ESPE Abstracts

Background: The growth and development of human tissues are critically regulated by the Insulin-like Growth Factor 1 Receptor (IGF1R) and its ligand IGF-1. Mutations in the IGF1R gene and less frequently in the IGF1 gene are associated with a heterogeneous group of growth disorders, manifesting as intrauterine and postnatal growth retardation.

Literature Review: In this review, a total of 47 papers were analyzed, providing a comprehensive overview of the genetic complexities associated with IGF1R and IGF1 mutations. These studies encompass a broad spectrum of familial cases, cohort studies, and functional analyses. They reveal a variety of genetic alterations in the IGF1R gene, including missense mutations, deletions, and CNVs, each leading to distinct clinical phenotypes of growth disorders. The phenotypes range from mild to severe growth deficiencies, often accompanied by microcephaly, cognitive impairments, and metabolic anomalies. For instance, certain studies identified specific missense mutations that resulted in aberrant retention of IGF1R in the endoplasmic reticulum, providing new insights into mechanisms of growth inhibition. Others highlighted the role of nonsense-mediated mRNA decay leading to IGF1R haploinsufficiency in familial short stature cases. A comparative analysis between IGF1R mutation carriers and SGA children reveals nuanced differences in growth patterns and responses to rhGH therapy. These comparisons underscore the variability in therapeutic outcomes, which are significantly influenced by the underlying genetic context. Additionally, advancements in diagnostic techniques, such as MLPA and WES, have emerged as crucial tools in identifying and characterizing these mutations, thus enabling more precise and targeted management strategies for affected individuals.

Conclusion: The IGF1R and IGF1 gene mutations contribute significantly to the spectrum of growth disorders, presenting a challenge in both management and treatment. This review highlights the necessity of a personalized approach to diagnosis and treatment, guided by genetic insights. Optimizing treatment protocols, elucidating genotype-phenotype correlations, and assessing long-term therapeutic outcomes are essential steps toward improving care for patients with these complex conditions.

Key words: IGF1, IGF1R, mutation, genotype, phenotype, growth, GH therapy.