ESPE Abstracts

The action of Thyroid hormone (T3) is mediated by the binding to nuclear receptors (TRa1, TRα1/2), which are ligand dependent transcription factors, encoded by the THRA and THRB genes. THRA germline mutations cause a rare genetic disease called resistance to thyroid hormone α (RTHα) first reported in 2012 . Only 20 missense and frameshift mutations have been reported to date, From this small group of patients, and analysis of animal models, it emerges that the disease severity correlates with the inability of the receptor to release transcription corepressors in the presence of T3 . This can result either from a decrease in the affinity of TRα1 for T3, or from an alteration of its C-terminal helix, which normally recruits transcription coactivators upon T3 binding, releasing corepressors.

We report here the first discovery of a patient with RTHα in China. The patient is the first and only child of healthy unrelated parents. This boy was born at full-term by vaginal delivery. His developmental milestones were delayed. He walked at eighteen month and knew only two words at 2 years (mama and baba). Poor coordination and clumsiness were noted. He had chronic constipation.

On examination at 2 years, his height was 80cm. He was disproportionately short, with short arm span (78cm). The heart rate was low.His skin was thick without skin tags. The face and nasal bridge were broad, but there was no macroglossia.

Results of the screening tests for metabolic defects, including blood and urine amino acids analysis and urinary organic acid analysis were normal. Routine karyotyping(G-bands) showed 46,XY.

The ultrasonic thyroid pelvic were normal. Head and pituitary MRI appeared normal. Radiographic studies showed a normal morphology of the vertebral column, DNA sequencing, using Target Region Sequencing and Sanger sequencing revealed that the patient was heterozygous for a THRA mutation (c.1183G>T,p.E395X) absent in parents.

The initial dose of L-T4 was ordered to 25 g/day. About half a year later, his motor coordination remained poor, and clumsiness was visible.

The E395X mutation eliminates the C-terminal helix of TRα1 and is thus expected to display consequences similar to the C392X, F397fs406X, E403X mutations, which exert a strong dominant-negative influence in heterozygous cells. for this type of mutation, L-T4 treatment provides little benefit, and the manifestations of RTHa are severe. This report also outlines the variability in RTHα manifestations, the large head circumference, which was reported for several other patients, was absent.