Endocrine Abstracts

Objectives: Only (~21 different) heterozygous mutations in thyroid hormone receptor a (TRa), causing Resistance to Thyroid Hormone a (RTHa) have been recorded to date. Here, we report the first known case of RTHa due to a homozygous mutation in THRA, with unique clinical features.

Methods: We ascertained clinical and biochemical features in the index case and his parents. Following identification of the THRA variant by next generation sequencing, functional properties of the TRa mutant were assessed in vitro. We studied T3-regulated gene expression, myogenic differentiation and muscle function of wild type and mutation-containing myoblasts derived from transdifferentiation of fibroblasts from the index case and a parent, ex vivo.

Results: A male child (age 11.0yrs) with mild intellectual disability, bradycardia, cold intolerance and ataxia but normal stature, head circumference and facies, exhibited abnormal thyroid function tests {P1: FT4 12.2 pmol/l (RR 10.5-21), FT3 7.7 pmol/l (RR 4-7.5), reverse T3 0.09 nmol/l (RR 0.12-0.36), TSH 1.42 mU/l (RR 0.35-5.5)} and markedly raised serum muscle enzymes {Creatine kinase (CK) 3650 U/l (RR 39-309); myoglobin 113 mg/l (RR 28-84)}, with calf muscle hypertrophy and myopathy. He is homozygous for a premature stop mutation (Arg152Stop, R152X) in the hinge region of TRa. In contrast, his parents, both heterozygous for R152X TRa, had normal thyroid function tests and CK levels and no clinical abnormalities. Although it is expressed and localises to the nucleus in transfected cells, R152X mutant TRa1 exhibits loss of DNA binding with negligible transcriptional or dominant negative activity. Correlating with his muscle phenotype, myogenic differentiation of R152X homozygous mutant TRa myoblasts was markedly impaired, with reduced expression of TH-regulated target genes (Myosin heavy chain, MYH 1,2,4; Troponin, TNNT 1,3; sarco-endoplasmic reticulum calcium ATPase, SERCA2) mediating muscle function.

Conclusions: Receptor haploinsufficiency, due to a heterozygous, premature stop mutation in TRa, does not cause RTHa. Homozygosity for this receptor defect is associated with RTHa, but without some recognised phenotypes (e.g. short stature, macrocephaly, dysmorphic facies), with the absence of these features possibly reflecting the lack of non-hormone bound TRa, capable of inhibiting target gene expression. Conversely, the severe abnormalities seen in some tissues (e.g. skeletal muscle), do resemble the phenotype observed in conventional hypothyroidism.