BSPED2011 Oral Communications Oral Communications 1 (8 abstracts)
Growth retardation and severe constipation due to the first human, dominant negative thyroid hormone receptor α mutation
Nadia Schoenmakers 1 , Elena Bochukova 1 , Maura Agostini 1 , Erik Schoenmakers 1 , Odelia Rajanayagam 1 , Elana Henning 1 , Evelien Gevers 2 , Margarita Sarri 3 , Amaka Offiah 4 , Assunta Albanese 5 , David Halsall 1 , John Schwabe 6 , Murray Bain 5 , Keith Lindley 7 , Francesco Muntoni 8 , Faraneh Vargha-Khadem 3 , Mehul Dattani 2 , Sadaf Farooqi 1 , Mark Gurnell 1 & Krishna Chatterjee 1
1Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK; 2Department of Endocrinology, Great Ormond Street Hospital, London, UK; 3Department of Neuropsychology, Great Ormond Street Hospital, London, UK; 4Academic Unit of Child Health, University of Sheffield, Sheffield, UK; 5Department of Paediatric Endocrinology, St George’s Hospital, London, UK; 6Department of Biochemistry, University of Leicester, Leicester, UK; 7Department of Gastroenterology, Great Ormond Street Hospital, London, UK; 8Institute of Child Health, Dubowitz Neuromuscular Centre, London, UK.
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 and intestinal function remained abnormal.
Conclusion: 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 (low-normal fT4, high-normal fT3, low rT3), may enable future identification of additional cases.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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