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J Clin Endocrinol Metab. 2015 Aug;100(8):2841-8. doi: 10.1210/jc.2015-1120. Epub 2015 Jun 2.

A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone.

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Centre Hospitalier Régional Universitaire de Lille (S.E., J.-L.W.), Hôpital Huriez, Service d'endocrinologie et métabolisme, 59000 Lille, France; Unité Mixte de Recherche (UMR) Institut national de la santé et de la recherche médicale (Inserm) 1048 (F.S.), Institut des Maladies Métaboliques et Cardiovasculaires 31000 Toulouse, France; Equipe d'accueil 3143 (F.S.), Laboratoire de neurobiologie et transgenèse, Université d'Angers, France; Université de Lyon (F.F., R.G.), Centre National de la Recherche Scientifique (CNRS), Institut National Recherche Agronomique, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Institut de Génomique Fonctionnelle de Lyon, 69008 Lyon France; Centre de recherche en Cancérologie de Lyon (V.V.-G.), UMR Inserm 1052 CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Université de Lyon, 69008 Lyon, France; Service de Biochimie Sud (V.V.-G.), Centre de Biologie Sud, Centre Hospitalier Lyon Sud, 69495 Pierre Bénite, France; Inserm (M.M., P.R.), CNRS, UMR Inserm 1083 CNRS 6214, Université d'Angers, 49100 Angers, France; Centre Hospitalier Régional Universitaire de Lille (M.H.), Centre de Biopathologie, Service de médecine nucléaire, 59000 Lille, France; UMR Inserm 1054 CNRS 5048 (W.B.), Centre de Biochimie Structurale, Universités Montpellier 1 & 2, 34000 Montpellier, France; Hôpital Necker Enfants Malades (G.P.), service d'endocrinologie pédiatrique, 75015 Paris, France; Hôpital St-Vincent de Paul (C.R.), Institut Catholique de Lille Service d'oncologie et d'hématologie, 59000 Lille, France; and Centre Hospitalier Universitaire d'Angers (P.R.), centre de référence des maladies rares de la réceptivité hormonale, 49100 Angers, France.



RTHα is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TRα1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T4/free T3 (FT4/FT3) ratio.


A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated.


Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives.


The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T3. rT3, SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c.1075A>T), which affected both the TRα1 and the non-receptor isoform TRα2. The mutant TRα1 had a decrease in transcriptional activity related to decreased T3 binding and a dominant-negative effect on the wild-type receptor.


This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRα1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHα.

[Indexed for MEDLINE]

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