Primary congenital hypothyroidism: defects in iodine pathways

Abstract

The thyroid gland is the only source of thyroid hormone production. Thyroid hormone is essential for growth and development, and is of special importance for the development of the central nervous system. It was for that reason that neonatal screening on congenital hypothyroidism was introduced and is now performed in many countries. Defects in thyroid hormone production are caused by several disorders in hormone synthesis and in the development of the thyroid gland (primary hypothyroidism) or of the pituitary gland and hypothalamus (central hypothyroidism). This paper describes defects in the synthesis of thyroid hormone caused by disorders in the synthesis or iodination of thyroglobulin, leakage of iodinated proteins by a stimulated thyroid gland and the presence of abnormal iodoproteins, mainly iodinated albumin, in the thyroid gland and blood circulation. Circulating thyroglobulin and abnormal iodoproteins, as well as the breakdown products of these iodoproteins excreted in urine, are used for etiological diagnosis and classification. Moreover, our finding of an enzyme that catalyses the dehalogenation of iodotyrosines, which is important for iodine recycling and required for economical use of iodine, is also referred to.

Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity

“…F, Patients with defective intracellular Tg transport; E, controls. One patient homozygous for Tg C1245R is not included because data of serum FT 4 and FT 3 were not available. C, Northern blot analysis of thyroidal D2 mRNA.…”

“…In the experiment of endoglycosidase H (Endo H) digestion, the thyroid gland obtained from a patient with Graves' disease was used as control. FT 4 and FT 3 were measured before surgery. The analyses of the Tg genes of patients was approved by the Ethics Committees at Nagoya University School of Medicine and Dokkyo University School of Medicine.…”

“…Although the degree of thyroid dysfunction varies considerably among patients with defective Tg synthesis, patients usually have a relatively high serum free T 3 (FT 3 ) concentration with disproportionately low free T 4 (FT 4 ) level. The maintenance of relatively high FT 3 levels prevent profound tissue hypothyroidism except in brain and pituitary, which are dependent on T 4 supply (11,12), resulting in the neurological and intellectual defects in some cases (2).…”

Nuclear Medicine in the First Year of Life

“…Untreated congenital hypothyroidism is one of the most common preventable causes of mental retardation (24). Causes of neonatal hypothyroidism include thyroid agenesis, dysgenesis, or ectopia (25); dyshormonogenesis due to inborn errors in thyroid hormone synthesis (26,27); and transient infantile hypothyroidism caused by maternal thyroid-blocking antibodies, maternal antithyroid medications, or iodine exposure (28). In North America, congenital hypothyroidism has an incidence of approximately 1 in every 3,000-4,000 births, with approximately a 2:1 female predominance (24,27).…”

The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone

“…In spite of this, it appears that most congenital hypothyroidism with deficient Tg is caused by mutations in which intracellular Tg transport is blocked, rather than by defects in the ability to synthesize thyroid hormone per se (1,32). Evolutionary pressure definitely exists for Tg to be maintained as a secreted protein, as its inability to do so (at least in Merino sheep) compromises viability to a stage where animals cannot reach reproductive age (33,34). We now present what we believe to be the first evidence directly implicating the ChEL domain in assisting the intracellular protein transport of Tg.…”