Mutations of the TSH receptor as cause of congenital hyperthyroidism^*

Abstract

4 patients of two families with congenital persistent hyperthyroidism without detectable autoantibodies are reported. The members of the first family affected by hyperthyroidism, i.e. the mother and her two children, showed a germline mutation, a transition of GCC to GTC in the genomic DNA of the TSH receptor, leading to an exchange of alanine by valine at the position 623. The mother was thyroidectomized at two times because of recurrent nodular goiter. The third child of a healthy second family showed a transition of AGC to AAC leading to an exchange of serine by asparagine at the position 505 of the TSH receptor. The mutation of family 1, as a somatic point mutation leading to autonomous thyroid adenoma, has originally been demonstrated to constitutively activate TSH independent cAMP accumulation. The functional tests of the TSH receptor gen mutation, detected in family 2, are ongoing, but an exchange of serine by arginine at the same position has been shown to lead to constitutively active cAMP accumulation. The cases of congenital hyperthyroidism in the first family lead to a reduction of the birth weight and head circumference and to a neonatal but not fetal tachycardia. Bone age of both children was accelerated by one year. In contrast to that, congenital hyperthyroidism of the second family lead to more marked signs of intrauterine hyperthyroidism. The mother observed marked symptoms of fetal and neonatal hyperthyroidism. The bone age at a chronological age of 6 months was 4-6 years and the neonate showed a mild exophthalmus. We conclude, that congenital hyperthyroidism due to constitutively activating TSH receptor mutations has to be considered, if hyperthyroidism is not transient but persistent, and the parameters of autoimmunity are absent. Constitutively active TSH receptor germline mutations lead to different degrees of congenital hyperthyroidism. In contrast to patients with Graves' disease, more aggressive means of treatment like total thyroidectomy and/or radiation seem to be recommendable in cases with severe hyperthyroidism to control the disease.

Detection of combined genomic variants in a Jordanian family with familial non-autoimmune hyperthyroidism

“…Through previous genotyping of 23 reported family members with FNAHT, a hot TSHR mutation locus was mapped to the chromosomal location 14q exon 10 (Duprez et al 1994;Schwab et al 1996;Tonacchera et al 1996;Führer et al 1997Führer et al , 2000Khoo et al 1999;Biebermann et al 2000Biebermann et al , 2001Alberti et al 2001;Arturi et al 2002;Lee et al 2002;Vaidya et al 2004;Claus et al 2005;Elgadi et al 2005;Karges et al 2005;Nwosu et al 2006;Ringkananont et al 2006;Nishihara et al 2007;Ferrara et al 2007;Akcurin et al 2008;Liu et al 2008). However, none of the reported hot TSHR mutations of exon 10 were found in our family.…”

“…So far, 18 different germline TSHR mutations have been reported in related families (Duprez et al 1994;Schwab et al 1996;Tonacchera et al 1996;Führer Claus et al 2005;Nwosu et al 2006;Ringkananont et al 2006;Nishihara et al 2007;Akcurin et al 2008;Liu et al 2008). These reports have facilitated the characterization of the clinical features of FNAHT associated with activating TSHR mutations, including the variable severity of hyperthyroidism and goiter, absence of thyroid-associated ophthalmopathy and dermopathy, negative thyroid autoantibodies and absence of lymphocytic infiltration in the thyroid histology (Vaidya et al 2004).…”

Sporadic congenital nonautoimmune hyperthyroidism caused by P639S mutation in thyrotropin receptor gene

“…To date, 15 cases were described associated with 11 different mutations of this gene [6][7][8] that may cause a wide range of clinical consequences associated with this condition. Although there are reports of patients with relatively severe courses also in cases of FNAH [4,5,13,17], inherited TSHR mutations usually present later in life with rather mild clinical manifestation. Sporadic TSHR mutations were found to cause severe thyrotoxicosis and goiter with onset in the neonatal period or infancy.…”

Sporadic Nonautoimmune Neonatal Hyperthyroidism Due to A623V Germline Mutation in the Thyrotropin Receptor Gene-Case Report

“…The clinical features of sporadic nonautoimmune hyperthyroidism include earlier onset of thyrotoxicosis and more severe clinical symptoms, which are difficult to control as compared to familial cases (3). However, a severe course in familial nonautoimmune hyperthyroidism has also been reported (4, 5). …”