Diagnosis of familial dysalbuminemic hyperthyroxinemia in a family initially suspected of thyroid hormone resistance beta

Elise Nauwynck; Eynde Nathalie Vanden; Jelle Vlaeminck; Dalem Annelien Van; Willem Staels; David Unuane; Schepper Jean De

doi:10.1530/endoabs.112.030

030

Prev Next

Section Contents Cite

Endocrine Abstracts (2025) 112 030 | DOI: 10.1530/endoabs.112.030

BES2025 BES 2025 CLINICAL CASE REPORTS (13 abstracts)

Diagnosis of familial dysalbuminemic hyperthyroxinemia in a family initially suspected of thyroid hormone resistance beta

Elise Nauwynck ^1,2 , Nathalie Vanden Eynde ³ , Jelle Vlaeminck ³ , Annelien Van Dalem ⁴ , Willem Staels ^1,5 , David Unuane ⁶ & Jean De Schepper ^1,2

Author affiliations

¹Division of Pediatric Endocrinology, KidZ Health Castle, UZ Brussel, Vrije Universiteit Brussel, 1000, Brussels, Belgium; ²Vrije Universiteit Brussel (VUB), Growth & Development (GRON), 1000, Brussels, Belgium; ³Centre for Medical Genetics, Research Group Genetics, Reproduction and Development (GRAD), Clinical Sciences, Universitair Ziekenhuis Brussel (UZ Brussel) - Vrije Universiteit Brussel (VUB), Brussels, Belgium; ⁴Division of Clinical Chemistry, UZ Brussel, Vrije Universiteit Brussel, 1000, Brussels, Belgium; ⁵Vrije Universiteit Brussel (VUB), Genetics, Reproduction, and Development (GRAD), 1000, Brussels, Belgium; ⁶Division of Endocrinology, UZ Brussel, Vrije Universiteit Brussel, 1000, Brussels, Belgium

Introduction: Isolated elevation of serum free thyroxine (FT4) with normal thyroid-stimulating hormone (TSH) may indicate several conditions such as thyroid hormone resistance beta (THRβ), TSH-secreting pituitary adenoma, assay interference, or familial dysalbuminemic hyperthyroxinemia (FDH). We report a case of FDH in a mother and son, both initially misdiagnosed with familial THRβ.

Methods: Targeted genetic analysis of the thyroid hormone receptor beta (THRB) and albumin (ALB) genes was conducted using whole-exome and confirmatory Sanger sequencing. Variant classification was performed according to ACMG guidelines.

Case presentation: A 7-year-old boy was referred for suspected THRβ following detection of elevated FT4 (25pmol/l) with normal TSH (4.08mU/l) on a Roche immunoassay, during evaluation for attention deficit disorder. He displayed no signs of thyrotoxicosis. Serum sex hormone-binding globulin (SHBG) and thyroglobulin (TG) concentrations were within normal range, while free triiodothyronine (FT3) was slightly increased (7.2pmol/l). His mother had previously been diagnosed with THRβ, despite negative THRB gene analysis, after presenting at age 38 with palpitations and mild exophthalmos. Genetic testing of the THRB gene revealed no variant in the mother. However, both mother and son carried the ALB gene variant NM_000477.7:c.725G>A (p.Arg242His), confirming FDH. This variant is the most prevalent FDH-causal variant (hotspot) in Western Europe and is associated with a mild hyperthyroxinemia phenotype. It is a missense variant that increases thyroxine binding affinity due to substitution of the bulky arginine with histidine, leading to artifactual FT4 elevation in one-step immunoassays.

Conclusion: FDH should be considered in THRB-negative patients with isolated hyperthyroxinemia, particularly when FT3 is normal or only mildly elevated. ALB gene analysis is essential for accurate diagnosis. This case highlights the risk of misdiagnosis with the Roche Cobas e601 platform, which overestimates FT4 in FDH.

Keywords: Hyperthyroxinemia, familial dysalbuminemic hyperthyroxinemia, ALB gene, immunoassay interference, thyroid hormone resistance