Hyperthyroxinemia, Euthyroid, Caused By Generalized 5-Prime-Deiodinase Deficiency

Clinical Features

Jansen et al. (1982) described 2 patients, an 8-year-old boy and a 60-year-old woman, with elevated levels of serum thyroxine but normal serum triiodothyronine. The pituitary-thyroid axis could be normally stimulated by thyrotropin-releasing hormone. High levels of serum T4-binding globulin decreased during T3 treatment in the boy. In both patients, raised serum T4 was necessary to produce in the peripheral tissues sufficient T3 to maintain the euthyroid state. The authors suggested that the defect resides either in the transport of T4 into tissue cells or in 5-prime-deiodinase activity catalyzing the T4 to T3 conversion. Studies of the families showed no clue as to whether the disorder was hereditary. The boy was ascertained because of constitutional delay and problems in infancy related perhaps to toxemia of pregnancy and umbilical cord strangulation and amniotic fluid aspiration at birth. The woman had undergone subtotal thyroidectomy for Graves disease.

Kleinhaus et al. (1988) described an 11-year-old girl with asymptomatic hyperthyroxinemia who remained euthyroid and healthy during 5 years of observation. Besides having elevated serum T4 concentrations, she showed low-normal or definitely low levels of deiodinated forms of T4. The girl had a small diffuse goiter, her serum TSH (see 188540) response to TRH was exaggerated, and thyroid radioiodine was elevated, suggesting slightly increased TSH secretion and, consequently, increased thyroid secretion. Kleinhaus et al. (1988) interpreted the findings as indicating reduced activity of several, and perhaps all, peripheral 5-prime-deiodination (see 147892) pathways, including possibly also thyrotroph T4 5-prime-deiodination. Thus, the girl appeared to have a previously unrecognized syndrome of generalized 5-prime-deiodinase deficiency. The genetic nature of the abnormality could not be determined; all relatives, including the parents and 4 sibs, had normal serum T4 levels and were healthy.

Toyoda et al. (1996) analyzed the exon/intron structure of the human DIO1 gene (147892) and compared it with that of the patient reported by Kleinhaus et al. (1988) with suspected congenital type I deiodinase deficiency. They found no mutations in the sequences of all 4 exons of the patient's genomic DNA. Functional studies by transient expression techniques showed no difference in basal promoter activity or T3 responsiveness between the patient's and the normal gene. Toyoda et al. (1996) concluded that a structural abnormality in the type I iodothyronine deiodinase gene is not a likely explanation for this patient's deiodinase-deficient phenotype.

Animal Model

Maia et al. (1995) identified an abnormality of the dio1 gene in mice with inherited deficiency of type 1 deiodinase.