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Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation. ispartof: BLOOD vol:141 issue:7 pages:713-724 ispartof: location:United States status: published

Nineteen children, of them 11 boys (57,9%) and 8 girls (42,1%) aged from 1,3 to 16 were diagnosed with verified Fanconi`s anemia in the Republic of Belarus in the period from 1992 to 2010. Pathologic skin pigmentation, bone and eye anomalies were the most widespread anomalies in the children`s development. To perform the mutagenic analysis of FANCA gene, DNA from the peripheric blood and marrow mononuclears of 9 patients was extracted. The fragmentary analysis of FANCA gene revealed DNA abnormalities in 2 patients (1-6 exone deletion and 6 exone deletion). The mutation screening of 43 exones of FANCA gene detected mutation in three more patients (exone 19, exone 27, exone 28). Two mutations of 5 detected ones were new. The mutation screening in this group in the combination with FANCA gene mutations in five patients revealed also numerous one-nucleotide polymorphism (SNP), 3 patients revealed only SNP, and one patient had neither mutations nor SNP.

Six boys aged from 4 months to 15 years old were diagnosed with Wiskott-Aldrich syndrome in the Republican Research Centre for Pediatric Oncology and Hematology. All the patients revealed WAS gene mutations. The missence-mutations in exones 2 and 3, detected in 4 patients prevailed in the spectrum of the mutations. WASP was fully absent in lymphocytes and rather a severe course of the disease was observed in all the patients. Only one child with WAS gene mutation in second exone had a mild course of the disease. The mutations were localized in tenth exone in two patients, which is a nonsense of the mutation. The WASP expression was partially preserved in one patient with such mutation.