X-Chromosome Linked Familial Decrease in Thyroxine-Binding Globulin Activity

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Abstract
Absent or reduced thyroxine-binding globulin (TBG) activity has been found in 3 generations of a family. Ten male members of the kindred had no detectable binding activity, whereas 8 females, heterozygous for the trait, had binding activity varying from very low to normal, but always present. The character of the deficit and the mode of transmission of the trait are consistent with a sex-linked or X-chromosome linked dominant inheritance. The affected males had low protein-bound iodine(PBI) levels (mean =2.1 [mu]g/100 ml) and high resin T3 uptake levels (mean =61%). Serum cholesterol levels were normal (mean =196 mg/100 ml) and the individuals appeared clinically euthyroid. Other serum proteins, including total protein, albumin, thyroxine-binding prealbumin, corticosteroid-binding globulin, ceruloplasmin, haptoglocin and transferrin were normal. The response of these proteins to estrogen treatment was normal in an affected male, but TBG activity remained undetectable. The heterozygous females presented a more variable picture with TBG activity ranging from 2 to 20 [mu]g/100 ml and with a corresponding variability of serum PBI and T3 uptake values. During the study, one of these women delivered a full-term, healthy boy with zero TBG activity in a cord blood sample. This indicates TBG activity is not essential for normal fetal development, even in the face of TBG activity present in the maternal circulation. Also, it would appear that the protein does not cross the placental vascular barrier from the maternal to fetal circulation. Previously published kindreds of low and high thyroxine-binding globulin levels are reinterpreted in terms of the X-chromosome linkage hypothesis and probable consistency with this mechanism is shown.