A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone

作者：Espiard Stephanie^*; Savagner Frederique; Flamant Frederic; Vlaeminck Guillem Virginie; Guyot Romain; Munier Mathilde; d'Herbomez Michele; Bourguet William; Pinto Graziella; Rose Christian; Rodien Patrice; Wemeau Jean Louis

来源：Journal of Clinical Endocrinology & Metabolism, 2015, 100(8): 2841-2848.

DOI：10.1210/jc.2015-1120

Context: RTH alpha is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TR alpha 1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T-4/free T-3 (FT4/FT3) ratio.
Objective: A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated.
Design: Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives. Results: The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T-3. rT(3), SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c. 1075A>T), which affected both the TR alpha 1 and the non-receptor isoform TR alpha 2. The mutant TR alpha 1 had a decrease in transcriptional activity related to decreased T-3 binding and a dominant-negative effect on the wild-type receptor.
Conclusions: This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TR alpha 1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTH alpha

• 出版日期2015-8