Improved transplant survival and long-term disease outcome in children with MHC class II deficiency

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

MHC Class II Deficiency with Normal CD4+ T Cell Counts: A Case Report

Major histocompatibility complex (MHC) class II deficiency is a rare primary immunodeficiency disorder (PID) with less than 200 cases worldwide. Here, we report an 8 month–old girl with MHC class II deficiency with a novel homozygous mutation in RFXANK gene (NM_001278728: exon 5: c.495G>A: p.Trp165*) and normal CD4+ T cell counts, diagnosed by whole exome sequencing (WES) and negative HLA–DR proteins on peripheral blood mononuclear cell (PBMC) in flow cytometry. She was referred with pneumonia, prolonged fever, resistance to antibiotics (ceftriaxone, clindamycin, and vancomycin), and low serum immunoglobulin (IG) levels, while natural killer (NK), B, and T cells were normal. She received intra-venous immune-globulin (IVIG) replacement, broad spectrum antibiotics, and anti-fungal treatments. The presented case report is interesting not only because of the rarity of the PID but also due to normal CD4+ T cell counts. According to our experience, we suggest that physicians consider MHC class II deficiency in families with consanguineous marriages, even with normal CD4+ T cell counts. At the first, the diagnosis of the disease could be successfully perform using WES, and finally, treatment with hematopoietic stem cell transplantation can save the patients’ lives.

A novel homozygous mutation in CIITA resulting in MHC Class II deficiency in an adult patient

Introduction: Major histocompatibility (MHC) class II deficiency is a rare autosomal recessive primary immunodeficiency with fewer than 200 patients reported worldwide. Patients usually present within their first year of life with severe and recurrent infections, failure to thrive, and chronic diarrhea. The disorder is caused by absent or reduced MHC class II expression on cell surfaces, leading to defective cellular and humoral immune responses. The disease is associated with a poor prognosis, with most patients dying in early childhood due to infectious complications. Aim: To report the clinical, immunological, and genetic features of an adult patient with MHC class II deficiency who did not undergo hematopoietic stem cell transplant (HSCT). We also explore proposed theories as to why some patients with MHC class II deficiency survive to adulthood, beyond the typical life expectancy. Results: We present a 23-year-old gentleman who was diagnosed with MHC class II deficiency at the age of 6 months based on a near complete absence of Human Leukocyte Antigen - DR isotype on peripheral blood mononuclear cells and CD4+ lymphopenia. He is one of a few patients with the condition reported in the literature to have survived to adulthood despite not having undergone HSCT. Next generation sequencing revealed a novel homozygous mutation in the CIITA gene, 1 of 4 genes involved in the regulation of MHC class II transcription. Discussion: MHC class II deficiency is considered a single entity phenotypic condition where the main problem lies in reduced or absent MHC class II expression and results in downstream immunologic effects, including CD4+ lymphopenia and impaired antigen specific responses. However, phenotypic differences between patients are emerging as more cases are described in the literature. Our patient, now 23 years old, has survived significantly beyond life expectancy despite not having HSCT. Statement of novelty: We describe a case of an adult patient diagnosed with MHC class II deficiency due to a novel homozygous intronic splice site variant in the CIITA gene.