Familial dysalbuminaemic hyperthyroxinaemia: a rapid and novel mass spectrometry approach to diagnosis

BACKGROUND: Familial dysalbuminaemic hyperthyroxinaemia is an important cause of discordant thyroid function test results (due to an inherited albumin variant); however, the diagnosis can be challenging. A 51-year-old man had persistently elevated free thyroxine (T4), with discordant normal thyroid-stimulating hormone and normal free triiodothyronine. He was clinically euthyroid and had a daughter with similar thyroid function test results. We aimed to apply a whole protein mass spectrometry method to investigate this case of suspected familial dysalbuminaemic hyperthyroxinaemia. METHODS: Intact serum albumin was assessed directly using electrospray time-of-flight mass spectrometry. Results were confirmed using tryptic peptide m/z mapping and targeted DNA sequencing (exons 3 and 7 of the albumin gene). We also used this sequencing to screen 14 archived DNA samples that were negative for thyroid hormone receptor mutations (in suspected thyroid hormone resistance). RESULTS: Mass spectrometry analysis demonstrated heterozygosity for an albumin variant with a 19 Da decrease in mass, indicative of an Arg→His substitution. The familial dysalbuminaemic hyperthyroxinaemia variant was confirmed with peptide mapping (showing the precise location of the substitution, 218Arg→His) and DNA sequencing (showing guanine to adenine transition at codon 218 of exon 7). The same familial dysalbuminaemic hyperthyroxinaemia variant was identified in one additional screened sample. CONCLUSIONS: Time-of-flight mass spectrometry is a novel procedure for diagnosing familial dysalbuminaemic hyperthyroxinaemia. The test is rapid (<10 min), can be performed on <2 μL of serum and requires minimal sample preparation.