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. 2020 Jul 3;9(7):2105.
doi: 10.3390/jcm9072105.

Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity

Xavier Dieu  1   2 , Nathalie Bouzamondo  1   3 , Claire Briet  2   3   4 , Frédéric Illouz  3   4 , Valérie Moal  1   3 , Florence Boux de Casson  1   3 , Natacha Bouhours-Nouet  3   5 , Pascal Reynier  1 , Régis Coutant  3   5 , Patrice Rodien  2   3   4 , Delphine Mirebeau-Prunier  1   2   3
Affiliations

Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity

Xavier Dieu et al. J Clin Med. .

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.

Keywords: THRB; albumin; familial dysalbuminemic hyperthyroxinemia; immunoassay interference; resistance to thyroid hormone.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Molecular analysis performed on samples received for suspected impaired sensitivity to TH or family studies in the Reference center for rare thyroid disease of Angers University Hospital, France, between 2000 and 2015. Family members: family members related to index cases; unavailable (no DNA for ALB molecular analysis).
Figure 2
Figure 2
Location of 56 variants in the THRB gene and number of families for each variant. The x-axis indicates the consecutive amino acid numbers, exon, and functional domains of THRB gene. The y-axis indicates the numbers of families. Plain bars represent known variants, while grey bars represent variants with unknown significance.
Figure 3
Figure 3
Distribution of the different clinical features among patient with RTHβ and FDH. Radar plot showing the proportion of patients (%) with each clinical feature: goiter, signs of hyperthyroidism, or asymptomatic.
Figure 4
Figure 4
Thyroid function assays (free T4 (fT4) and free T3 (fT3) levels) in several patients with RTHβ or FDH. fT4 and fT3 levels are expressed as multiples of the upper limit of the assay. The * symbol indicates a statistically significant p-value after correction for multiple statistical tests (p < 0.05).
See this image and copyright information in PMC

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