Thyroid Hormone Resistance, Generalized, Autosomal Recessive

A number sign (#) is used with this entry because the autosomal recessive form of thyroid hormone resistance is caused by mutation in the thyroid hormone receptor gene (THRB; 190160). An autosomal dominant form of the disorder (188570) is caused by mutation in the same gene, as is selective pituitary resistance to thyroid hormone (145650).

Clinical Features

Among 2 of 6 children of a consanguineous marriage, Refetoff et al. (1967) observed congenital deafness, stippled epiphyses, goiter, and abnormally high PBI. They postulated end-organ unresponsiveness to thyroid hormone. A later-born sib was recognized as affected in the neonatal period (Refetoff, 1982).

A different type of unresponsiveness to thyroid hormones, presumably genetic, was reported by Lamberg (1973), who described a 25-year-old woman who had had goiter at birth and had undergone thyroidectomy twice for nontoxic goiter during childhood. Concentrations of thyroid hormones and of thyrotropin in the blood were about twice normal and responses to thyrotropin-releasing hormone were normal. The findings were considered compatible with partial resistance to thyroid hormones in peripheral tissues, including the anterior pituitary. A similar patient may have been reported by Bode et al. (1973). These patients may have a defect in the nuclear receptor(s) for thyroid hormone (Charles et al., 1975).

Ohzeki et al. (1984) reported a brother and sister, aged 12 and 9, respectively, with large goiters and high levels of thyroid hormones in the face of clinical euthyroidism. The brother showed low birth weight for dates and was also lean and had exophthalmos which prompted the diagnosis of Graves disease. Relevant to this disorder is information on thyroid hormone action at the nuclear level (Oppenheimer, 1985). A stereospecific energy-dependent transport system appears responsible for translocation of triiodothyronine from cytosol to nucleus. The nuclear receptor for T3 is an integral component of a larger chromatin fragment.

Refetoff (1982) stated that global resistance to thyroid hormone had been observed in more than 60 persons, most of them in 17 families. Consanguinity was established or suspected in 3 of 17 families and the defect occurred in a set of identical twins and in only 1 of a set of fraternal twins. Some of the families represented autosomal dominant inheritance (see 188570). In no instance had a defect in conversion of T4 and T3 been demonstrated; when measured, serum T3 was found elevated.

Molecular Genetics

In affected members of the original family reported by Refetoff et al. (1967), in which GRTH segregated as an autosomal recessive, Takeda et al. (1991) identified deletion of the thyroid hormone receptor gene (190160.0003). Heterozygous members of the family were clinically normal. The affected members of the family had severe hyposensitivity to thyroid hormone and exhibited congenital deafness, epiphyseal dysgenesis, and other minor somatic abnormalities; however, the defect was adequately compensated in most tissues by high circulating levels of thyroid hormone. Takeda et al. (1991) concluded that the presence of a single normal allele was sufficient for normal receptor function, and suggested that in autosomal dominant GRTH the presence of an abnormal thyroid hormone receptor interferes with the function of the normal receptor in a dominant-negative fashion.