Suppressor of cytokine signaling 1 haploinsufficiency in a patient with granulomatous lymphocytic interstitial lung disease and inflammatory bowel disease-like disease.

Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is an inborn error of immunity with dysregulated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling and heterogeneous autoimmune, infectious, and inflammatory phenotypes; its spectrum and management remain unclear. We report a 29-year-old woman with a novel heterozygous SOCS1 variant (c.494C>T; p.Pro165Arg) identified by whole-exome sequencing. Variant impact was assessed in silico (combined annotation dependent depletion, conservation mapping, AlphaFold3, and PremPS) and functionally by measuring total and phosphorylated STAT1 (p-STAT1) expression in patient vs control cells at baseline and after interferon-γ stimulation. We also reviewed data from 20 previously reported SOCS1-deficient patients. The patient had granulomatous lymphocytic interstitial lung disease (GLILD), rheumatoid arthritis, inflammatory bowel disease-like enteropathy, and hypogammaglobulinemia, initially diagnosed with common variable immune deficiency. GLILD responded to rituximab; sirolimus was ineffective for enteropathy. Segregation revealed an asymptomatic father carrying the same variant. The patient was found to have an additional heterozygous TACI gene variant. Poststimulation flow cytometry showed higher STAT1 [24.7 vs 5.8 median fluorescence intensity (MFI)] and p-STAT1 (43.4 vs 2.4 MFI) levels; however, these differences were not statistically significant (P > 0.05). Structural modeling predicted Src homology 2 domain destabilization (ΔΔG + 1.16 kcal/mol). Literature synthesis for SOCS1 deficiency patients (n = 21) showed median symptom onset of 8 years (range 5 months to 44 years), autoimmune diseases (immune thrombocytopenia, psoriasis, etc.), and frequent immunophenotypic abnormalities: lymphopenia 4/8 (50%); high IgE 5/7 (71.4%); low CD3+ 11/17 (64.7%); CD4+ 6/19 (31.5%); CD8+ 5/17 (29.4%); B cells 5/17 (29.4%); and natural killer (NK) cells 4/19 (21%). SOCS1 haploinsufficiency presents heterogeneous phenotypes with variable penetrance. Early genetic testing and targeted interventions, such as JAK inhibitors or cytokine-blocking biologics, may improve outcomes.