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

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Germline TSHR activating mutation-associated hyperthyroidism (GTAMH) presents as sporadic or familial forms.
• Existing studies show a weak correlation between TSHR receptor activity and clinical manifestations of GTAMH.
• A knowledge gap exists in fully understanding the genotype-phenotype relationships in GTAMH.

Purpose of the Study:

• To classify GTAMH based on the age of symptom onset: infantile, childhood, and adulthood.
• To analyze demographic, clinical, biochemical, and genotype-phenotype correlations within these classifications.
• To improve the understanding of GTAMH and guide patient management.

Main Methods:

• Systematic literature review of 82 GTAMH probands.
• Classification of patients by age of onset: infantile (n=36), childhood (n=33), and adulthood (n=13).
• Analysis of demographic, clinical, biochemical data, and TSHR variant genotypes for genotype-phenotype correlation.

Main Results:

• 47 different TSHR variants were identified in 82 probands.
• Infantile-onset GTAMH was less often familial (19.4%) compared to childhood (93.9%) and adult-onset (84.6%).
• Median serum free-T3 and T4 levels were highest in infantile-onset, followed by childhood, and then adult-onset cases, with a moderate correlation observed for age at diagnosis within families (r=0.40) and across families with the same variant (r=0.46).

Conclusions:

• A phenotypic classification of GTAMH into infantile-onset severe hyperthyroxinemia, childhood-onset overt hyperthyroidism, and adulthood-onset overt/subclinical hyperthyroidism correlates with TSHR variant genotypes.
• This classification, particularly noting de novo variants in infantile cases, provides a framework for understanding GTAMH.
• The proposed classification may assist in guiding patient management strategies for GTAMH.