7308 A Case of Thyroid Hormone Resistance Associated With a Novel Mutation in the THRA Gene

Abstract

Abstract Disclosure: J.A. Siddiqui: None. M. Barbosa: None. V. Fettig: None. C.J. Romero: None. Introduction: Thyroid hormone resistance (THR) is a syndrome leading to decreased response of target organs to thyroid hormone. Normal thyroid hormone action is mediated by thyroid hormone nuclear receptors and is essential for normal development and metabolism. Two isoforms are encoded by the thyroid hormone receptor α and β genes (THRA and THRB). Mutations in THRB are commonly reported with limited cases of THRA mutations. We report a 15-month-old and her mother with a pathogenic variant in the THRα receptor leading to thyroid hormone resistance. CASE: A 15-month-old ex-39-week gestation female was born small for gestational age (birth weight: 2450 grams,3rd %ile and birth length: 17 inches,1st %ile). The newborn screen was normal. She presented with macroglossia, low tone and global developmental delay. She had severe constipation complicated by rectal prolapse that required surgical correction. There are multiple relatives (mother, maternal half-brother and maternal grandparents) with neurodevelopmental issues. The mother’s previous genetic evaluation was non-diagnostic. Mother reports a thyroid condition but without treatment. The patient was initially referred to genetics and whole exome sequencing revealed a heterozygous c.1205 T>C p. (L402P) variant in the THRα gene, which was maternally inherited and reported as a variant of uncertain significance. On physical exam, Heart rate was 112 bpm; height <1%ile (Z-score -3.22 SD), weight 3%ile (Z-score -1.89 SD). Patient has a wide anterior fontanelle (4x3 cm), macroglossia and delayed teeth eruption. Other exam findings: non-palpable thyroid and postaxial polydactyly on the 5th digit of the right toe. Thyroid hormone testing: normal TSH 1.829 uIU/mL, low total T4 4.4 mcg/dL, low Free T4 of 0.58 ng/dL and high free T3 of 4.24 pg/mL. Levothyroxine treatment was initiated(25 mcg daily). After 1 month treatment, TSH level was 0.23 uIU/mL, total T4 was 6.1 mcg/dL and low reverse T3 of 5.8 ng/dL. DISCUSSION: Thyroid hormone resistance due to THRα mutations are rare and under-recognized. The main clinical phenotype includes growth retardation, delayed development, decreased muscle tone, delayed tooth eruption and constipation. Unlike patients with THRβ mutations, the hypothalamus-pituitary-thyroid axis in patients with THRα mutations is minimally affected with a normal TSH level. Total T3 levels are elevated with slightly low total T4 and free T4:T3 ratio is low. Treatment with levothyroxine leads to suppressions of TSH levels, therefore confirming intact central T3 feedback loop. Reports, however, show minor clinical improvements with treatment; therefore further research is needed in these patients to explore more effective therapeutic options. We present a case of a novel congenital THRA mutation leading to a clinical phenotype consistent with THR. She continues care in our clinic with hopes to further study her mutation. Presentation: 6/2/2024