A Novel Mutation Causing Complete Thyroid Binding Globulin Deficiency (Tbg-Cd Mia) In A Male With Coexisting Graves Disease

ABSTRACT Objective: To report the case of an asymptomatic male diagnosed with Graves disease that, upon further testing, was found to have a complete deficiency of thyroxine-binding globulin (TBG) as the result of a novel frameshift mutation in the TBG (SERPINA7) gene. Methods: The laboratory testing included total thyroxine (T4), free T4 by analog method and direct dialysis, and TBG measurements. Sequencing of genomic DNA was performed using peripheral blood. Results: A 35-year-old East Indian male was referred to endocrinology because of abnormal thyroid function tests (TFTs) done as part of a routine office visit: thyroid-stimulating hormone 0.01 mIU/L (reference range, 0.4 to 3.6 mIU/L) and total T4 3.0 μg/dL (reference range, 5.5 to 10.5 μg/dL). Upon further testing, serum free T4 (2.0 ng/dL; reference range, 0.8 to 1.8 ng/dL) and thyroid-stimulating immunoglobulin (355%; reference, <140%) were elevated and the diagnosis of Graves disease was made. TBG deficiency was suspected because the total T4 concentration was inconsistent with hyperthyroidism and further testing confirmed TBG was undetectable. Sequencing of the TBG gene revealed a novel hemizygous frameshift mutation, p.Ala64ProfsTer106 (numbering excludes 20 amino acid signal peptide), referred to as TBG complete deficiency Miami, associated with the complete deficiency of TBG in a patient with Graves disease. Conclusion: Patients with Graves disease harboring a TBG mutation have conflicting TFTs. If a clinically hyperthyroid patient presents with normal or low total T4, serum TBG should be measured to identify an abnormality and prevent unnecessary testing.