Abstract

Thyroid gland dyshormonogenesis is an inborn error of thyroid metabolism. Variable defects have been described. We present clinical, laboratory, and radiologic data of five patients with thyroid dyshormonogenesis due to organification defect; two of them were associated with sensorineural deafness (Pendred's syndrome). Discussion of different defects is included with emphasis on the organification defect.

Inborn errors of thyroid metabolism presenting with goitrous hypothyroidism or euthyroidism may result from partial or complete defect at any stage of thyroid hormone synthesis. These are genetically determined inheritable diseases,¹ believed to be autosomal recessive.

Five cases of thyroid dyshormonogenesis are described. Their mode of presentation, biochemical and radiologic data, as well as different defects that may be encountered in thyroid hormone synthesis are discussed.

Patients and Methods

In 1988, five patients were diagnosed as having thyroid gland dyshormonogenesis. They were referred to the endocrinology clinics for assessment of goiter (five patients), symptoms suggestive of hypothyroidism (one patient), and deafness and mutism (two patients). Thyroid function tests were done by the radioimmunoassay method using commercially available kits. Quality control of the assays was monitored by the Middle East extended quality assessment scheme (MEEQAS) in Riyadh. Antithyroid antibodies were done using the hemagglutination method.

Perchlorate discharge test was performed after oral administration of 100 to 200 μCiof radioactive iodine 123 (¹²³I). Using a scintillation probe and scaler, 1- and 2-hour thyroid uptake was determined followed by a 1-g oral dose of potassium perchlorate. Thyroid uptake was subsequently measured every 15 minutes for 1 hour and every 30 minutes for an additional 1 hour. Each uptake after perchlorate administration was compared with the 2-hour uptake, and the test was considered positive if a drop of 20% or more was obtained.

Technetium 99m scan was performed initially for assessment of enlarged thyroid.

Results

The clinical, biochemical, and radiologic findings in the five patients with thyroid gland dyshormonogenesis are summarized in Table 1.

Discussion

Inborn errors of thyroid metabolism were first reported over 80 years ago by Pendred,² when he described a patient with inherited goiter, deafness, and mutism.

Thyroid hormone synthesis is a sequential process where circulating iodide is trapped by the thyroid, followed by oxidation of iodide mediated by peroxidase enzyme. Tyrosyl residues are then iodinated within thyroglobulin to make monoiodotyrosine and diiodotyrosine, which through a coupling process form tetraiodotyrosine (T4) and triiodotyrosine (T3). T3 and T4 are stored within thyroglobulin, and hydrolysis of thyroglobulin by protease enzyme leads to release of active hormones. Defects of thyroid hormonesynthesis at any stage lead to goiter formation with or without hypothyroidism.

With the advent of accurate means of assessing thyroid function through radioimmune assays, radioactive iodine uptake, and thyroid peroxidase activity and thyroglobulin measurement, detailed classification and identification of these defects have become available.³ An inherited defect at any step of hormone biosynthesis, whether partial or complete, may result in goitrous hypothyroidism or euthyroidism. Homozygous members of the family usually present with a complete defect and goitrous hypothyroidism, while heterozygous members of the family usually have a partial defect and goitrous euthyroidism.

The five patients described had an organification defect; hence, detailed discussion of organification defect follows. Other specific defects of thyroid dyshormonogenesis are summarized in Table 2.

Organification Defect

This could be either a quantitative deficiency or a qualitative abnormality of the thyroid peroxidase enzyme.^12,13 Because trapped iodine is not organified and bound to thyroglobulin properly, it can be discharged into plasma with perchlorate, and the perchlorate discharge test can thus be used to diagnose organification defect.

A wide spectrum of clinical presentation of thyroid decompensation is seen with organification defect, depending on whether it is partial or complete.¹⁴ This is evident in our patients where the first four cases were clinically and biochemically euthyroid while the fifth patient was clinically and biochemically hypothyroid.

Pendred's Syndrome

Pendred's syndrome is an inheritable disease with an autosomal recessive pattern of inheritance. It is a variant of an organification defect characterized by small to moderate-sized goiter, as well as clinical and biochemical euthyroidism in most patients. Although the perchlorate discharge test suggests an organification defect, the peroxidase activity appears to be normal.⁵Pendred's syndrome is associated with congenital sensorineural deafness. The cause of deafness is not clear; since most of patients with Pendred's are euthyroid, hypothyroidism cannot be implicated as a cause of deafness. Patients 3 and 4 had both sensorineural deafness and organification defects. Patients with Pendred's syndrome usually have normal intelligence.

Table 2. Possible defects in thyroid gland dyshormonogenesis (other than organification defect).

Investigation and Treatment

Organification defect is diagnosed by demonstration of rapid uptake and release of radioiodine and discharge of 15% to 70% of iodide perchlorate, depending on whether the defect is partial or complete. In autoimmune thyroiditis, positive perchlorate discharge test due to intracellular organification defect is seen in approximately 40% of the patients.¹⁶ Thyroid antibodies in our patients were not detectable or positive at very low titers.

Treatment of an organification defect depends on clinical and biochemical findings and the degree of the organification defect judged by the perchlorate discharge test. Patients whose clinical and biochemical findings are in keeping with hypothyroidism tend to have more severe organification defect with high value of perchlorate discharge test, and these patients are treated with thyroxine replacement. Other patients have only goiter with no clinical or biochemical evidence of hypothyroidism, and thyroxine may be given as suppressive therapy for the goiter. Other defects of dyshormonogenesis can be treated by thyroxine as replacement and/or suppressive therapy judged by the clinical and biochemical parameters.

Acknowledgment

The authors thank Juliet G. Miranda for her secretarial assistance.

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