CSEMO1 - Thyroid Hormone Resistance Related to THRα Mutation: Diagnostic Challenges in a Pediatric Case

Abstract: Thyroid hormone resistance due to nuclear receptor α (THRα) mutation is a rare entity, clearly distinct from the more common THRβ-related form. It is characterized by a specific phenotype combining impairment of motor coordination, growth retardation, dysmorphic features, constipation, and often subtle biochemical abnormalities.

We report the case of a 27-month-old girl referred to genetics at 14 months for developmental delay and growth failure. Despite being born eutrophic, growth rapidly declined below the 3rd percentile, while head circumference remained preserved. Clinical history revealed gastroesophageal reflux and severe constipation. Examination showed axial hypotonia, motor developmental delay, delayed dental eruption, joint hyperlaxity, as well as dysmorphic features including upturned nose, macroglossia, bilateral ptosis and relative macrocephaly. Thyroid function tests revealed normal TSH and free T4 levels, with elevated free T3. Additional investigations demonstrated macrocytic anemia.

Whole-exome trio sequencing identified a de novo heterozygous likely pathogenic frameshift variant in the last exon of THRA (c.1125_1132dup, p.Gly378Alafs*2). To our knowledge, this variant has not been previously reported.
L-thyroxine therapy was initiated at 18 months, leading to significant improvement in constipation, but with no impact on growth.

To date, fewer than 40 cases of THRA mutations have been reported in pediatric patients. Diagnosis remains challenging due to the highly distinctive clinical presentation, differing from other thyroid disorders, and the discordance between clinical features of hypothyroidism and near-normal thyroid function tests. This case highlights the importance of considering thyroid hormone resistance in the presence of clinical-biological discrepancy and the need for early referral to genetic testing.