JOURNAL ARTICLE

A novel mutation in the Albumin gene (R218S) causing familial dysalbuminemic hyperthyroxinemia in a family of Bangladeshi extraction

Solomon Maximo Greenberg, Alfonso Massimiliano Ferrara, Everton S Nicholas, Alexandra M Dumitrescu, Vivian Cody, Roy E Weiss, Samuel Refetoff
Thyroid: Official Journal of the American Thyroid Association 2014, 24 (6): 945-50
24494774

BACKGROUND: Familial dysalbuminemic hyperthyroxinemia (FDH) is a common cause of euthyroid hyperthyroxinemia. Clinical recognition of FDH is crucial for preventing unnecessary therapy in clinically euthyroid patients with abnormal thyroid function tests. Our goal was to identify the cause of abnormal serum tests of thyroid function in a Canadian family of Bangladeshi extraction.

PATIENTS: The proposita was found to have elevated free thyroxine (fT4) and free triiodothyronine (fT3) with nonsuppressed thyrotropin (TSH) on screening blood work. After detailed studies excluding hyperthyroidism and resistance to thyroid hormone, blood was obtained from all members of her immediate family for further investigation.

METHODS: We conducted laboratory analyses and sequencing of candidate genes.

RESULTS: Two members of this family have FDH, caused by a not previously identified mutation in the albumin gene. This mutation, located in exon 7 of the gene (652A>C), produces a single amino acid substitution in the protein molecule (R218S). The mutant albumin is associated with a ninefold increase in serum total T4 and a twofold increase in serum total reverse T3 compared to patients with normal albumin. Modeling data for the R218S variant are compatible with the increased binding affinity of this variant albumin for T4.

CONCLUSIONS: The R218S substitution reported here causes FDH that, in terms of the magnitude of serum iodothyronine elevation, is intermediate to the two previously reported mutations at codon 218 FDH: R218H being more mild and R218P more severe.

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