Abstract
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 19Da 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 mu L of serum and requires minimal sample preparation.