Familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) and sporadic congenital non-autoimmune hyperthyroidism (SNAH) are rare forms of hyperthyroidism caused by germline mutations in the TSH receptor (TSHR) gene. FNAH and SNAH are caused by constitutively activating TSHR germline mutations. Furthermore, somatic constitutively activating TSHR mutations are found in 60–70% of single hot thyroid nodules, in hot nodules of toxic multinodular goiters, in hot thyroid carcinomas and in small hot areas of euthyroid goiters detected by autoradiography. Moreover, euthyroid hyperthyrotropinemia or primary (thyroidal) congenital hypothyroidism may be caused by inactivating (loss of function) TSHR germline mutations.
In 1999 we have launched the TSH receptor mutation database compiling all reported TSHR mutations with their associated clinical conditions and functional characterizations. An update of the database was done in 2003 and the TSHR database was installed as one of the locus-specific HUGO mutation databases.
10 years after the 2003 revision a further update was performed in 2012. The TSHR database now contains all naturally occurring TSHR mutations reported up to April 2012. The updated 2012 TSHR database is accessible under the address http://tsh-receptor-mutation-database.org with R. Paschke as the curator. Further updates will be performed at 5-year intervals. The present TSHR database also includes the results of several re-analyses of previously reported constitutive activities of several TSHR mutations. Large variations for the extent of constitutive activity for several mutations characterized in different laboratories and several discrepant reports have highlighted the difficulties to determine whether a TSHR mutation is constitutively active or not especially for borderline cases with only a slight increase of the basal cAMP activity.