investigate the prevalence and clinical impact of TSHR alterations in a large series of pediatric patients with NAHT and to dissect their mechanism of action. Design and Setting: For this prospective multicenter study, clinical data and samples were collected in the clinical units and conveyed to a centralized laboratory for analysis. Patients: Subjects included 284 unrelated patients with NAHT aged 18 yr. Exclusion criteria included thyroid dysgenesis or major associated congenital defects. Main Outcome Measures: Parameters of thyroid function, TSHR gene analysis, and TSHR functional assays were evaluated. Results: The frequency of heterozygous nonpolymorphicTSHRvariationswas11.8%.Weidentified seven previously unknown variations: a frameshift (p.Q33PfsX46), two intronic (g.IVS4+ 2A<G, IVS4-1T<G), and nine novel missense (p.P162L,p. P160S, p.Y466C, p.I583T, p.I607T,p.L57P, p.P668L, p.S745C and p.R609Q) variations. The missense variations variably affected TSHR membrane expression and Gs and/or Gq/11 signaling. Several variations cosegregated with NAHT in the affected families. Parameters of thyroid function were similar between affected and unaffected family members. Conclusions: Nonpolymorphic alterations in the TSHR gene are commonly associated with isolated NAHT in young patients, thus configuring partial TSH resistance as the most frequent inheritable cause of isolated NAHT. The identification of TSHR defects may thus be helpful for a tailored management of subclinical hypothyroidism. We provide further evidence that besides the wellknown defects inGs signaling, TSHR genetic alternations found in NAHT may frequently impair the Gq/11 pathway.