ESPE Abstracts (2019) 92 P1-291

An Incidental Finding of Thyroid Hormone Resistance Due to a De Novo Mutation in the THRB Gene

Noa Shefer Averbuch1,2, Monica França3, Liora Lazar1,2, Ariel Tenenbaum1,2, Moshe Phillip1,2, Liat de Vries1,2


1Schneider Children's medical center of Israel, Petach-Tikva, Israel. 2Tel-Aviv University, Tel-Aviv, Israel. 3University of Chicago, Chicago, USA


Background: Thyroid hormone resistance (THR) is a rare genetic disorder that may be caused by thyroid hormone (TH) cell transporter defects or metabolism defects, but most cases are caused by an inherited mutation in the TH receptor beta (THRB) gene. The reduced responsiveness of target tissues to TH is characterized by elevated TH and a normal or elevated thyroid-stimulating hormone (TSH) level. Differentiating between THR and TSH-producing pituitary tumors is challenging

Patient and Methods: Previously healthy five-year-old boy was found to have elevated FT4 and FT3 (38.8 pmol\L (and 12 pmol\L, respectively)) with a normal TSH of 1.1 mIU\L, in a routine work-up. He had no symptoms or signs of hyperthyroidism. Anti-thyroglobulin, thyroid peroxidase and thyroid receptor antibodies were negative. Parents and three siblings were all found to have normal thyroid functions. To rule out a TSH-secreting adenoma performance of a brain MRI and a TRH test were considered. We decided to start with genetic testing. After proper consent, DNA samples were obtained from all six family members, and the THRB gene was sequenced using Sanger sequencing.

Results: The proband was found to have a de novo mutation in one allele of the THRB gene. The missense mutation, occurring in a CpG dinucleotide hot spot (C GAG), involves a single nucleotide substitution of an adenine for the normal guanine at codon 460, resulting in replacement of the normal glutamine with a lysine (E460K). This mutation, previously described in 10 families, reduces the binding affinity for T3 to 25% that of the normal receptor. The mutation was not found in the other family members tested.

Conclusion: Thyroid hormone resistance should be considered in the differential diagnosis of patients with non-autoimmune, non-goiterous hyper-thyrotropinemia. Most patients are asymptomatic and elevated thyroid hormone levels could be an incidental finding. Although inheritance is autosomal dominant, normal thyroid function in the parents does not rule out the diagnosis because of the possibility of de novo mutations in the THRB gene. The main differential diagnosis to be considered is TSH-secreting adenoma. A fast genetic diagnosis can avoid an unnecessary, costly and complicated work-up, including brain MRI, which requires general anesthesia in small children. Accurate diagnosis is crucial to appropriate follow-up and genetic counseling.

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