Clinical, immunological, treatment characteristics, and outcomes in 22 patients with major histocompatibility complex class II deficiency

Background Major histocompatibility complex (MHC) class II deficiency is a rare, life-threatening primary immunodeficiency that presents in early infancy with a SCID phenotype. However, emerging data indicate substantial clinical and immunological heterogeneity, including atypical presentations and neurological involvement. Methods We retrospectively evaluated the clinical, immunological, genetic, and treatment-related characteristics and outcomes of 22 patients from 19 unrelated families diagnosed with MHC class II deficiency at a single referral center (2000–2019). Ten patients underwent HSCT at our center; transplant-related outcomes were evaluated, and long-term follow-up data were available for the six surviving patients through 2025. Results The median age at symptom onset and diagnosis was 9 and 12 months, respectively. Pneumonia, chronic diarrhea, and failure to thrive were the most common presenting features; neurological manifestations and developmental delay were observed in a subset of patients. Two patients showed residual HLA-DR expression and survived with a milder clinical course. CD4 + T cell lymphopenia and humoral dysfunction were consistent, while total lymphocyte counts were variable. RTE levels were mildly to moderately reduced in all tested patients, suggesting impaired thymic output. Severe viral infections were frequent and could be rapidly fatal. Fourteen patients required PICU admission, associated with high mortality. Genetic analysis (n:15) identified homozygous pathogenic variants in RFXANK (n=5), RFXAP (n=4), RFX5 (n=3), and CIITA (n=3). Ten patients underwent HSCT, with superior survival compared to non-transplanted patients (60% vs. 18%). Among transplanted patients, survival appeared higher following RTC than MAC (75% vs. 50%). Post-transplant mortality was observed in association with severe pre-transplant disease, delayed diagnosis, graft failure, and infectious complications. At ≥10 years post-HSCT, all survivors were IVIG-independent; CD4 + T cell recovery was higher after MAC than RTC, while T-cell chimerism remained mixed in both groups. Conclusion MHC class II deficiency is a SCID-like pediatric immunological emergency that is fatal without HSCT in most patients. Early diagnosis is critical, as initial infections may be rapidly progressive. HSCT provides durable engraftment and sustained clinical stability in long-term survivors. Incorporating HLA-DR expression analysis into first-line immunological screening, even in the absence of profound lymphopenia, may facilitate earlier diagnosis, prompt HSCT referral, and improve survival.