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

Abstract

BACKGROUND:

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.

METHODS:

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.

FINDINGS:

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.

INTERPRETATION:

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.

• Authors: Anna Tylki-Szymańska, Rocio Acuna-Hidalgo, Małgorzata Krajewska-Walasek, Agnieszka Lecka-Ambroziak, Marloes Steehouwer, Christian Gilissen, Han G Brunner, Agnieszka Jurecka, Agnieszka Różdżyńska-Świątkowska, Alexander Hoischen, Krystyna H Chrzanowska
• Journal: Journal of medical genetics (J Med Genet) Vol. 52 Issue 5 Pg. 312-6 (May 2015) ISSN: 1468-6244 [Electronic] England
• PMID: 25670821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• Thyroid Hormone Receptors alpha
• Thyroxine

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• DNA Mutational Analysis
• Facies
• Female
• Genetic Association Studies
• Genotype
• Humans
• Male
• Mutation
• Phenotype
• Thyroid Hormone Receptors alpha (genetics)
• Thyroid Hormone Resistance Syndrome (diagnosis, drug therapy, genetics)
• Thyroxine
• Treatment Failure
• Young Adult