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J Med Genet. 2015 May;52(5):312-6. doi: 10.1136/jmedgenet-2014-102936. Epub 2015 Feb 10.

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA).

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Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
Department of Human Genetics, Radboud University Medical Center, Radboud Institute of Molecular Life Sciences, Nijmegen, The Netherlands.
Department of Clinical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
Department of Endocrinology and Diabetology, The Children's Memorial Health Institute, Warsaw, Poland.
Anthropology Laboratory, The Children's Memorial Health Institute, Warsaw, Poland.



Resistance to thyroid hormone is characterised by a lack of response of peripheral tissues to the active form of thyroid hormone (triiodothyronine, T3). In about 85% of cases, a mutation in THRB, the gene coding for thyroid receptor β (TRβ), is the cause of this disorder. Recently, individual reports described the first patients with thyroid hormone receptor α gene (THRA) defects.


We used longitudinal clinical assessments over a period of 18 years at one hospital setting combined with biochemical and molecular studies to characterise a novel thyroid hormone resistance syndrome in a cohort of six patients from five families.


Using whole exome sequencing and subsequent Sanger sequencing, we identified truncating and missense mutations in the THRA gene in five of six individuals and describe a distinct and consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia and constipation), specific facial features (round, somewhat coarse and flat face) and macrocephaly. Laboratory investigations revealed anaemia and slightly elevated cholesterol, while the thyroid profile showed low free thyroxine (fT4) levels coupled with high free T3 (fT3), leading to an altered T4 : T3 ratio, along with normal thyroid-stimulating hormone levels. We observed a genotype-phenotype correlation, with milder outcomes for missense mutations and more severe phenotypical effects for truncating mutations.


THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended.


thyroid hormone receptor alpha gene; thyroid hormone resistance syndrome; thyroid receptor

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