From Severe Combined Immunodeficiency to Omenn syndrome after hematopoietic stem cell transplantation in a RAG1 deficient family

Background:  Mutations in RAG genes cause a spectrum of severe immunodeficiencies ranging from Severe Combined Immunodeficiency(SCID) T-B-NK+ to Omenn syndrome(OS) through intermediate phenotypes, even for the same alteration. Nowadays, hematopoietic stem cell transplantation (HSCT) is the unique curative treatment available. Methods:  We describe three related patients from a Moroccan consanguineous family. Patient 1 developed at 1 month of age moderate eczematous dermatitiswith eosinophilia, followed by infections and enteritis. He was transplanted and received reduced intensity conditioning regimen previous to HSCT. His brother, patient 2, was born preterm with a severe neonatal erythroderma, hepatosplenomegalyand lymphadenopathy. Patient 3, cousin of the two siblings, was also born preterm and fulfilled all criteria for classical OS. Immunologicalevaluation was performed and RAG genes were sequenced. Results:  Immunologicaldata from all three patients were very diversed, from T lymphopenia to marked lymphocytosis, and different degrees of eosinophiliaand IgE levels. Non-responder T cells and absent B cells were constant. All patients presented the same homozygous mutation in RAG1 gene (c.631delT). Patient 1 fully recovered both clinically and immunologicallyafter HSCT. Two years later, he lost the accomplished lymphoid chimera and the disease relapsed as a classical OS, leading to patient’s death. Conclusions:  This is the first report of a RAG1 deficient patient with a changed clinical and immunologicalphenotype from SCID to OS after HSCT. The use of a myeloablative conditioning regimen that eliminates reminiscent T cells might have improved patient’s outcome and it should be considered in similar cases.