Thyroid Dyshormonogenesis 1

A number sign (#) is used with this entry because thyroid dyshormonogenesis-1 (TDH1) is caused by homozygous or compound heterozygous mutation in the sodium-iodide symporter (NIS) gene (SLC5A5; 601843) on chromosome 19p13.

Description

Approximately 10% of patients with congenital hypothyroidism harbor inborn errors of metabolism in one of the steps for thyroid hormone synthesis in thyrocytes (Vono-Toniolo et al., 2005). Dyshormonogenesis can be caused by recessive defects at any of the steps required for normal thyroid hormone synthesis. In untreated patients thyroid dyshormonogenesis is typically associated with goitrous enlargement of the thyroid secondary to long-term thyrotropin (TSH; see 188540) stimulation.

Park and Chatterjee (2005) reviewed the genetics of primary congenital hypothyroidism, summarizing the different phenotypes associated with known genetic defects and proposing an algorithm for investigating the genetic basis of the disorder.

Genetic Heterogeneity of Thyroid Dyshormonogenesis

Other forms of thyroid hormone dysgenesis include TDH2A (274500), caused by mutation in the thyroid peroxidase gene (TPO; 606765) on 2p25; Pendred syndrome, a form of thyroid hormone dysgenesis associated with deafness (TDH2B; 274600) and caused by mutation in the SLC26A4 gene (605646) on 7q31; TDH3 (274700), caused by mutation in the thyroglobulin gene (TG; 188450) on 8q24; TDH4 (274800), caused by mutation in the iodotyrosine deiodinase gene (IYD; 612025) on 6q25; TDH5 (274900), caused by mutation in the DUOXA2 gene (612772) on 15q21; and TDH6 (607200), caused by mutation in the DUOX2 gene (606759) on 15q21.

Clinical Features

A defect in thyroid hormonogenesis is characterized by an inability of the thyroid to maintain a concentration difference of readily exchangeable iodine between the plasma and the thyroid gland. The defect is also found in the salivary gland and gastric mucosa. It is presumed to arise either because of a deficient supply of energy for the transport system or because of abnormality of a carrier or receptor substance. Parental consanguinity was present in the case of Stanbury and Chapman (1960). Medeiros-Neto et al. (1972) described a brother and sister with a partial defect. Affected sibs were reported by Gilboa et al. (1963), Toyoshima et al. (1977), and others.

Fujiwara et al. (1997) studied a patient in whom an iodide transport defect was diagnosed on the basis of failure to concentrate radioiodide by the salivary gland (saliva/plasma (123)I ratio was 1.6, in contrast to the normal ratio of more than 20) and the clinical and biologic response to potassium iodide treatment. The patient's physical findings and serum thyrotropin T4 and T3 levels were maintained at normal levels by the treatment. However, mild goiter and multiple mass lesions developed in one lobe of the thyroid and then in the other lobe at 8 and 11 years of age, respectively. The tumor removed from the left lobe was found to be follicular adenoma. Resected thyroid from the patient was used as a source of RNA for the production of cDNA by reverse transcriptase.

Kempers et al. (2009) examined the body surface of 242 Dutch patients with congenital hypothyroidism (CH) of thyroidal origin with thyroid agenesis, an ectopic thyroid rudiment, or eutopic thyroid gland, for visually detectable morphologic abnormalities. The percentage of patients with 1 or more major anomalies in the total CH cohort (33%) and in patients with ectopic thyroid (37.2%) was significantly higher than in 1,007 Dutch controls (21.8%; p less than 0.001), and specific major malformations such as bilateral ear pits and oligodontia were more frequent in the group of patients with ectopic thyroid. In addition, the percentage of patients in the CH cohort with 1 or more minor anomalies (96.3%) was significantly higher than in the control group (82.5%; p less than 0.001).

Molecular Genetics

In a patient with hypothyroidism who was suspected of having an iodide transport defect, Fujiwara et al. (1997) identified homozygosity for a missense mutation in the SLC5A5 gene (T354P; 601843.0001).

In a Japanese patient with iodide transport defect, Kosugi et al. (1998) identified compound heterozygous missense mutations in the SLC5A5 gene: T354P and G93R (601843.0005).