Thyroid Hormone Resistance, Generalized, Autosomal Dominant

A number sign (#) is used with this entry because the autosomal dominant form of generalized thyroid hormone resistance is caused by mutation in the thyroid hormone receptor gene (THRB; 190160). An autosomal recessive form of the disorder (274300) is caused by mutation in the same gene, as is selective pituitary resistance to thyroid hormone (145650).

Clinical Features

Brooks et al. (1981) found thyroid hormone resistance in 8 persons in 4 generations of a kindred. All were clinically euthyroid but all had goiters and markedly increased serum thyroid hormone levels. Serum thyrotropin (TSH) levels were normal or slightly elevated and responded normally to the administration of thyrotropin-releasing hormone (TRH) and L-triiodothyronine. The kindred had 3 instances of male-to-male transmission. Dominant inheritance has also been noted by Lamberg et al. (1975), Elewaut et al. (1976), and Maxon et al. (1980). A recessive form of thyroid hormone resistance is also well substantiated (see 274300). Gharib and Klee (1985) observed a family with 6 affected persons in 4 sibships of 3 generations of a family. Of the 6, 5 had goiter and all had increased concentrations of triiodothyronine and free thyroxine without symptoms or signs of hyperthyroidism. Basal serum levels of TSH were normal in all 6; in the 4 tested, these levels responded normally to TRH. This is, then, a form of familial euthyroid hyperthyroxinemia not due to abnormality in the binding proteins, albumin ('dysalbuminemic hyperthyroxinemia'; 103600) or prealbumin (176300). Hopwood et al. (1986) described 2 affected families with involvement of 2 or more generations and examples of male-to-male transmission in each. They emphasized the probable frequency of this condition, particularly in children. Thyrotoxicosis is often suspected because of the goiter and the elevated thyroxine and triiodothyronine levels. Misdiagnosis can have obvious ill effects. Sakurai et al. (1989) stated that about 200 cases of generalized resistance to thyroid hormone have been described. They demonstrated the defect in father and son. The proband was 6.5 years when first suspected of having this disorder. Delayed verbal expression led to a diagnosis of attention-deficit/hyperactivity disorder at age 3. At age 5.5, thyroid gland enlargement and elevated serum thyroxine and triiodothyronine were interpreted as hyperthyroidism but specific therapy for this condition was not successful. Indeed, normalization of the thyroid hormone levels in blood slowed his growth rate and strikingly increased TSH concentration. His verbal IQ was 85% but his performance IQ was 120% of the standard score. The father also had a history of delayed speech development, hyperactivity, and learning disability but later obtained higher education including a master's degree. Physical examination was normal except for minimal thyroid gland enlargement. In studies of 18 families with 49 persons with generalized resistance to thyroid hormone, Hauser et al. (1993) found a high frequency of attention deficit/hyperactivity disorder in the affected individuals as children.

See the review of the syndromes of resistance to thyroid hormone by Refetoff et al. (1993).

Mapping

Bale et al. (1988) found no recombination between generalized thyroid hormone resistance and RFLPs of the ERBA2 (THRB) gene; the maximum lod score was 3.91 at theta = 0.0 (Usala et al., 1988). The family studied was 'kindred A' of Magner et al. (1986). Usala et al. (1990) showed linkage between GRTH and ERBA2 in 2 other families (kindreds B and D); the combined maximum lod score for the 3 kindreds was 5.77 at a recombination fraction of 0.0.

Molecular Genetics

In a father and son with generalized resistance to thyroid hormone, Sakurai et al. (1989) identified heterozygosity for a missense mutation in the THRB gene (190160.0001).

In affected members of a family with GRTH, originally reported by Magner et al. (1986) as 'kindred A,' Usala et al. (1990) identified a mutation in the THRB gene (190160.0002). A mutation in the THRB gene appears to result in abnormalities of thyroid hormone action in many tissues: in addition to inappropriate secretion of TSH from the pituitary, affected members of the kindred showed delayed bone age and short stature. Most also showed mild mental retardation, diminished or inappropriately normal basal metabolic rates, and hepatic resistance to thyroid hormone (relatively low sex hormone binding globulin and relatively high cholesterol).

Generalized thyroid hormone resistance is a notable example of a phenotype which can be either completely recessive or completely dominant even though the causative mutations are in the same gene. The dominant forms represent dominant-negative mutations in which the mutant gene product interferes with the function of the normal receptors; the completely recessive forms are due to a deletion of the THRB gene (see 190160.0003).

In 10 affected members of a family known as 'kindred D,' in which generalized thyroid hormone resistance segregated as an autosomal dominant, Usala et al. (1991) identified heterozygosity for a mutation in the THRB gene (190160.0004). The mutation was not found in 6 unaffected members of the family. Patients from kindred D had cognitive impairments similar to those in kindred A, but did not have short stature and displayed significant resistance to the chronotropic effects of thyroid hormone.

Genetic Heterogeneity

Weiss et al. (1996) reported a family in which dominantly inherited GRTH was not associated with abnormalities in the TR-alpha (THRA; 190120) or TRHB genes, as determined by sequencing and linkage analysis. Affected family members manifested a severe form of GRTH, with reduced responses of thyrotrophs and peripheral tissues requiring 8 to 10 fold the normal replacement doses of L-T4 and L-T3. No other endocrine abnormalities were detected. The defect developed de novo in the proposita and was transmitted to her 2 children from unrelated fathers. An abnormal cofactor with a specific function in the regulation of thyroid hormone action was probably involved in the expression of the GRTH phenotype in this family.

Pohlenz et al. (1999) reported 5 families with GRTH who had no nucleotide substitutions, deletions, or insertions in the coding and noncoding portions of TR-beta-1- and TR-beta-2-specific and common exons. Furthermore, linkage analysis excluded involvement of the TR-beta and TR-alpha genes in 2 and 3 of the 5 families, respectively. The GRTH phenotype in the patients without TR-beta gene defects was not different from that in patients with GRTH due to TR-beta gene mutations in terms of clinical presentation and reduced responsiveness of the pituitary and peripheral tissues to TH. However, the degree of thyrotroph hyposensitivity to TH appeared to be among the more severe, similar to that of patients with mutant TR-betas that have more than 50-fold reduction of T3 binding affinity and strong dominant-negative effect. In these 5 families and another with non-TR-alpha/non-TR-beta GRTH that had been previously identified (Weiss et al., 1996), there was evidence for dominant inheritance in 2 families and for a novel defect or recessive inheritance in the remaining 4 families. The authors found that GRTH without structural TR-beta defects occurred in about 10% of families expressing the classic phenotype of TH hyposensitivity, and TR-beta and TR-alpha gene involvement had been excluded in 5%. They postulated that a cofactor that interacts with TR was potentially responsible for the manifestation of GRTH in these families. As affected subjects were not infertile, the high prevalence of putative neomutations and the low rate of transmission in this non-TR form of GRTH may be due to reduced survival of embryos harboring the defect.

Mamanasiri et al. (2006) reported a Turkish family in which 2 sibs with RTH inherited a THRB mutation (190160.0023) from their father, who was mosaic for the mutation. They suggested that the possibility of mosaicism should be considered in subjects with RTH without apparent mutations in the THRB gene.