Genotype-Phenotype Correlation in Germline TSH Receptor Activating Mutation Associated Hyperthyroidism: A Systematic Review.

Objective: Germline TSHR activating mutation-associated hyperthyroidism (GTAMH) manifests as sporadic or familial forms. Studies have shown poor correlation between receptor activity and clinical manifestations, highlighting a knowledge gap in understanding genotype-phenotype relationships.

Design: A classification based on age of symptom onset: infantile (n = 36), childhood (n = 33) and adulthood (> 18 years, n = 13) was attempted by performing a systematic review of literature of GTAMH (n = 82 probands, including a 25-year-old woman with TSHR p.Ile640Val variant and subclinical hyperthyroidism managed at our centre). Patients were analysed for various parameters such as demographic, clinical, biochemical and genotype-phenotype correlation.

Results: Eighty-two probands harbouring 47 different TSHR variants are reported. Probands with infantile-onset were less often familial (19.4%, p = 0.00) than childhood (93.9%) and adult-onset (84.6%) cases. Median serum free-T3 and T4 were highest in infantile (3.1 and 3.4 XULN) followed by childhood (1.6 and 1.9 X-ULN) and adult-onset (1.2 and 0.8 X-ULN) cases. All infant/childhood onset probands had overt hyperthyroidism, whereas 1/3 of adult-onset cases were subclinical. Most (15/18) recurrent variants were exclusive to infantile, childhood or adult-onset disease groups, except for p.Ser505Asn, p.Asp619Gly and p.Asn670Ser. Including data for probands and genetically affected family members, there was a moderate correlation for the age at diagnosis (infancy, childhood or adulthood), among family members (r = 0.40, p = 0.00), and members of multiple families harbouring the same TSHR variants (r = 0.46, p = 0.00).

Conclusion: A phenotypic classification of GTAMH into infantile-onset severe hyperthyroxinemia (mostly due to de novo variants), childhood-onset overt hyperthyroidism or adulthood-onset overt/subclinical hyperthyroidism correlates with the genotype of TSHR variants, may guide patient management.