Endocrine Abstracts (2012) 28 OC1.5

Growth Retardation and Severe Constipation due to the first human, dominant negative Thyroid Hormone Receptor Alpha mutation

Nadia Schoenmakers1, Elena Bochukova1, Maura Agostini1, Erik Schoenmakers1, Odelia Rajanayagam1, Julia Keogh1, Elana Henning1, Jana Reinemund1, Evelien Gevers2, Margarita Sarri3, Kate Downes5, Amaka Offiah6, Assunta Albanese7, David Halsall1, John Schwabe8, Murray Bain7, Keith Lindley4, Francesco Muntoni9, Faraneh Vargha-Khadem3, Mehul Dattani2, Sadaf Farooqi1, Mark Gurnell1 & Krishna Chatterjee1


1Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; 2Department of Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom; 3Department of Neuropsychology, Great Ormond Street Hospital for Children, London, United Kingdom; 4Department of Gastroenterology, Great Ormond Street Hospital for Children, London, United Kingdom; 5Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Cambridge, United Kingdom; 6Academic Unit of Child Health, University of Sheffield, Sheffield, United Kingdom; 7Department of Paediatric Endocrinology, St George's Hospital, London, United Kingdom; 8Department of Biochemistry, Univesity of Leicester, Leicester, United Kingdom; 9Dubowitz Neuromuscular Centre, Institute of Child Health, London, United Kingdom.


Introduction: Thyroid hormones act via receptors encoded by different genes (THRA and THRB) generating receptor subtypes (TRα1, TRβ1, TRβ2) with differing, tissue-specific expression. Resistance to Thyroid Hormone due to THRB defects is well recognised, but no THRA mutations have yet been reported. We describe the first case of human TRα-mediated thyroid hormone resistance due to a dominant negative THRA mutation.

Results: A 6-year-old female presented with lower segmental growth retardation (height <10th centile), skeletal dysplasia (delayed bone age, femoral epiphyseal dysgenesis, delayed fusion of cranial sutures) and severe constipation. Thyroid function tests showed low/low-normal free T4 (fT4), high/high-normal free T3 (fT3), low reverse T3 (rT3) and normal TSH resulting in a markedly subnormal fT4/fT3 ratio. Heart rate, blood pressure (BP) and basal metabolic rate (BMR) were subnormal, but serum sex hormone binding globulin concentrations (SHBG), a hepatic marker of thyroid hormone action, were elevated. Whole exome sequencing identified a heterozygous nonsense mutation (E403X) in THRA, generating a carboxyterminally truncated receptor protein which binds corepressors aberrantly and inhibits wild type receptor action in a dominant-negative manner. Thyroxine treatment suppressed TSH and normalised BMR with a further rise in SHBG; but heart rate, BP, growth retardation and intestinal dysmotility remained refractory.

Conclusions: This patient exhibits tissue-specific hypothyroidism paradoxically associated with only borderline abnormal thyroid hormone levels, synonymous with findings in TRα mutant mice. Some parameters (TSH, SHBG) responded to thyroxine treatment, but cardiac, gastrointestinal and skeletal tissues remained refractory. Such differential tissue sensitivity to thyroid hormone action, reflects preserved hormone responsiveness in TRβ-expressing tissues (e.g. hypothalamus, pituitary and liver) but resistance in TRα-expressing tissues (skeleton, gastrointestinal tract and myocardium). Recognition of hypothyroid features, but associated with a distinctive biochemical profile (subnormal fT4/fT3 ratio, low rT3), may enable future identification of additional cases.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work was supported by The Wellcome Trust (grant numbers 082390 and 080237) and the MRC Centre for Obesity and Related Metabolic Disease, the Great Ormond St Children’s Charity and the National Institutes of Health Research Cambridge Biomedical Research Centre.

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