Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity.

Xavier Dieu,Nathalie Bouzamondo,Claire Briet,Pascal Reynier,Delphine Mirebeau-Prunier,Natacha Bouhours-Nouet,Florence Boux De Casson,Valérie Moal,Régis Coutant,Patrice Rodien,Frédéric Illouz

doi:10.3390/jcm9072105

Abstract

Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired sensitivity of tissues to thyroid hormone (TH). The alteration of TH-binding proteins, such as in Familial Dysalbuminemic Hyperthyroxinemia (FDH), can mimic the abnormal serum thyroid tests typical of RTH. We aimed to characterize a population referred to our center with suspected RTH and estimate the proportion of patients with FDH. For 303 different families, we collected clinical and hormonal data and sequenced the thyroid hormone receptor β gene (THRB) and exon 7 of the albumin gene (ALB). We found 56 THRB variants (i.e., 38% of the 303 index cases, called RTHβ group). Among the samples screened for FDH variants, 18% had the variant R218H in ALB (FDH group); in addition, 71% of the cases had neither variant (non-FDH/RTHβ group). Patients with FDH had significantly lower free T3 (fT3) and free T4 (fT4) levels and more often an isolated elevation of fT4 than RTHβ patients. Clinically, patients with FDH had fewer symptoms than patients with RTHβ. Our study suggests that FDH should be systematically considered when examining patients suspected of having RTH. In most cases, they present no clinical symptoms, and their biochemical alterations show an elevation of fT4 levels, while fT3 levels are 1.11 times below the upper limit of the assay.

Highlights

First described in 1967 by Refetoff et al [1], resistance to thyroid hormone (RTH) is a syndrome defined by elevated serum T4 and, to a lesser degree, T3, with non-suppressed thyroid-stimulating hormone (TSH) serum levels
We found that 38% of the index cases (i.e., 115 of the 303 index cases) and 87% of the of kin (i.e., 79 of 91) tested were carriers of pathogenic THRB variants or variant of unknown significance” (VUS)
We found that patients with Familial Dysalbuminemic Hyperthyroxinemia (FDH) tended to have lower levels of free T4 (fT4) and free T3 (fT3) compared to the RTHβ group

Summary

Introduction

First described in 1967 by Refetoff et al [1], resistance to thyroid hormone (RTH) is a syndrome defined by elevated serum T4 (thyroxine) and, to a lesser degree, T3 (triiodothyronine), with non-suppressed thyroid-stimulating hormone (TSH) serum levels. More than 600 families and at least 219 mutations, mostly substitutions, have been described, with an estimated frequency of 1 case per 40,000 live births [2] Pathogenic variants of this gene impair the receptor ability to bind T3, release co-repressors, and/or recruit co-activators, which prevents the positive or negative transactivation of target genes [2]. The liver and the pituitary mostly express TRβ, while TRα is predominantly expressed in the brain, heart, bones, and digestive tract This distribution explains the impaired feedback loop of thyroid hormone (TH) to TSH secretion when TRβ is non-functional, and the symptoms generally found in those individuals due to functional TRα include tachycardia, hyperactivity, diarrhea [5,6]. Since its first description [7,8], the potential involvement of abnormal nuclear co-activators or co-repressors and, possibly, of THRB mosaicism [9], has been suspected [10,11]

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