Complete thyroxine-binding globulin deficiency in a girl caused by a novel mutation in the TBG gene from maternal origin

PAPENDIECK, PATRICIA; OLCESE, MARÍA CECILIA; BELFORTE, FIORELA SABINA; CITTERIO, CINTIA ELIANA; TARGOVNIK HÉCTOR MANUEL; RIVOLTA, CARINA MARCELA; GRUÑEIRO-PAPENDIECK, LAURA; CHIESA, ANA

Glasgow

Congreso; 50th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE); 2011

European Society for Paediatric Endocrinology (ESPE)

P1-d3-402 Thyroid 2 Background: Thyroxin-binding globulin (TBG) is the main thyroid hormone transport protein in serum. Inherited TBG defects caused by mutations in the TBG-gene (locus: Xq22.2), are X-linked transmitted and lead to complete (TBG-CD) or partial deficiency (TBG-PD). Objective and hypotheses: Describe the clinical, biochemical and molecular characterization of a patient with TBG-CD inherited from her mother. Method: DNA was extracted from the patient and her parents. TBG exons and flanking intronic regions were amplified by PCR and sequenced. Polymorphisms were ruled out by SSCP analysis in normal population. Case report: In a 10 year old insulin dependent diabetic girl thyroid function was studied during follow up finding total thyroxine (T4) of 3,7 ug/dl (NR: 6-14), free T4 (fT4) of 1,33 ng/dl (NR: 0,8-2,2), thyrotropin (TSH) of 4,67 mUI/L (NR:0,5-6,5) and negative thyroid antibodies. Serum TBG levels were <3,5ug/ml (NR:15-40). She is the only child of a non-consanguineous couple. The mother´s thyroid profile showed also low serum levels of thyroid hormones with undetectable TBG and positive thyroid antibodies. The father had normal thyroid profile and TBG values. Results: A novel and heterozygous mutation in the TBG gene, a T deletion at the 5’ donor splice site of exon 0, in nucleotide 2 of intron 1 (g.IVS1+2delT), was identified in the patient and her mother. This change was not present in normal population. Conclusions: We report a novel mutation (g.IVS1+2delT) in the TBG gene responsible for TBG-CD. Proposed mechanisms for the expression of the disease in two heterozygous females may be selective X-chromosome inactivation or dominant X-linked inheritance, which will be studied further.Identification of the molecular basis of this disorder will lead to an accurate diagnosis and will be useful to understand the pathophysiology of abnormalities in the thyroid hormone transport. Thyroxin-binding globulin (TBG) is the main thyroid hormone transport protein in serum. Inherited TBG defects caused by mutations in the TBG-gene (locus: Xq22.2), are X-linked transmitted and lead to complete (TBG-CD) or partial deficiency (TBG-PD). Objective and hypotheses: Describe the clinical, biochemical and molecular characterization of a patient with TBG-CD inherited from her mother. Method: DNA was extracted from the patient and her parents. TBG exons and flanking intronic regions were amplified by PCR and sequenced. Polymorphisms were ruled out by SSCP analysis in normal population. Case report: In a 10 year old insulin dependent diabetic girl thyroid function was studied during follow up finding total thyroxine (T4) of 3,7 ug/dl (NR: 6-14), free T4 (fT4) of 1,33 ng/dl (NR: 0,8-2,2), thyrotropin (TSH) of 4,67 mUI/L (NR:0,5-6,5) and negative thyroid antibodies. Serum TBG levels were <3,5ug/ml (NR:15-40). She is the only child of a non-consanguineous couple. The mother´s thyroid profile showed also low serum levels of thyroid hormones with undetectable TBG and positive thyroid antibodies. The father had normal thyroid profile and TBG values. Results: A novel and heterozygous mutation in the TBG gene, a T deletion at the 5’ donor splice site of exon 0, in nucleotide 2 of intron 1 (g.IVS1+2delT), was identified in the patient and her mother. This change was not present in normal population. Conclusions: We report a novel mutation (g.IVS1+2delT) in the TBG gene responsible for TBG-CD. Proposed mechanisms for the expression of the disease in two heterozygous females may be selective X-chromosome inactivation or dominant X-linked inheritance, which will be studied further.Identification of the molecular basis of this disorder will lead to an accurate diagnosis and will be useful to understand the pathophysiology of abnormalities in the thyroid hormone transport.