title: Familial dysalbuminaemic hyperthyroxinaemia: a rapid and novel mass spectrometry approach to diagnosis.
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 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.
authors.affiliation: Biochemistry Department, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Ryan
authors.affiliation: Biochemistry Department, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Stephen O
authors.initials: SO
authors.lastname: Brennan
authors.affiliation: Biochemistry Department, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Howard
authors.initials: H
authors.lastname: Potter
authors.affiliation: Endocrinology Department, Waikato Hospital, Hamilton, New Zealand.
authors.forename: Louise
authors.initials: L
authors.lastname: Wolmarans
authors.affiliation: Biochemistry Department, Canterbury Health Laboratories, Christchurch, New Zealand chris.florkowski@cdhb.health.nz.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Florkowski
authors.affiliation: Biochemistry Department, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Peter M
authors.initials: PM
authors.lastname: George
mesh_terms: D004252:DNA Mutational Analysis; D006801:Humans; D050010:Hyperthyroxinemia, Familial Dysalbuminemic / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D012709:Serum Albumin
keywords: Familial dysalbuminaemic hyperthyroxinaemia; albumin variant; discordant thyroid function tests; mass spectrometry