Complete Thyroxine-Binding Globulin deficiency, due a novel mutation in p.A64D, associated with increased affinity in Transthyretin (p.A109T mutation) in an hypothyroid patient.

SKLATE, RT ; MACCALLINI, GUSTAVO C; OLCESE, MARÍA CECILIA; AGUERO, M; SANCHEZ, M; GONZÁLEZ-SARMIENTO, ROGELIO; TARGOVNIK , HÉCTOR MANUEL; NIEPOMNISZCZE, HUGO

París

Congreso; 14th International Thyroid Congress; 2010

European Thyroid Association, American Thyroid Association, Asia & Oceania Thyroid Association, Latin American Association

Abnormalities of serum thyroid hormone binding proteins affect the thyroid hormone test results, limiting its utility and leading to confusion. A 52-year-old man was referred to us for the management of his hypothyroidism. He had a thyroidectomy for hyperthyroidism 30 years earlier. There was no history of disease in his parents, but his sister and nieces are hypothyroid. He was treated with 150 ìg/day of L-T4 and was asymptomatic. Under this treatment, TSH was 0.32ìIU/ml, free T4 (FT4) = 3.21 ng/dl (normal range [nr]:0.8-1.7), T3 = 66 ng/dl (nr: 80-200) (Elecsys). Due to these results, L-T4 treatment was stopped. Six weeks later, TSH was >100 ìIU/ml, T3 <20 ng/dl, FT4 <0.1 ng/dl. He developed clinical hypothyroidism and L-T4 treatment was restored: 125 ìg/day. Then, he had TSH=3.37ìIU/ml and FT4=3.05 ng/dl. By decreasing L-T4, from 125 to 88 ìg/day, it was observed normalization of FT4 (1.55 ng/dl) but high TSH (43 ìIU/ml). The possibilities of inappropriate TSH secretion, due to resistance to thyroid hormone, or a TSH-secreting pituitary adenoma were excluded. Pituitary NMR was normal and anti T4-antibodies were negative. Serum thyroxinebinding globulin (TBG) was <3 mg/l (nr:17-27 mg/l). This finding was also found in one brother. His sister had low TBG level (3.6 mg/l). Additional tests were performed using different methods: FT4= 4.36 ng/dl (nr:0.8 – 1.9), Free T3= 1.42 pg/ml (nr:1.5 – 4.1) in Immulite and Total T3= 61 ng/dl, Total T4= 4.51 ug/dl, FT4= 0.8 ng/dl, TSH= 3.19 ìIU/ml in Architect. FT4 levels by one step method (Elecsys and Immulite) was discordant with TSH under L-T4 treatment as well as clinical outcome. FT4 by two step method (Architect) was reliable and concordant with the TSH level. These differences in the FT4 results leaded to consider another binding protein abnormality. A T4-binding protein radioelectrophoresis confirmed that Transthyretin (TTR)-bound T4 was significantly increased: 92.6 ìg/dl (nr:48.8–70.4) and TBG-bound T4 was absent, indicating the presence of two abnormalities in binding proteins with opposite effects. The entire coding regions of the TBG and TTR genes were analyzed by direct DNA sequencing. A novel mutation was identified in the TBG gene, an hemizygous c.251C>A transversion, resulting in a p.A64D substitution. In addition, a previously reported mutation was identified in the TTR gene, an heterozygous c.385G>A transition causing a p.A109T change, which increases the affinity for T4. Taking into account that a brother had also no detectable TBG, while a sister had low TBG level, these familiar findings lead to diagnose an inherited complete TBG deficiency. The mutation in TTR gene was the cause of high FT4 levels in the one step method. The combination of these two different alterations in binding proteins, with opposite effects, was the cause of the discordance between thyroid function test results and clinical outcome in a patient without thyroid gland and a previous history of hyperthyroidism. This is the first time that simultaneous mutations in these different T4-binding proteins are reported in the literature. Moreover, one of them is a novel mutation in the TBG gene, producing a lack of this protein.