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. 2017 Spring;3(2):e134-e139.
doi: 10.4158/EP161421.CR.

A NOVEL MUTATION CAUSING COMPLETE THYROID BINDING GLOBULIN DEFICIENCY (TBG-CD MIA) IN A MALE WITH COEXISTING GRAVES DISEASE

Hara Rosen Berger  1   2 , Matthew K Creech  1 , Zeina Hannoush  1   2 , Yui Watanabe  1 , Atil Kargi  1 , Roy E Weiss  1
Affiliations

A NOVEL MUTATION CAUSING COMPLETE THYROID BINDING GLOBULIN DEFICIENCY (TBG-CD MIA) IN A MALE WITH COEXISTING GRAVES DISEASE

Hara Rosen Berger et al. AACE Clin Case Rep. 2017 Spring.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

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.

Keywords: Complete Deficiency; Graves’ disease; TBG; Thyroxine-binding globulin.

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Figures

Fig. 1
Fig. 1
Phenotype of the TBG-CD Mia family. Abnormal values are in bold type.
Fig. 2
Fig. 2
Direct sequencing of PCR product. An unreported 1 bp (G) deletion in the first exon of the TBG gene (c.189_191 delG; p. Ala64ProfsTer106) associated with the complete deficiency of TBG in a male patient with Graves’ disease. Female subjects I2 and III1 were heterozygous for this mutation (B).
See this image and copyright information in PMC

References

    1. Mori Y, Miura Y, Oiso Y, Hisao S, Takazumi K. Precise localization of the human thyroxine-binding globulin gene to chromosome Xq22.2 by fluorescence in situ hybridization. Hum Genet. 1995;96:481–482. - PubMed
    1. Mandel S, Hanna C, Boston B, Sesser D, LaFranchi S. Thyroxine-binding globulin deficiency detected by newborn screening. J Pediatr. 1993;122:227–230. - PubMed
    1. Refetoff S, Murata Y, Mori Y, Janssen OE, Takeda K, Hayashi Y. Thyroxine-binding globulin: organization of the gene and variants. Horm Res. 1996;45:128–138. - PubMed
    1. Refetoff S. Inherited thyroxine-binding globulin abnormalities in man. Endocr Rev. 1989;10:275–293. - PubMed
    1. Arisaka O, Hosaka A, Shimura N, Yabuta K. Thyroxine-binding globulin deficiency misdiagnosed as hypothyroidism. J Pediatr. 1993;123:333–334. - PubMed

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