The Complexity of Patients with STAT Pathway Immunodeficiency

Background Patients with STAT pathway immunodeficiency have a diverse phenotype, presenting a challenge in establishing treatment guidelines. HSCT is often reserved for complicated and young patients. JAK inhibitors provide an important therapeutic option, yet data on the benefits and optimal patient selection are lacking. Objective To evaluate the spectrum of patients with STAT pathway immunodeficiency and immune dysregulation and the therapeutic experience with Jakinhibs and other therapeutic options. Methods We included patients followed by the immunology service at Schneider's Children Medical Center of Israel. Clinical, laboratory, genetic, and therapeutic data were gathered. Results 9 patients, all of which had different STAT pathway mutations, were followed during the study period 2012-2024. 5 had STAT1 GOF mutations, 1 had partial STAT1 LOF, 2 had STAT3 GOF mutations, and 1 had STAT3 LOF HIGES. The clinical presentation of patients with STAT1 GOF mutations was varied, from a severe neonatal course to a more typical course of mucocutaneous candidiasis. 3/5 of the patients with STAT1 mutations suffered from CMV viremia, 4/5 had significant bowel disease, and 3/5 had NTM infection. One patient underwent a successful HSCT. 2 patients were successfully treated with Ruxolitinb. 2 patients had severe esophagitis due to Candida albicans infections. Both had evolved to Candida strains resistant to azoles. One patient received oral amphotericin and the other is currently on IV Caspofungin. He is now starting Ruxolitinib treatment and underwent balloon dilatation of the esophagus. 2 patients had severe neurological manifestations of chronic meningitis and peripheral neuropathy. Increased ICP occurred in 2 patients. Both patients with STAT3 GOF presented with immune cytopenias. Both were treated with Ruxolitinib. One stopped treatment due to significant weight gain. Conclusion STAT mutations causing immunodeficiency and immune dysregulation cause significant morbidity. Resistant C. albicans esophagitis, CMV and NTM infections, and enteropathy were the major symptoms of STAT1 mutations in our cohort, whereas immune cytopenias and lymphoproliferation were the common presenting picture in patients with STAT3 GOF. 3 patients suffered from severe neurological complications. Ruxolitinib therapy is effective but not without side effects. One patient presenting and diagnosed before one year of age underwent successful bone marrow transplantation Table 1.