Kanou et al. (2007) reviewed characteristics of thyroid dyshormonogenesis caused by mutations in the thyroglobulin (TG) gene. This form of thyroid dyshormonogenesis has an estimated prevalence of one in 100,000 newborns. Inherited in an autosomal recessive manner, the ... Kanou et al. (2007) reviewed characteristics of thyroid dyshormonogenesis caused by mutations in the thyroglobulin (TG) gene. This form of thyroid dyshormonogenesis has an estimated prevalence of one in 100,000 newborns. Inherited in an autosomal recessive manner, the disorder in the majority of patients causes large goiters of elastic and soft consistency. Although the degree of thyroid dysfunction varies considerably among patients with defective TG synthesis, patients usually have a relatively high serum free T3 concentration with disproportionately low free T4 level. The maintenance of relatively high FT3 levels prevents profound tissue hypothyroidism except in brain and pituitary, which are dependent on T4 supply, resulting in neurologic and intellectual defects in some cases.
Riddick et al. (1969) reported 3 goitrous members of a sibship of 4. These patients had hypothyroidism or compensated hypothyroidism, and had normal or high uptake of radioiodine; biochemical measurements on removed thyroid tissue showed absence of thyroglobulin ... Riddick et al. (1969) reported 3 goitrous members of a sibship of 4. These patients had hypothyroidism or compensated hypothyroidism, and had normal or high uptake of radioiodine; biochemical measurements on removed thyroid tissue showed absence of thyroglobulin with the appearance of abnormal light iodoproteins. Lissitzky et al. (1975) found a marked reduction of the carbohydrate moieties, supposedly necessary for secretion, in the thyroglobulin from a congenital goiter. Electron micrographs showed scarcity of colloid in the follicular lumen and overdistended, protein-filled endoplasmic reticulum. Cooper et al. (1981) reported a large kindred of patients with congenital goiter, followed for 15 years, in which a brother and sister developed metastatic follicular thyroid carcinoma (see 188470). Neither patient had evidence of the classic defects of T4 biosynthesis, but both had extremely rapid rates of iodine turnover. Based on their study of these patients and a review of published reports, Cooper et al. (1981) stated that development of metastatic thyroid cancer in patients with congenital goiter, occurring years after subtotal thyroidectomy without thyroid hormone replacement therapy, suggested a role for TSH in the genesis of thyroid cancer. De Vijlder et al. (1983) described a presumably autosomal dominant form of hereditary congenital goiter in a mother and 4 of her 8 children. Goiter was present in other members of the mother's family. Thyroglobulin was found to be reduced in the thyroid (17 mg/g thyroid tissue; normal value = 50) and was more negatively charged than normal, as shown by isoelectric focusing and DEAE-cellulose chromatography. Yoshida et al. (1996) identified a variant type of adenomatous goiter in 24 of 2,160 patients with adenomatous goiter who underwent thyroidectomy. The characteristics of the thyroid gland in these 24 patients included large goiter, small follicles, scant colloid, and columnar follicular cells containing yellow-green granules on hematoxylin-eosin staining. The thyroid gland was slightly orange-red, and electron microscopic examination showed abundant lysosomes with colloid droplets. When the features of this group were compared with those of 24 patients with common adenomatous goiter, the incidence of familial predisposition to thyroid disease in the former group was higher. The age at the time of detection of goiter was lower, i.e., 17 years in the variant type as opposed to 44 in the common type. Serum total T4 concentrations were lower in the variant group and serum TSH concentrations were higher in the variant group. Thyroid radioiodine uptake was remarkably increased, and lower levels of serum thyroglobulin were noted. The thyroglobulin content was low in the thyroid gland studied. The data suggested to Yoshida et al. (1996) that the etiology of this variant type of goiter is a hereditary abnormality in thyroglobulin synthesis. Hishinuma et al. (2005) reported a high incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations. The authors reviewed 14 adult