Familial dysalbuminemic hyperthyroxinemia: a rare example of albumin polymorphism and its rapid molecular diagnosis.
Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of euthyroid hyperthyroxinemia, although a rare example of albumin polymorphism. FDH is inherited in an autosomal dominant manner and is characterized by enhanced binding of thyroxine to a mutant form of albumin, probably at Site 1, subdomain 11A. Previous laboratory tests of FDH have been cumbersome, rarely available, and required demonstration of anti-albumin precipitable T4, isoelectric focusing of serum for albumin in presence of labeled T4 and, occasionally, comparison of the concentrations of metabolites of T4 that have different binding affinities to the abnormal albumin. Recent studies have shown that the same mutation in the albumin gene that results in FDH has been found in 13 unrelated families. A G-->A transition in codon 218 of the albumin gene resulted in the replacement of arginine with histidine. An intragenic Sac-1 polymorphic site was found in association with the specific FDH mutation, suggesting a founder effect. FDH in our Hispanic family was confirmed by isoelectric focusing of serum. Results of thyroid function tests in our affected patients were typical for the phenotype: high total T4 and normal total T3. Genomic DNA was amplified by PCR using a mismatched oligonucleotide primer that produced a unique restriction site (Dra III) only if the DNA sample contained the mutation in codon 218: CGC (Arg) to CAC (His). In affected individuals of this family expression of the FDH phenotype was associated with the presence of His218 in one of the two alleles. Analysis linking the FDH mutation to the Sac-1 polymorphism in this family was not informative. DNA analysis is a rapid and simple method to diagnose FDH in individuals with euthyroid hyperthyroxinemia.
AvRuskin
Theodore W
TW
Department of Pediatrics, The Brookdale University Hospital and Medical Center, State University of New York at Brooklyn, 11212-3198, USA. tavruski@brookdale.edu
Juan
Christina S
CS
Weiss
Roy E
RE
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000235:genetics*; D007525:Isoelectric Focusing; D007962:Leukocytes / Q000737:chemistry; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000235:genetics*; D013960:Thyroid Function Tests; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood*; D014284:Triiodothyronine / Q000097:blood; D014285:Triiodothyronine, Reverse / Q000097:blood
D012709:Serum Albumin; D014284:Triiodothyronine; D014285:Triiodothyronine, Reverse; D013972:Thyrotropin; D004247:DNA; D013974:Thyroxine