Review
Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism

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Abstract

TSH receptor (TSHR) germline mutations occur as activating mutations in familial non-autoimmune hyperthyroidism (FNAH) or sporadic non-autoimmune hyperthyroidism (SNAH). Up to date 17 constitutively activating TSHR mutations have been reported in 24 families with FNAH. The diagnosis of FNAH should be considered in cases with a positive family history, early onset of hyperthyroidism, goiter, absence of clinical stigmata of autoimmunity and recurrent hyperthyroidism. Moreover, 14 subjects with sporadic non-autoimmune hyperthyroidism and 10 different TSH receptor germline mutations have been reported. The main characteristic of SNAH is a negative family history. Additional consequences of prolonged neonatal hyperthyroidism (mental retardation, speech disturbances and craniosynostosis) have often been reported in SNAH. No genotype–phenotype relationship has been reported in patients with germline TSHR mutations. There is no association of in vitro activities determined by linear regression analysis (LRA) and several clinical indicators of hyperthyroidism activity for SNAH. However, the comparison of the LRA values of sporadic TSHR mutations with LRA values of familial TSHR mutations does show a significantly higher median LRA value for sporadic as compared to familial autosomal dominant hyperthyroidism. This finding is in line with the clinical impression of a more active clinical course in patients with SNAH. However, additional genetic, constitutional or environmental factors are most likely responsible for the phenotypic variations of the disease and the lack of correlation between in vitro activities of the TSHR mutations and the severity of hyperthyroidism.

Introduction

Overt neonatal hyperthyroidism (HT) is rare and affects only one neonate out of 50,000 (Polak et al., 2006). Although neonatal thyrotoxicosis is a rare entity, it necessitates immediate treatment because of its high mortality (Ogilvy-Stuart, 2002, Radetti et al., 2002) which has been reported to be 12–20%, usually from heart failure (Ogilvy-Stuart, 2002). Neonatal thyrotoxicosis is predominantly caused by maternal Graves’ disease associated with transplacental passage of maternal thyroid-stimulating antibodies (Ogilvy-Stuart, 2002, Radetti et al., 2002, Hung and Sarlis, 2004, Peters and Hindmarsh, 2007) and is less frequently caused by mutations in the stimulatory G protein or in the thyrotropin receptor (TSHR) inducing constitutive activation of intracellular signaling cascades. The prevalence of Graves’ disease in pregnant women is estimated to about 0.2%; however, only 1% of the babies born to mothers with Graves’ disease develop neonatal Graves’ disease (Polak, 1998, Ogilvy-Stuart, 2002). Neonatal thyrotoxicosis is a transient disorder and disappears with the clearance of the maternal antibodies (half life about 14 days) from the neonate serum within the first 4 months of life. Fetal tachycardia, increased fetal motility and intrauterine growth retardation are consequences of fetal thyrotoxicosis. Prematurity is frequent. Tachycardia, goiter, hyperexcitability, poor weight gain, hepatomegaly, growth retardation, craniosynostosis, accelerated bone maturation, splenomegaly, stare and eyelid retraction are among the most frequent clinical signs noticed after birth (Polak, 1998, Lafranchi and Hanna, 2005). The patients with neonatal thyrotoxicosis should be treated promptly either with methimazole (MMI) or propylthiouracil (PTU). Propranolol is helpful in slowing the heart rate down and in reducing hyperactivity. Glucocorticoids should be given to patients with severe neonatal thyrotoxicosis in order to inhibit the extrathyroidal conversion of T4 to T3 and to inhibit thyroid hormone secretion from the thyroid gland (Lafranchi and Hanna, 2005).

An even more uncommon type of neonatal hyperthyroidism results from mutations in the stimulatory G protein or the thyrotropin receptor (TSHR) causing constitutive activation of intracellular signaling cascades. These mutations may be inherited as autosomal dominant non-autoimmune hyperthyroidism (NAH) (also called familial or hereditary NAH) or occur sporadically as denovo mutations (also called congenital NAH or sporadic NAH) (Gozu et al., 2009a, Gozu et al., 2009b). Table 1, Table 2 show references of all cases of SNAH and FNAH reported up to date. These germline mutations are predominantly localized in the transmembrane segments of the TSHR (see Fig. 1).

Section snippets

Constitutive activation of TSH receptor signaling induces hereditary and sporadic non-autoimmune hyperthyroidism

The TSH receptor (TSHR) belongs to the superfamily of seven transmembrane domain receptors coupled to G proteins (Kopp, 2001, Rodien et al., 2003). This gene is encoded by 10 exons which spread over 60 kb on chromosome 14. The large part of the extracellular domain is encoded by nine exons. The carboxyterminal part of the extracellular domain (EC), the seven transmembrane domains (TMDs) and intracellular loops (ICLs) are encoded by exon 10. The polypeptide backbone is 764 amino acids in length (

Clinical hallmarks of inherited non-autoimmune hyperthyroidism

Although various features have been described in different families, they share the common characteristics:

Clinical and biochemical stigmata of thyroid autoimmunity are absent in familial non-autoimmune hyperthyroidism. No circulating thyroid antibodies (including TSH receptor antibodies) were detected in these patients.

A positive family history for NAH is the pathognomonic feature of FNAH. Familial non-autoimmune hyperthyroidism segregates in the families with constitutively activating TSHR

Clinical hallmarks of sporadic non-autoimmune hyperthyroidism

Clinical characteristics of the subjects with sporadic non-autoimmune hyperthyroidism are described in Table 2, Table 3 (see also http://innere.uniklinikum-leipzig.de/tsh/for further details).

Sporadic non-autoimmune hyperthyroidism is more severe than familial autosomal dominant hyperthyroidism

The family history for non-autoimmune hyperthyroidism is negative in sporadic non-autoimmune hyperthyroidism. The phenotype of a patient with congenital sporadic hyperthyroidism was first described by Kopp et al. (1995). A thymidine to cytosine (T to C position) transition causing the substitution of leucine (CTC) for phenylalanine (TTC) at position 631 in one allele was identified in the DNA from the patient's leucocytes and nodular thyroid tissue. This mutation could not be detected in the

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