Endocrine Abstracts (2017) 51 OC2.1 | DOI: 10.1530/endoabs.51.OC2.1

Discordant TSH measurements in an euthyroid child due to a homozygous TSHbeta subunit gene variant with variable immunoreactivity

Eva van Walree1, A Emile J Hendriks2, Carla Moran1, Adeline K Nicholas1, Greta Lyons1, Anne McGowan1, David Halsall3, Sue Oddy3, V Krishna Chatterjee1 & Nadia Schoenmakers1


1University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK; 2Department of Paediatrics, Addenbrooke’s Hospital, Cambridge, UK; 3Department of Clinical
Biochemistry, Addenbrooke’s Hospital, Cambridge, UK.


Introduction: Thyroid function tests are frequently undertaken in children with non-specific symptoms suggestive of thyroid dysfunction. Infrequently, susceptibility of automated thyroid hormone assays to interference may generate misleading results, with the potential for inappropriate diagnosis and management. We report an unusual case with apparent subclinical hyperthyroidism, due to negative interference in particular TSH assay platforms, with an underlying genetic basis.

Case report: An 8 year old boy presenting with tiredness exhibited undetectable TSH levels (<0.03; (Reference Range, RR 0.35–5.5 mU/l)), but normal thyroid hormone measurements (FT4 14.4; (RR 10–19.8 pmol/l), FT3 6.6; (RR4-7.5 pmol/l)) prompting further endocrine investigation. He had been born at term to non-consanguineous South Indian parents, following IVF treatment. He was clinically euthyroid and growing along the 91st centile. Following an episode of non-autoimmune thyroiditis his mother was euthyroid; and his father and sibling were well. Further evaluation of his thyroid function tests revealed undetectable TSH levels in two assays (Centaur and Immulite 2000, both manufactured by Siemens), but normal TSH in three other platforms (Wallac Delfia, Roche Elecsys and Abbot Architect, Table 1). FT4 and FT3 were consistently normal, and the discordancy of TSH measurements suggested assay interference. TSH is a heterodimeric glycoprotein comprising alpha and beta subunits encoded by separate genes. Sequencing of TSHB revealed a homozygous, Arginine to Glycine aminoacid change (R75G) which has been identified previously.

Table 1
CentaurImmulite 2000Wallac DelfiaRoche ElecsysAbbott Architect
TSH (mU/l)<0.03 (0.35–5.5)<0.03 (0.4–4)0.93 (0.4–4)2.67 (0.27–4.2)1.69 (0.35–5.5)
FT4 (pmol/l)15.4 (10–19.8)14.7 (11.5–22.7)14.6 (9–20)15.4 (12–22)

Conclusions: Unlike loss-of-function TSHB mutations mediating central hypothyroidism, in silico modelling predicts that R75G mutant TSHβ generates a bioactive TSH heterodimer. However, Arginine-75 is part of an epitope recognised by antibodies used in some immunoassays, explaining loss of TSH immunoreactivity in such platforms. The high allele frequency of R75G TSHβ in South Asian populations (1.2%, Exac), mandates that discordant, subnormal TSH readings in patients of this ethnicity should be reanalyzed using an alternate TSH assay known to cross react with this variant or prompt TSHB sequencing for this substitution.