FRI479 Resistance To Thyroid Hormone Due To Thyroid Hormone Receptor Alpha (THRA) Gene Mutation

Disclosure: J.O. Abdelkarim: None. S. Parveen: None. M.G. Jakoby: None. J. Fleischer: None. Introduction: Resistance to thyroid hormone (RTH) is a heritable disorder characterized by diminished response to triiodothyronine (T3). Most cases of RTH are due to mutations in the thyroid hormone receptor beta (THRB) gene (“RTH-beta”). Mutations in thyroid hormone receptor alpha (THRA) gene appear to be a rare cause of RTH (“RTH-alpha”), with the first case reported in 2012. We present a case of RTH-alpha in a patient confirmed to have a pathogenic THRA mutation. Clinical Case: A 38-year-old Caucasian male was referred to genetic clinic due to mild developmental delay, dyscalculia and mild autism spectrum disorder. He was born at term by uncomplicated spontaneous vaginal delivery. Parents first noticed developmental delays at age 5 y, though no evaluation occurred during childhood. As an adult, the patient completed seminary studies and was employed as a Catholic priest. An intellectual disability gene panel revealed a pathogenic variant of the THRA gene (c.1151G>A p.R384H). Both parents tested negative for the mutation. Examination was notable for obesity (183 cm, 186 kg, BMI 55.5), macrocephaly, hypertelorism, pectus excavatum and small hands with short digits. No thyroid anatomic thyroid abnormalities were appreciated on neck examination or ultrasonography. TSH was 1.860 mIU/L (0.358-3.740), free T4 0.71 ng/dL (0.76-1.46), and free T3 3.2 pg/mL (2.2-4.0). The patient had no symptoms of hypothyroidism, and supplemental thyroid hormone was deferred. Discussion: There are 29 reported THRA gene mutations and 32 cases of RTH-alpha reported in the peer reviewed literature. Common clinical features include mild-to-moderate intellectual impairment, low basal metabolic rate (BMR), mild skeletal dysplasia, normocytic anemia, bradycardia, consistent with high expression of THRA in brain, heart, gastrointestinal tract, skeletal muscle, and bone. TSH is normal to slightly increased, free T4 is low to low normal, and free T3 is normal to modestly elevated. This is the third reported case of the c.1151G>A missense mutation resulting in an arginine to histidine substitution at codon 384. Thyroid function tests conform to the pattern described for other cases of RTH-alpha. Like the other two patients with the R384H mutation, developmental delays occurred, though intellectual manifestations mitigated with time and the patient completed seminary studies without difficulty. Mitigation of phenotype with age has been reported in RTH-alpha mice with the R384C missense mutation. Short stature did not occur in this patient or the other R384H cases. Unlike other patients, this patient did not experience anemia or constipation. Macrocephaly is a common feature of the three R384H cases, but the patient’s other skeletal manifestations (e.g. pectus excavatum) were not reported. This case demonstrates the difficulty of recognizing THR-alpha and extends our understanding of the R384H phenotype. Presentation: Friday, June 16, 2023