Japanese patients from 9 unrelated families, born before the initiation of neonatal thyroid screening in Japan, who had undergone multiple operations for very large goiters that first appeared in childhood. Of 11 patients who had undergone surgery, 7 had thyroid cancers; histologic examination revealed that 4 were multifocal papillary, 2 were unifocal papillary, and 1 was multifocal follicular. Analysis of exon 15 of the BRAF gene (164757) in 5 patients for whom thyroid tissue was available revealed 2 different heterozygous activating BRAF mutations (164757.0001 and 164757.0005) in 2 patients, respectively. Alzahrani et al. (2006) reported 2 brothers, born of consanguineous parents, who developed recurrent large goiters beginning at 1.5 years of age, requiring multiple partial thyroidectomies. At 15 years of age, the older brother underwent partial bilateral thyroidectomy and was diagnosed with thyroid cancer. Several years later, he presented with pain in the right femur; fine-needle aspiration of a subtrochanteric lesion revealed metastatic follicular thyroid carcinoma. He underwent completion thyroidectomy, for which histopathologic examination showed only hyperplastic nodules consistent with dyshormonogenesis, followed by apparently successful chemotherapy, with a negative iodine-123 whole-body and bone scans 3 years later. Diagnostic iodine-123 whole-body scans in his brother showed only residual tissue in the thyroid bed without evidence of distant activity; fine-needle aspiration of thyroid tissue showed no malignancy. The parents were unaffected, and there was a third unaffected brother.
Ieiri et al. (1991) gave the first report of individuals with documented TG gene mutations. The index patient and 2 of her 5 sibs presented with hypothyroidism, congenital goiter, and a marked impairment of TG synthesis. Analysis of ... Ieiri et al. (1991) gave the first report of individuals with documented TG gene mutations. The index patient and 2 of her 5 sibs presented with hypothyroidism, congenital goiter, and a marked impairment of TG synthesis. Analysis of a restriction fragment length polymorphism (RFLP) in the TG gene demonstrated that the affected individuals were homozygous for this allele and TG mRNA obtained from the goitrous tissue was slightly reduced in size compared to that from normal individuals. Sequencing of the cDNA revealed that exon 4 was missing from the major TG transcript in the goiter, and analysis of genomic DNA revealed a C-to-G transversion in the acceptor splice site of intron 3 (IVS3-3C-G; 188450.0001). Targovnik et al. (1989) provided the original description of a Brazilian family in which 3 mutations in 2 compound heterozygous combinations were found to segregate with the disorder (Gutnisky et al., 2004) (see 188450.0013). In 2 sibs with adenomatous goiter, Hishinuma et al. (2006) identified homozygosity for a mutation in the TG gene (188450.0006). Kitanaka et al. (2006) reported a Japanese girl with congenital goitrous hypothyroidism who was compound heterozygous for 2 mutations in the TG gene (188450.0017-188450.0018). She was identified with increased TSH in a neonatal screening test. Although serum T4 was low and serum TG undetectable, serum T3 was increased. Kanou et al. (2007) measured iodothyronine deiodinase type II (DIO2; 601413) in the thyroid gland of several patients with goiter who had mutations in the TG gene that cause a defect in the intracellular transport of TG (e.g., 188450.0005 and 188450.0015). They found a positive correlation between DIO2 activity and free T3/T4 ratios. In 2 brothers with recurrent large goiters, 1 of whom developed metastatic follicular thyroid carcinoma (see 188470), Alzahrani et al. (2006) analyzed the TG gene and identified homozygosity for a splice site mutation (188450.0018). The unaffected consanguineous parents were heterozygous for the mutation, which was not found in an unaffected brother. Alzahrani et al. (2006) also screened for RAS oncogene mutations by direct sequencing of thyroid tumor DNA, but identified no mutation in codons 12, 13, and 61 of the HRAS (190020), KRAS (190070), and NRAS (164790) oncogenes. The authors concluded that the malignant transformation of the congenital goiter was likely the result of prolonged TSH stimulation, probably in combination with mutations of oncogenes and/or tumor suppressor genes other than RAS.