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[Congenital deficiency of thyroxine binding globulin (TBG). Study of 3 families]
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Low thyroxine-binding globulin (TBG) capacity was found in seven members of a family in four generations. The effect on peripheral metabolism, as measured by the basal metabolic rate (BMR), of single 1000 μg intravenous doses of sodium L-thyroxine (T4) and sodium L-triiodothyronine (T3) was studied. In TBG deficient patients and those loaded with diphenylhydantoin (DPH) so that the PBI was depressed to low levels, T4 produced an effect on the BMR within 2–5 days similar in rapidity of onset and magnitude to that produced by T3 in all subjects. In normal controls or patients on maintenance DPH therapy, T4 produced little or no effect on the BMR within 8 days. The calorigenic studies were compared mainly in the TBG deficient patient with the acute (20–50 min) disappearance from plasma as well as with the chronic fate of the ¹³¹I-labelled hormones. The acute and chronic disappearances of T4 were more rapid in the TBG deficient patients whereas the acute and chronic disappearances of T3 were similar to that of subjects with normal TBG. These observations support the hypothesis that in normal humans TBG acts as a rate-regulating factor in the peripheral metabolism of acutely administered T4 by limiting the access of T4 to the tissues, thereby slowing its action on the cell. Therefore, the difference in peripheral metabolic effect of T4 and T3 would appear to be related to the presence of TBG in human plasma.
Near absence of the thyroxinebinding by serum thyroxine-binding globulin (TBG) was found in 6 members of a family who displayed no clinical manifestations of thyroid disease. This protein-binding defect appears to be transmitted as a mendelian autosomal dominant. The decreased binding by TBG was associated with a decreased concentration of PBI (1.9–3.3 μg/100 ml). A compensatory increase in the fractional rate of disappearance of thyroxine from the plasma resulted in a normal rate of daily hormonal turnover in the propositus. Although predictable elevations in TBG-binding capacity are found in normal pregnancy, extrapolations of the present data suggest that disparate thyroxine-binding capacities between mother and fetus do not affect gestation. This trait is thus an isolated, benign defect of a serum protein.
A kindred with deficiency of thyroxine-binding globulin (TBG) is presented in which the propositus also has XO Turner's syndrome. The pattern of inheritance supports previous reports that TBG activity is X-chromosome linked. This genetic anomaly appears to be specific for TBG since no alterations in other hormone-binding proteins could be demonstrated. No inhibitor of thyroxine (T4) binding to TBG could be demonstrated. The presence of approximately half the normal maximal T4-binding capacity of TBG in heterozygous females is compatible with Lyon's hypothesis of random and permanent inactivation of one X chromosome during early fetal development of female somatic cells. There is no evidence of peripheral tissue thyroxine deficiency despite an absence of binding of T4 to the TBG zone and low total circulating T4. Daily hormonal utilization is normal. TBG deficiency in Turner's syndrome has not previously been described. The abnormality of TBG binding permitted identification of the maternal origin...
Partial thyroxine-binding globulin (TBG) deficiency was observed in a euthyroid boy. A family study was conducted in order to trace the defect. Of the 15 members, 3 male subjects were found to be affected, whereas 6 female subjects were shown to be carriers of the trait. The inheritance pattern of the partial TBG deficiency was found to meet the criteria for X chromosome linked transmission. No association with other X-linked characters (colour blindness, glucose-6-phosphate dehydrogenase activity) was present. Karyotype analysis in the female subjects did not show any abnormality. TBG deficiency does not impair thyroid function. No difference was noted in free thyroxine levels in normal and affected subjects.
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THE existence of decreased or absent thyroxine-binding globulin in the serums of certain asymptomatic subjects has been recognized since 1959, when the first case was described by Tanaka and Starr.¹ In addition to a low serum protein-bound iodine concentration, serums from persons affected demonstrate a decrease or absence of thyroxine-binding globulin on paper electrophoresis, a normal binding capacity for thyroxine by thyroxine-binding prealbumin and an increase in the in vitro resin uptake of radioactive tri-iodothyronine. The disorder presents no clinical symptoms and causes no discernible ill-effects. The low concentration of protein-bound iodine is accompanied by an accelerated turnover of thyroxine, . . .
*From the departments of Medicine and Preventive Medicine, Western Reserve University School of Medicine.
Supported in part by an Aging Research Grant (HD 0669–06) and a Clinical Heart Center Grant (HE 06304–05), National Institutes of Health.
¶We are indebted to Dr. Samuel Spector for calling the index case to our attention.
ǁPerformed by Dr. J. R. Leonards's Laboratory.
**Kindly supplied by Abbott Laboratories, North Chicago, Illinois.
We are indebted to Dr. Sam H. Langstaff, of Littleton, Colorado, who obtained the serums from 1 branch of the family, as well as to Lucy S. Tompkins and Barbara Crann for invaluable technical help.
Source Information
CLEVELAND, OHIO
†Instructor in medicine, Western Reserve University School of Medicine.
‡Assistant professor of medicine, Western Reserve University School of Medicine.
§Professor of biology and associate professor of human genetics, Western Reserve University.
Absent or reduced thyroxinebinding globulin 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 levels (mean = 2.1 μg/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, corticosteroidbinding globulin, ceruloplasmin, haptoglobin 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 ...
We have presented evidence for the inheritance of absent or reduced thyroxine binding globulin (TBG) capacity as a co-dominant, sex-linked trait (J Clin Endocr 26: 835, 1966). The study of a second unrelated family with this defect has yielded additional evidence that the trait is transmitted by x-chromosome linked dominant inheritance. The 8 male members of the present 3-generation kindred had no detectable TBG binding activity for either thyroxine or triiodothyronine. The 13 presumably heterozygous females had binding activity varying from very low to normal but always present. This pedigree contains normal male children of affected fathers, not demonstrated in the previous study. Thyroxine half-life studies in affected males gave times of 3.8 days as compared to the normal of 6–8 days. However, the daily thyroxine degradation rate was normal. Estrogen treatment of affected males did not elicit detectable TBG activity, whereas heterozygous females responded to treatment with increases in activi...