Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT

Introduction Biallelic loss-of-function mutations in the GTPase of immunity-associated protein 5 ( GIMAP5 ) cause a severe syndrome characterized by altered immunity, lymphoproliferation, and progressive hepatopathy. This study aims to delineate the immunophenotypic signatures and clinical management of this deficiency by reporting the first Italian pediatric case alongside his mono-allelic carrier twin, integrated with a review of twenty previously published patients. Methods We utilized trio-based clinical exome sequencing, flow cytometric immunophenotyping, protein expression profiling, and curated database analysis to evaluate the clinical trajectories. Results The 11-year-old proband presented with autoimmune cytopenias, severe viral infections, and early biochemical liver anomalies. Genetic analysis identified compound heterozygous variants (p.Leu204Pro and p.Arg214Ter) in GIMAP5 gene resulting in absent protein expression, alongside an expanded atypical memory B-cell population and T-cell exhaustion. Notably, his dizygotic twin harbored the heterozygous p.Leu204Pro variant and exhibited decreased protein expression coupled with a localized fibro-adipose vascular anomaly, but lacked immune defects. Discussion This observation suggests complex genotype-phenotype interactions, raising the question of whether partial GIMAP5 deficiency might subtly predispose to localized vascular anomalies under specific environmental or epigenetic conditions, likely requiring multi-hit mechanisms. Therapeutically, the proband achieved sustained clinical remission of cytopenias through immunomodulation with the mTOR inhibitor sirolimus. These findings expand the phenotypic spectrum of this disorder, underscoring a dual role in immune and endothelial homeostasis. Furthermore, the successful application of sirolimus highlights the efficacy of precision medical management as a viable strategy to stabilize patients, allowing time to carefully weigh the risks and benefits of definitive interventions, such as hematopoietic stem cell transplantation.