Genotype–Phenotype Correlation in Germline TSH Receptor Activating Mutation Associated Hyperthyroidism: A Systematic Review
Authors' 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.
Study context
- Population
- Probands with germline TSHR activating mutation-associated hyperthyroidism (GTAMH), sporadic or familial, from the literature plus a 25-year-old woman with TSHR p.Ile640Val variant and subclinical hyperthyroidism
- Participants
- 82 probands
- Comparison
- Infantile- vs childhood- vs adult-onset GTAMH
- Infantilen = 36
- Childhoodn = 33
- Adulthoodn = 13
- Outcome
- Familial cases
Methodological detailsclassification by age of symptom onset, includes one case managed at authors' centre
- Classification by age of symptom onset
- Includes one case managed at authors' centre
Pooled result
As reported in the abstract
P = 0.00
- Different TSHR variants among probands
- 47
Further pooled results
| Outcome | Infantile | Childhood | Adulthood |
|---|---|---|---|
| Median serum free-T3 | median 3.1 XULN | median 1.6 X-ULN | median 1.2 X-ULN |
| Median serum free-T4 | median 3.4 XULN | median 1.9 X-ULN | median 0.8 X-ULN |
Hyperthyroidism type
- Adult-onset cases subclinical
- 1/3
- All infant/childhood onset probands had overt hyperthyroidism
Recurrent variants exclusive to one onset group
- Recurrent variants exclusive to infantile, childhood or adult-onset group (except p.Ser505Asn, p.Asp619Gly and p.Asn670Ser)
- 15/18
Correlation of age at diagnosis (probands and genetically affected family members)
- Among family members, r (p = 0.00)
- 0.40
- Among members of multiple families with the same TSHR variants, r (p = 0.00)
- 0.46
- Moderate correlation
Original publication
Genotype–Phenotype Correlation in Germline TSH Receptor Activating Mutation Associated Hyperthyroidism: A Systematic Review. Clin Endocrinol (Oxf). Published 5 June 2025. doi:10.
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