ESPE Abstracts

Background: Thyroid hormones act via receptors (TRα; TRβ) encoded by separate genes (THRA, THRB). Mutations in THRA are a recently-recognised cause of Resistance to Thyroid Hormone alpha (RTHα), a disorder with tissue-specific hypothyroidism but near-normal thyroid function tests.

Aim: We describe the youngest recorded case of RTHa, in a 2yr old boy with disproportionate short stature, global developmental delay, constipation and a heterozygous missense mutation (p.G291S) in THRA.

Case Report: A 16-month old male was referred to endocrine clinic with short stature. He had disproportionate stature with reduced subischial leg length (Table 1). He is in care, with a maternal antenatal history of substance abuse (exposure to methadone, heroine and alcohol in utero). He has global developmental delay and is mildly dysmorphic with constipation, all attributed to chromosome 16p13.11 microduplication.

Examination revealed coarse facial appearance, depressed nasal bridge, long philtrum and central hypotonia. He had delayed visual maturation, hypermetropia, small kidneys and gastroesophageal reflux. His motor milestones (unable to sit without support) and speech are delayed. Laboratory analysis revealed normocytic anaemia, elevated creatine kinase levels, low-normal T4 and elevated T3 levels leading to altered T4:T3 ratio, with normal TSH levels. THRA sequencing identified a heterozygous missense (p.G291S) mutation, which is homologous to a known pathogenic mutation in THRB (G345S), causing RTHβ. Correlation of genotype with phenotype and assessment of response to thyroxine therapy (25mcg/day) is being undertaken.

Conclusion: We suggest that THRA sequencing should be considered in patients with clinical features of hypothyroidism, raised CK, anaemia and near-normal thyroid function tests but altered T4:T3 ratio. This case broadens the phenotypic spectrum of RTHα.