FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA

Abstract

INTRODUCTION
Euthyroid hyperthyroxinemia is a common clinical conundrum. It requires careful assessment to establish an accurate diagnosis. Differential diagnosis of euthyroid hyperthyroxinemia include assay interference, thyroid hormone resistance syndrome, familial dysalbuminemic hyperthyroxinemia (FDH) and TSH-oma.

CASE
A 7-month-old male was referred for incidental finding of persistent euthyroid hyperthyroxinemia. His birth history was unremarkable. Antenatally, his mother did not have any thyroid disorder. His paternal grandmother has been undergoing treatment for hyperthyroidism.

Thyroid stimulating hormone (TSH) was elevated at 16.89 mIU/L. Routine prolonged jaundice investigations revealed free thyroxine (FT4) of 33.7 pmol/L and TSH of 7.4 mIU/L. Other investigations were normal. Clinically, he was euthyroid, not dysmorphic, no goitre and thriving well with normal developmental milestones. Repeated thyroid function test (TFT) via standard immunoassay at 2, 3 and 5 months of age showed similar results of high FT4 with unsuppressed TSH. FT3 was not available. TFT using a different assay was not done. Thyroid antibody screening was normal. He was initially suspected of having thyroid hormone resistance syndrome.

Family screening showed similar TFT pattern for his father and sister who were clinically euthyroid. His mother’s TFT was normal. His family was referred for confirmatory genetic testing. Whole exome sequencing (WES) for his father identified a pathogenic missense mutation in albumin gene, resulting in the replacement of an arginine with a histidine (p.Arg242His) that is associated with FDH. No genetic testing was done for the children.

CONCLUSION
FDH is a rare cause of euthyroid hyperthyroxinemia. It is an autosomal dominant disorder characterized by an abnormally increased affinity of a mutant albumin molecule to serum thyroxine causing elevated total thyroxine (T4) and elevated or normal FT4 with normal TSH level. Genetic analysis is important to establish diagnosis, to avoid further unnecessary laboratory testing and even inappropriate treatment in FDH.