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

Abstract

An asymptomatic male was found on screening to have a low serum TSH and total T4. The diagnosis of Graves' disease was made with positive thyroid stimulating immunoglobulin (TSI) and elevated free T4 in the presence of complete TBG deficiency (TBG-CD). Genetic testing of the patient and family members revealed a novel frameshift mutation in the TBG (SERPINA7) gene resulting in a complete deficiency of the protein. The laboratory testing included total T4, free T4 by analog method and direct dialysis and TBG measurements. Sequencing of genomic DNA was performed from peripheral blood. A 35-year-old East Indian male was referred to endocrinology because of abnormal thyroid function tests (TFTs): TSH 0.01 mIU/L (0.4-3.6), total T4 3.0 µg/dl (5.5-10.5) done as part of a "routine office visit". Upon further testing, the serum free T4 2.0 ng/dl (0.8-1.8) and TSI 355% (<140% baseline) 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, TBG-CD Mia (numbering excludes 20 a.a. signal peptide) associated with the complete deficiency of TBG in a patient with Graves' disease. 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.