ReviewGenetics and phenomics of inherited and sporadic non-autoimmune 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
References (66)
- et al.
The human thyrotropin receptor activates G-proteins Gs and Gq/11
J. Biol. Chem.
(1994) - et al.
Management of neonatal endocrinopathies—best practice guidelines
Early Hum. Dev.
(2007) - et al.
Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism
J. Pediatr.
(1997) - et al.
Expression of beta-arrestins in toxic and cold thyroid nodules
FEBS Lett.
(2000) - et al.
Persistent neonatal thyrotoxicosis in a neonate secondary to a rare thyroid-stimulating hormone receptor activating mutation: case report and literature review
Endocr. Pract.
(2008) - et al.
A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism
Eur. J. Endocrinol.
(2001) - et al.
A family with a novel TSH receptor activating germline mutation (p.Ala485Val)
Eur. J. Pediatr.
(2008) Recommendations for a nomenclature system for human gene mutations
Hum. Mutat.
(2002)- et al.
Similarities and differences in the phenotype of members of an Italian family with hereditary non-autoimmune hyperthyroidism associated with an activating TSH receptor germline mutation
J. Endocrinol. Invest.
(2002) - et al.
The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism
J. Clin. Endocrinol. Metab.
(2001)