ESPE Abstracts

Background: Congenital thyroid dysgenesis usually occurs sporadically and may even be discordant in monozygotic twins. However, when caused by inactivating mutations in the TSH receptor (TSHR) it can be inherited recessively, typically resulting in thyroid gland hypoplasia. We present a new familial case of thyroid dysgenesis with two siblings of consanguineous parents. The daughter was identified in neonatal screening with severely elevated TSH and thyroid agenesis on ultrasound. Only when her brother was affected by CH and thyroid hypoplasia and a third child was found to have a hyperthyreotropinemia the diagnosis of a TSHR-mutation was considered.

Objective and Hypotheses: To perform sequencing and functional analysis of the TSHR in the affected family members.

Method: The identified variant p.Ala579Val was tested in cell-systems for signalling capabilities and cell surface expression compared to WT. Furthermore, tight interactions of Ala579 to residues of the second extracellular loop (ECL2) were suggested by a structural TSHR model. This hypothesis was tested by different side chain variations at position 579.

Results: We demonstrated a new TSHR-mutation with complete loss of cAMP and IP signalling and decreased cell surface expression down to 30% affecting the tight interaction within the receptor conformation. Substitutions with more bulky and branched side chains compared to alanine resulted in a complete loss of cAMP and IP signalling. The homozygote clinical phenotype ranged from thyroid agenesis and nearly undetectable thyroglobulin levels in one sibling to a hypoplastic thyroid gland and normal thyroglobulin levels in the other.

Conclusion: The newly identified TSHR-mutation Ala579Val widens the phenotypical spectrum of thyroid dysgenesis to agenesis of the thyroid gland. TSHR-mutations need to be considered also in cases with athyreosis, especially in a consanguineous family. The TSH receptor seems to play a critical role in thyroid development as shown by the variable manifestation in this family.