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Variable Clinical Characteristics and Molecular Spectrum of Patients with Syndromes of Reduced Sensitivity to Thyroid Hormone: Genetic Defects in the THRB and SLC16A2 Genes.

Abstract：

BACKGROUND/AIMS:Syndromes of reduced sensitivity to thyroid hormone can be caused by innate resistance to thyroid hormone (RTH), thyroid hormone cell transporter defects, or thyroid hormone metabolism defects. This study was performed to describe clinical, endocrinological, and molecular characteristics of patients with disorders associated with impaired sensitivity to thyroid hormone due to THRB or SLC16A2 mutations. METHODS:This study included 5 probands (1 male and 4 females) with RTH and 6 patients with Allan-Herndon-Dudley syndrome (AHDS). Clinical features and endocrine findings were reviewed retrospectively. Molecular analysis of two candidate genes, THRB or SLC16A2, confirmed the diagnosis. RESULTS:Among RTH patients, median age at diagnosis was 5.6 years. Three patients were classified as having generalized RTH, whereas the other 2 patients were regarded as having isolated pituitary RTH. Three novel heterozygous mutations and 2 known mutations in THRB were identified from 5 independent pedigrees. All mutations were located in the major ligand-binding domain. In AHDS patients, delayed development was apparent between 3 and 6 months of age. Direct sequencing of SLC16A2 identified 6 hemizygous missense mutations in each patient: p.I188N, p.G221R, p.A224V, p.G276R, p.W398R, and p.G401R. CONCLUSIONS:This study identified 3 novel mutations in THRB in RTH patients and 1 novel mutation in SLC16A2 in AHDS patients. Routine neonatal screening based on the TSH assay has a limited role in detecting RTH or AHDS. Therefore, genetic testing of the candidate genes THRB and SLC16A2 should be performed for diagnosis of RTH and AHDS in patients with the suggestive clinical phenotype.

journal_name

Horm Res Paediatr

journal_title

Hormone research in paediatrics

authors

Choi JH,Cho JH,Kim JH,Yoo EG,Kim GH,Yoo HW

doi

10.1159/000493468

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

283-290

issue

eissn

1663-2818

issn

1663-2826

pii

000493468

journal_volume

pub_type

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Variable Clinical Characteristics and Molecular Spectrum of Patients with Syndromes of Reduced Sensitivity to Thyroid Hormone: Genetic Defects in the THRB and SLC16A2 Genes.