Endocrine Abstracts

Three siblings of Pakistani origin presented shortly after birth with failure to thrive and hyperkalemia and were found to have isolated hyperreninaemic hypoaldosteronism. They were all well controlled on fludrocortisone therapy during childhood and adolescence. When reassessed in adult life off fludrocortisone treatment, hyperreninaemic hypoaldosteronism was confirmed in all subjects, but with significant hyperkalemia in only one case. None of the subjects developed orthostat...

Objectives: All known (>230) different mutations in thyroid hormone receptor β (TRβ) causing Resistance to Thyroid Hormone β (RTHβ), localise to three clusters within its hormone binding domain. Here, we report phenotypes and molecular studies in an unique family with RTHβ due to a mutation in the DNA binding domain (DBD) of TRβ.Methods: We ascertained clinical and biochemical features in four children and their parents ...

Resistance to Thyroid Hormone alpha (RTHα) is characterised by tissue-selective hypothyroidism with near-normal thyroid function tests, and is due to thyroid receptor α gene mutations. We sought to correlate the clinical characteristics and response to thyroxine treatment of two RTHα patients with the properties of their defective TRα proteins.Clinical, biochemical and physiological parameters were assessed in each patient at baseline...

The nuclear receptor PPARgamma is important for biological processes including adipogenesis and glucose homeostasis. In subjects with severe insulin resistance, we have previously reported two types of human PPARgamma gene defect: heterozygous, missense mutations (P467L, V290M) in the ligand binding domain (LBD) which inhibit wild type (WT) receptor action in a dominant negative manner by recruitment of transcriptional corepressors; or double heterozygosity for a frameshift/pr...

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...

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...

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.<p cl...

Objectives: THRA mutations cause Resistance to Thyroid Hormone α (RTHα), an underdiagnosed disorder with hypothyroid features but near-normal thyroid function tests (TFTs). We developed a pathway, combining molecular analyses, new biomarkers and physiological measurements, to better diagnose and treat this disorder.Methods: Structural and functional analyses of THRA variants, discovered by next generation sequencing in specifi...