A number sign (#) is used with this entry because thyroid dyshormonogenesis-3 (TDH3) is caused by homozygous or compound heterozygous mutation in the thyroglobulin gene (TG; 188450) on chromosome 8q24.

For a general phenotypic description and a discussion of genetic heterogeneity of thyroid dyshormonogenesis, see TDH1 (274400).

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 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 188550). 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.

Vono-Toniolo et al. (2005) stated that in most instances of TG-related goitrous hypothyroidism affected individuals have related parents and are homozygous for inactivating mutations in the TG gene. More rarely, compound heterozygous mutations lead to a loss of function of both alleles.

Vono-Toniolo et al. (2005) noted that molecular analyses had shown that at least some TG mutations result in a secretory defect and an endoplasmic reticulum storage disease.

Increased metabolic activity of the gland or any block in thyroglobulin synthesis results in iodination of the serum albumin that diffuses into the hyperplastic thyroid (Stanbury, 1978). Patients previously classified as having familial plasma iodoprotein defects can be categorized as having some type of thyroglobulin abnormality or a familial abnormality of the thyroid such as Hashimoto struma (140300) or Graves disease (275000).

Prenatal Diagnosis

Medeiros-Neto et al. (1997) reported diagnosis of fetal dyshormonogenetic goiter with hypothyroidism, probably due to defective thyroglobulin synthesis, by ultrasound and cordocentesis at 28 weeks of gestation. They found that after a single injection of levothyroxine the fetal goiter decreased in size, and at birth the neonate had normal thyroid function. They concluded that congenital goitrous hypothyroidism can be diagnosed and treated prenatally with intraamniotic injection of thyroxine.

In 5 affected and 5 unaffected members of a family with goiter due to a qualitative and quantitative defect in TG, Baas et al. (1984) analyzed the presence of an RFLP in the TG gene (188450) and found mendelian segregation of the polymorphism and goiter, suggesting that the rare variant was linked to a normal TG allele providing strong evidence for autosomal dominant inheritance of the TG synthesis defect in this family.

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 188550), 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.

Reports of patients with goitrous hypothyroidism caused by thyroglobulin defects have varied, with few patients having severe hypothyroidism. Some have a low protein-bound iodine level (PBI) commensurate with their low serum T4; others have a normal or elevated PBI with a low or low-normal serum T4. The thyroid may contain very small amounts of normally iodinated thyroglobulin or ample amounts of immunologically identifiable thyroglobulin with abnormal physical properties such as solubility (Michel et al., 1964), protease digestibility (McGirr et al., 1960), and iodinatibility (Kusakabe, 1972).

In a review of inherited disorders of thyroid metabolism, Lever et al. (1983) discussed the heterogeneous group of disorders of hormonogenesis related to abnormal TG formation or secretion. Hypothyroidism in the goat and sheep has been related to a defect in mRNA for TG (Van Voorthuizen et al., 1978; Falconer et al., 1970).

In 90 unrelated persons, Baas et al. (1984) screened the TG gene for RFLP; 1,164 nucleotides were screened using 15 different restriction enzymes. The average number of nucleotides screened per individual was 354. Only 1 polymorphism was found in these 1,164 nucleotides, with a minor allele frequency of 2.2%. The polymorphism was located in an intervening sequence. In the family with hereditary congenital hypothyroidism due to a defect in the synthesis and structure of thyroglobulin (de Vijlder et al., 1983), cosegregation of the rare defect and the polymorphism indicated that the hypothyroidism was caused by a mutation in the structural gene for thyroglobulin. Baas et al. (1984) suggested that since the tertiary and quaternary structure of TG is very important for hormone formation, a change in 1 of the 2 subunits (heterozygosity) may lead to severely impaired hormonogenesis of the heterodimeric TG and thus autosomal dominant inheritance of this disorder characterized by relatively high levels of abnormal TG.

Van Ommen (1987) pointed out that the defects in the TG gene can cause either dominant or recessive disorders depending on the nature of the defect. When the gene is absent or at least when no thyroglobulin is synthesized, the disorder is likely to be recessive, whereas the presence of an abnormal subunit leads to a dominantly inherited disorder. The explanation for this is that in a dimeric protein such as thyroglobulin, 75% of the dimers in heterozygotes will contain 1 or more abnormal subunits. This should profoundly disturb thyroglobulin metabolism, since this protein fulfills a dual storage/catalytic role as a dimer, is present in bulk quantities (100 mg Tg/g thyroid mass), and needs to be exocytosed, iodinated, endocytosed, and degraded.