Sporadic Congenital Hyperthyroidism due to a Spontaneous Germline Mutation in the Thyrotropin Receptor Gene*

Abstract

Neonatal hyperthyroidism in the absence of maternal autoimmune thyroid disease and without thyroid-stimulating antibodies in the child is rare. We here describe a boy with severe intrauterine hyperthyroidism and advanced bone age in the absence of thyroid-stimulating autoantibodies. After long term antithyroid treatment and relapse of hyperthyroidism, a near-total thyroid resection was performed. The necessity to progressively decrease postoperative thyroid hormone replacement indicates thyroid tissue regrowth in the small thyroid remnant. Analysis of the genomic DNA of the child's peripheral leukocytes showed a G to A base exchange that led to a heterozygous Ser to Asn conversion at position 505 in the third transmembrane region of the TSH receptor (TSHR). The absence of the Ser505 Asn mutation in all other family members identifies the child's TSHR mutation as a sporadic germline mutation. Transient expression of the mutated TSH receptor in COS-7 cells showed a constitutively activated cAMP cascade. We thus identified a new constitutively activating germline mutation. Neonates with persistent nonautoimmune hyperthyroidism should be investigated for TSHR germline mutations. Because of frequent relapses, patients with sporadic congenital nonautoimmune hyperthyroidism should be treated with early subtotal to near-total thyroid resection. Moreover, post-operative radioiodine treatment should be considered.

Sporadic Congenital Hyperthyroidism due to a Germline Mutation in the Thyrotropin Receptor Gene (Leu 512 Gln) in a Japanese Patient

“…Based on the previous reports of sporadic congenital nonautoimmune hyperthyroidism [3][4][5][6][7][8][9][10][11] (Table 1), almost all cases were marked by premature delivery and the onset of hyperthyroidism within 1 year. In cases who were poorly controlled with antithyroid therapy, surgery was performed before the age of 10 years [3,[5][6][7][8][9][10]. The most common clinical findings in these patients were marked bone age acceleration, causing abnormality of bone structure in several cases [5][6][7].…”

“…In cases who were poorly controlled with antithyroid therapy, surgery was performed before the age of 10 years [3,[5][6][7][8][9][10]. The most common clinical findings in these patients were marked bone age acceleration, causing abnormality of bone structure in several cases [5][6][7]. When the exophthalamus is detected at the onset of hyperthyroidism, it usually does not progress during the years of follow-up, but resolves after antithyroid drug therapy [4,5,7,10].…”

“…These mutant regions of TSHR which are the molecular basis for nonautoimmune hyperthyroidism overlap with those of toxic thyroid nodules, suggesting the same mechanism of constitutive activation of TSHR by permanent activation of the cAMP cascade that stimulates the growth and function of thyrocytes. De novo activating TSHR germline mutations have been reported in 9 cases as the cause of sporadic congenital nonautoimmune hyperthyroidism [3][4][5][6][7][8][9][10][11]. The clinical features of sporadic nonautoimmune hyperthyroidism are the earlier onset of thyrotoxicosis and more severe thyrotoxicosis, which is difficult to control with antithyroid drug therapy, than that of familial cases [12].…”

Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism

“…Further work is required to determine the true nature of this mutation. Another mutation, Ser-505<Asn, has been detected as a sporadic heterozygous germline mutation in four previous human studies (Schwab et al 1996, Holzapfel et al 1997b, Fuhrer et al 1999, Wonerow et al 2000, and also reported as a somatic heterozygous mutation in human hyperthyroidism (Trulzsch et al 2001).…”

The Clinical Spectrum of Thyrotropin Receptor Gene (TSHR) Mutations

“…The presence of either congenital or adulthood-onset hyperthyroidism, multinodular goiter (MNG) and follicular carcinoma has been reported in the same family (Karges et al, 2005). To date, more then 55 germline gainof-function mutations have been reported, about 14 of them sporadic and the others with familial occurrence (http: www.hgmd.cf.ac.uk/ac/gene.php?gene=TSHR) (Akcurin et al, 2008;Davies et al, 2005;Farid et al, 2000;Führer et al, 1997(b);Holzapfel et al, 1997;Karges et al, 2005;Khoo et al, 1999;Tonacchera et al, 1996;Van Sande et al, 1995). Hyperthyroidism in affected individuals is often resistant to the conventional treatment used in Graves' disease, and either radiotherapy or total thyroidectomy is required.…”