ESPE Abstracts (2018) 89 P-P2-385

Thyroid Hormone Receptor [beta] (THRB) Mutation: Two New Cases of Heterozygous Mutation with Significant Family History

James Blackburn, Senthil Senniappan & Dinesh Giri


Alder Hey Children’s Hospital, Liverpool, UK


Introduction: Resistance to thyroid hormone (RTH) is a relatively uncommon disorder that is usually associated with mutations in thyroid hormone receptor (THR) beta, although rarely THR alpha mutations have been described. RTH beta (RTHB) is often inherited in an autosomal dominant pattern. We describe two cases of RTHB to highlight the significant variations in both clinical presentation and family history.

Case 1: A 2 year old patient presented with a three week history of diarrhoea, weight loss and lethargy. On examination the patient was tachycardic, dehydrated and had evidence of faltering growth (weight 8.95 kg, SDS −2.8). Thyroid function taken at the time of admission showed a raised TSH of 6.35 mu/l [0.3–3.8 mu/l], raised Free T4 of 29.1 pmol/l [9–19 pmol/l] and a raised triiodothyronine (FT3) of 8.1 pmol/l [4.29–6.79 pmol/l]. Detailed evaluation revealed a family history of failure to thrive and childhood thyroid illness in the father and paternal aunt (who also has had thyroid surgery). In view of the biochemistry and family history, the patient underwent genetic analysis that revealed M334R mutation in THR confirming a diagnosis of RTH (beta). The patient was initially commenced on a short course of carbimazole and propranolol prior to genetic confirmation but the treatment was subsequently discontinued. On further follow-up she was noted to be symptom free and gaining weight adequately.

Case 2: A 5 year old patient was referred to the endocrine clinic with poor weight gain [weight 13.8 kg (−2.37 SDS)]. Thyroid function tests revealed raised TSH [5.93 mu/l, 0.3–3.8] and raised FT4 [28.6 pmol/l, 9–19]. On examination, the patient was euthyroid and asymptomatic. Further investigations revealed that the patient’s mother had an elevated T4 of 21.3 pmol/l and elevated T3 of 8.8 pmol/l with the TSH in the normal range. Patient’s 8 year old sister had a T4 of 24 pmol/l and T3 of 12 pmol/l with a normal TSH. Subsequent genetic analysis of the patient and family showed a single base change in Exon 10 [c.1357C>T Pro453Ser] of THR confirming RTH (beta). The patient did not require any treatment and remains under regular follow-up with good weight gain.

Conclusion: These cases demonstrate the highly variable presentation of RTHB. The combination of elevated serum levels of free T4 and TSH should suggest a diagnosis of RTHB. The inheritance pattern highlights the importance of thorough family history. Timely genetic analysis would help to confirm the diagnosis and avoid any unnecessary treatment.

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