ESPE Abstracts

Introduction: Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with barely normal thyroid function tests. Clinical features include dysmorphic facies, skeletal dysplasia, growth retardation, constipation, dyspraxia and intellectual deficit. Hormonal assessment often shows decreased/low-normal free thyroxine (fT4) and increased/high-normal free triiodothyronine (fT3) concentrations, resulting in a low fT4/fT3 ratio, with a non-adapted normal thyroid stimulating hormone (TSH) level.

We describe the case of a 14-year-old THRA mutant girl who was diagnosed at birth with peripheric congenital hypothyroidism and who developed marked hypercholesterolemia and severe non-alcoholic steatohepatitis (NASH). Phenotypical presentation includes marked abdominal obesity, macrocephaly, macroglossia, short and large nose, micrognathia and low-implanted ears, associated with mild intellectual impairment.

Materials and Methods: A panel of genes involved in congenital hypothyroidism was explored by next generation sequencing (NGS) on DNA sample. Pathogenic variant was confirmed by Sanger sequencing of exon 10 of the THRA gene for the proband and her mother.

Functional analysis was performed on HepG2 cell line using plasmid transfection of wild type (WT) TRα1 and TRβ, mutated TRα1 and reporter plasmids containing thyroid hormone responsive elements coupled to the luciferase gene. Transcriptional effect has been assessed through luciferase activity.

Results: Next generation sequencing identified a heterozygous single nucleotide c.1207G>A (p.E403K) THRA mutation on exon 10 resulting in impaired function of α1 receptor isoform. The patient's mother carried the same THRA mutation.

Transfection studies on HepG2 cells showed a significant lower transactivation effect of the mutant TRα1 compared to WT TRα and a dominant negative transcriptional effect of mutated TRα1 on both WT TRβ and TR α.

Discussion: This peculiar case associates classical clinical and biological features of RTHa with a previously unreported first-plan metabolic profile: obesity, hyperlipidaemia and severe NASH. Functional in vitro studies suggest a dominant negative effect of mutated TRα1 receptor on wild type TRβ, which is the main isoform expressed in the liver, as well as on wild type TRa, which is mainly represented in adipose tissue. Taken together, these data suggest a pathogenic role of TRα1^E403K in the development of this unique hepato-metabolic profile.

This case further strengthens the wide phenotypical variability of RTHα presentation and the pleiotropic effect of TRs.