Resistance to thyrotropin (TSH) (RTSH; defined by elevated TSH and a normal or hypoplastic thyroid gland) can be caused by mutations in genes encoding the TSH receptor and PAX8, and it has been linked to a locus on chromosome 15.
Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH).
Complete TSH resistance due to biallelic LOF TSHR mutations must be suspected in all patients with severe not syndromic CH and severe thyroid hypoplasia diagnosed at birth by neonatal screening.
The second one had a neonatal persistent moderate TSH levels increase associated with a thyroid gland hypoplasia and was treated with L-T4 since the first months of life.These two cases support the recent association of TSH-R mutations inheritance as an autosomal dominant pattern with variable expressivity and suggest that the decision to start replacement therapy in patients with persistent SH due to TSH resistance should be individualized.
Nonpolymorphic alterations in the TSHR gene are commonly associated with isolated NAHT in young patients, thus configuring partial TSH resistance as the most frequent inheritable cause of isolated NAHT.
In vitro effects of the mutations on cAMP production and TSH binding were investigated in COS7 cells. cAMP production was evaluated by transfecting a cAMP response element (CRE)-luciferase reporter with pSVL-TSHR and pSVK3-GNAS vectors.
Mutations in TSH receptor (TSHR) are notoriously associated with congenital hypothyroidism as well as with non-autoimmune subclinical hypothyroidism, a mild form of TSH resistance that is not as well characterized by diagnostic procedures.
To date, 23 inactivating mutations of the TSH receptor (TSHR) gene have been proven responsible for the clinical condition, but an absence of mutations in the TSHR gene has been reported for several cases of TSH resistance as well.
Inactivating mutations in the TSH receptor can be associated with severe TSH resistance presenting as congenital hypothyroidism with apparent athyreosis.