ESPE Abstracts (2014) 82 LBP-D--3-1016

The Diverse Phenotype of Mutations in T3 Receptor Alpha (TR[alpha])

Anja van Guchta, Korcan Demirb, Nitash Zwavelingc, Hanneke Wenninkc, Muammer Büyükinand, Gönül Çatlid, Bumin Nuri Dündare, Marcel Meimaa, Edward Vissera, Paul van Trotsenburgc, Theo Vissera & Robin Peetersa


aErasmus Medical Center, Rotterdam, The Netherlands; bDr Behcet Uz Children’s Hospital, Izmir, Turkey; cAcademic Medical Center, Amsterdam, The Netherlands; dTepecik Education and Research Hospital, Izmir, Turkey; eKatip Celebi University, Izmir, Turkey


Background: Recently, the first patients with resistance to thyroid hormone (RTHα) due to inactivating mutations in TRα1 have been identified. These patients are characterized by growth retardation, delayed bone development, mild cognitive defects, delayed motor development and abnormal thyroid function tests.

Objective and hypotheses: We hypothesized that the phenotype of a TRα mutation depends on its location, e.g. if it is present only in TRα1 or in both TRα1 and its non-T3-binding splice variant TRα2. Our objective was to characterize two patients (P1, P2) with such novel TRα mutations.

Method: Patients were assessed clinically and biochemically before and during LT4 treatment. In addition, we studied the influence of the mutations using cells co-transfected with WT and/or mutant TRα1 and a TR-dependent promoter-reporter construct.

Results: P1 was first seen at age 15 months and is now 21 months old. She presented with a mild phenotype comprising delayed motor development, hypotonia and growth retardation. P2 has been followed from age 2 and is now 12 years of age. She suffers from marked growth retardation and severe psychomotor retardation. Both patients showed low serum (F)T4 and rT3, increased T3 and normal TSH levels. P1 has a D211G mutation in both TRα1 and TRα2, resulting in decreased transcriptional activity of TRα1, overcome at higher T3 levels. P2 has a 380fs387X mutation in TRα1, known to completely inactivate TRα1 with dominant-negative activity over WT TRα1.

Conclusion: These results suggest that a mutation affecting both TRα1 and TRα2 does not result in a more severe phenotype than a mutation in TRα1 alone. The severity of the phenotype appears rather related to the location of the mutation in TRα1 and its consequences for binding of T3 and co-factors.