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Mutations in the receptor of TSH may lead to different clinical entities.
In the following report examples of the differences in disease expression
are reported.
Holzapfel et al., Leipzig and Freiburg, Germany, report on congenital non-autoimmune hyperthyroidism, caused by a sporadic germline mutation in the TSH-R in a boy at the age of 5 months. This boy was first treated with antithyroid drugs, but finally operated at the age of 26 months and subsequently put on thyroxine substitution. Esapa et al., Southampton and Newcastle upon Tyne, UK, had a similar report with regard to a female infant in whom the diagnosis was made at the age of 9 months. Finally Biebermann, Berlin, Germany, studied a 6 year old girl, who developed symptoms of hyperthyroidism at the age of 2 months and despite PTU treatment required thyroidectomy 6 years later. In this report the family was screened for the mutation and evidence was found for autosomal dominancy of the trait. Both the paternal grandmother and a paternal aunt had suffered from severe hyperthyroidism in the past in childhood, requiring also thyroidectomy. The father of the patient, who is carrying the mutation also, has still no symptoms of hyperthyroidism. In these 3 reported cases a diffuse goiter is present and the patients do not suffer from eyesigns and there are no signs of thyroid autoimmunity. The disease is caused by a mutation in the TSH-R (3 different mutations were found in these 3 patients), that leads to constitutive activation of the cyclic AMP pathway thereby rendering the thyroid overactive. Apparently other factors than the mutation only play a role in the development of hyperthyroidism, because of the fact that the father of the last patient, despite having the mutation, has not developed, so far, signs of hyperthyroidism. Another type of "TSH-R mutation disease" is when a mutation causes impossibility of TSH to normally stimulate the TSH receptor to elicit an intracellular response. Thus, Asteria et al., Naples, Italy, reported on a 25 year old man, who had elevated serum TSH (31.5 mU/l), but normal free T3 and free T4 levels. Normal bioactivity of TSH was found, but a mutation was present in the TSH-R causing this hyposensitivity to TSH. Pituitary-thyroid function was found to be normal in all relatives, but the same mutation was found also in the mother and a brother of the propositus, but evidently without clinical expression of the disease. A similar case was reported by Clifton-Bligh et al., Cambridge, UK. They describe a boy, who already at birth had elevated serum TSH levels. At the age of 2 years serum TSH was > 100 mU/l, but free T4 was normal. Two mutations were detected in the TSH-R gene, one coming from the mother, and one from the father, both having normal thyroid function. (Comment: In the first case, a mutation was found only in 1 allele and the authors suggest that another mutation should probably exist also, which they have not detected yet because normally, heterozygosity of both parents is commonly required for the disease to manifest itself. In the second patient, this is indeed the case. In these two patients no signs of autoimmunity were present and TSH bioactivity was found to be normal. The three mutations (one in the first patient and two in the second patient) were all at a different position.) Both congenital non-autoimmune hyperthyroidism and congenital TSH unresponsiveness are thus caused by germline mutations in the TSH-R gene. Somatic mutations (acquired during life) are also known to cause thyroid disease. Thus, Paschke et al., Leipzig, Germany, show somatic mutations in the TSH-R gene in 2 patients, each with two hyperfunctioning adenomas in a toxic multinodular goiter. In 1 patient two different mutations were identified in the two hyperfunctioning thyroid adenomas, but in the other patient the mutations in the two adenomas were the same. The mutations in the first patient have been previously reported to cause toxic adenoma, but in the second patient the found mutation was newly detected. Duprez et al., Brussels and Haine-St-Paul, Belgium, analyzed 24 toxic adenomas from 23 patients for somatic mutations in the TSH receptor gene and found mutations to be present in 75% of the adenomas. They also found in 4% mutations in the Gs-alpha coupled protein. They also found that multiple adenomas can harbour different mutations and the mutations detected were at different locations. (Comment: Although in the report of Paschke et al. the patients had toxic multinodular goiter, it is not proven that these mutations are the cause of the multinodular goiter, because somatic mutations may also occur in multinodular goiter, leading to the development of a toxic adenoma. On the other hand, it is not excluded that TSH-R gene mutations not only play a role in solitary adenomas, but also in the etiopathology of toxic multinodular goiter.) |
