ALB – Familial Dysalbuminemic Hyperthyroxinemia

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition resulting from mutations in the albumin gene (ALB) that increase serum thyroxine (T4) binding without true thyroid dysfunction (MONDO:0014448). Affected individuals exhibit elevated total T4 and artefactually increased free T4 in many immunoassays, yet maintain normal thyroid‐stimulating hormone (TSH) and are clinically euthyroid.

Genetic evidence is robust: the recurrent missense variant c.652G>A (p.Arg218His) has been identified in 21 probands across 8 unrelated families with dominant inheritance ([PMID:8048949]) and segregates with FDH in 9 affected relatives in the initial report ([PMID:8048949]). Additional missense substitutions at the same codon, c.653G>C (p.Arg218Pro) and c.725G>A (p.Arg242His, equivalent to R218S), have been described in multiple pedigrees, including Japanese ([PMID:15068631]) and Bangladeshi families ([PMID:24494774]), further supporting a mutation hotspot.

Functional assays confirm a gain-of-function mechanism: equilibrium dialysis and yeast‐expressed albumin mutants demonstrate a ~10-fold increase in T4 affinity for p.Arg218His ([PMID:8702585]), while site-directed mutagenesis of Arg218 to various residues delineates a key thyroxine binding site in subdomain 2A ([PMID:9188698]). These studies establish that replacement of the bulky guanidino group at position 218 with smaller residues removes steric hindrance and enhances hormone binding.

No studies dispute ALB’s role in FDH. Clinical misdiagnosis as hyperthyroidism or TSH-secreting tumors is common; recognition of FDH through targeted ALB sequencing and appropriate assay methods (e.g., ultrafiltration or two‐step immunoassays) prevents unnecessary treatment.

Clinical validity (ClinGen): Definitive. Over 20 unrelated probands across multiple populations, clear segregation, and concordant mechanistic data.

Genetic evidence: Strong (multiple missense variants in >20 probands; segregation in 9 relatives; founder effect) ([PMID:8048949]).

Functional evidence: Strong (equilibrium dialysis and mutagenesis confirm increased T4 binding by mutant albumin) ([PMID:8702585], [PMID:9188698]).

Key take-home: ALB mutation screening should be integrated into diagnostic workflows for unexplained euthyroid hyperthyroxinemia to avoid misdiagnosis and inappropriate therapy.

References

• Biochemical and biophysical research communications • 1994 • An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families. PMID:8048949
• The Journal of biological chemistry • 1996 • Mutations in a specific human serum albumin thyroxine binding site define the structural basis of familial dysalbuminemic hyperthyroxinemia. PMID:8702585
• Biochemistry • 1997 • Mutagenesis studies of thyroxine binding to human serum albumin define an important structural characteristic of subdomain 2A. PMID:9188698
• Thyroid : official journal of the American Thyroid Association • 2004 • Artifactually elevated serum-free thyroxine levels measured by equilibrium dialysis in a pregnant woman with familial dysalbuminemic hyperthyroxinemia. PMID:15068631
• Thyroid : official journal of the American Thyroid Association • 2014 • A novel mutation in the albumin gene (R218S) causing familial dysalbuminemic hyperthyroxinemia in a family of Bangladeshi extraction. PMID:24494774

Evidence Based Scoring (AI generated)