Familial dysalbuminemic hyperthyroxinemia (FDH) was first reported in 1979 and has been confirmed as an autosomal dominant benign trait characterized by elevated total thyroxine (T4) and normal thyroid-stimulating hormone (TSH) levels in serum. Serum free T4, as well as total and free triiodothyronine (T3), may also be elevated. Although individuals with FDH typically do not exhibit thyrotoxic symptoms, there is a risk of inappropriate treatment being offered to these individuals. Therefore, the identification of FDH through serum and genetic testing is clinically important to avoid unnecessary therapies. The molecular basis of FDH was elucidated with the identification of the most common variant, ALB c.725G>A (p.Arg242His), reported in 1994 (Petersen et al., PMID: 8064810). The ALB gene encodes albumin, which is responsible for the transport and sequestration of metabolites, including hormones, in the circulation. Four missense variants (c.725G>A, p.Arg242His; c.724C>A, p.Arg242Ser; c.725G>C, p.Arg242Pro; and c.737G>T, p.Arg246Ile) that have been identified in 25 probands were curated. These variants co-segregated with abnormal thyroid functional tests within families (PMID: 8064810, 12099390, 27834068, 29676214, 33728390, 38557642, 36864842, 32665066, 9329347, 32669045, 27904073, 24646103, 24494774, 27081329, 31582975). Notably, the level of total T4 was higher in homozygotes compared to heterozygotes (PMID: 29676214). The disease mechanism is a gain of function. Studies on the affinity between albumin and T4 in patient serum samples have demonstrated a high affinity of T4 to mutant albumin carrying either the Arg242His or Arg242Pro alteration (PMID: 8064810, 29676214, 9329347, 27904073). This increased affinity was also observed in experiments using recombinant human albumin (PMID: 26777880). In summary, there is moderate evidence supporting the gene-disease relationship for FDH. While additional evidence is needed to establish a causal role definitively, no convincing evidence has emerged to contradict this gene-disease relationship. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [May 9, 2025] (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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