ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2017) 48 O3 | DOI: 10.1530/endoabs.48.O3

Compensated hyperthyrotropinaemia due to partial loss-of-function mutation in TSH receptor gene

Anne McGowan1, Carla Moran1, Mark Vanderpump2, Mehul Dattani3, Krishna Chatterjee1 & Nadia Schoenmakers1


1Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2University College Hospital, London, UK; 3Great Ormond Street and University College Hospital, London, UK.


Case history: A clinically euthyroid 7-year-old boy was noted to have a persistently elevated TSH 7.35–14 mU/l (NR 0.27–4.2) and normal FT4 15.0 pmol/l (NR 10-24) with negative anti-thyroid peroxidase antibodies. Thyroid ultrasonography revealed a eutopically-located thyroid gland of normal size. Following commencement of levothyroxine, he developed insomnia, irritability and headaches, resulting in cessation of treatment. Growth and development proceeded normally, however sequential thyroid hormone measurements over 7 years revealed failure to suppress TSH fully despite high-normal FT4 concentrations and further trials of levo-T4 replacement.

Investigations: Re-evaluation off medication aged 16 years revealed an elevated TSH 20.1 mU/l (NR 0.4–4.0) in the setting of a normal FT4 14.3 pmol/l (NR 9–20) and FT3 6.0 pmol/l (NR 3.0–7.5). In addition, his serum calcium and PTH were normal. Direct sequencing of the TSH receptor gene (TSHR) was undertaken following exclusion of assay interference.

Results and treatment: A heterozygous, loss-of-function TSHR mutation (c.122G>C, p.Cys41Ser) was identified, supporting a diagnosis of partial TSH resistance. Cys 41 is located in the extracellular domain of the receptor and substitution with serine has previously been shown to result in impaired binding of TSH to the TSHR in vitro. This molecular diagnosis provided justification for withholding further levo-T4 treatment, and the patient subjectively improved.

Conclusions and points for discussion: Loss of function mutations in TSH receptor gene are associated with a spectrum of phenotypes. The degree of resistance is dictated by the severity of receptor functional impairment, with partial forms showing a heterogeneous hormonal and clinical profile. Levo-T4 replacement should be instituted in severe resistance but there is a paucity of evidence to guide treatment in partial TSH resistance cases. Available literature suggests that these individuals may not require treatment but should nonetheless continue sequential biochemical evaluation.

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