We also use radiation sensitivity testing on cultured skin fibroblasts to aid in the phenotypic characterization by identifying the radiation-sensitive varieties of SCID. In the majority of cases, a precise molecular genetic diagnosis can be made on the basis of the phenotype. The different genetic defects can be categorized according to pathways affected by the molecular defect ( Table 1) or by the specific immunologic phenotype arising from the genetic defect ( Figure 1). The genetic basis of at least 18 different forms of SCID has now been identified 2-18 (summarized in Table 1), and in all cases, the defect leads to a failure of T-cell development or function. Genetic basis and immunologic phenotype of the different forms of SCID For this reason, while we will outline some generic issues regarding HSCT in SCID, we will also look more closely at how transplant strategies can be tailored to the different forms of SCID. However, the rapid advances in gene identification technology now allow us to make a genetic diagnosis in the vast majority of SCID patients, and we increasingly base our HSCT strategy on the underlying genetic defect. Many of the major studies have tended to look at SCID as a whole, and outcomes have been presented for all types of SCID. The improvements are due to a number of different factors, including earlier diagnosis, better pre- and post-HSCT supportive care, improved HLA typing, the availability of compatible donors from unrelated volunteer and cord blood banks, and less toxic chemotherapy regimens to prepare patients for HSCT. Over the past several decades, the outcome for SCID as a whole has improved dramatically, and a number of large retrospective registry studies have documented the success in improving overall survival (OS) and immunologic recovery. The first ever successful transplant for SCID was performed in 1968. Gene therapy offers a cure for two specific forms of SCID and, although other SCID forms may become amenable to this form of treatment in the future, it is likely that HSCT will continue to be the mainstay of treatment of the majority of SCID patients. The severity of the clinical and immunologic phenotype requires prompt intervention, and for most patients, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). 1 The genetic defects in approximately 90% of the different forms of SCID have now been identified and, despite genetic heterogeneity, all patients are characterized by abnormalities of thymopoiesis and T-cell maturation and function. Affected infants present in the first few months of life with severe, recurrent, and opportunistic infections, and without definitive treatment, the condition is invariably fatal. Severe combined immunodeficiencies (SCIDs) are a genetically heterogeneous group of inherited defects characterized by severe abnormalities of immune system development and function. These developments together with the advent of universal newborn screening for SCID should allow for a highly favorable outcome for this otherwise lethal condition. The development of autologous hematopoietic stem cell gene therapy provides another treatment of the X-linked and adenosine deaminase–deficient forms of SCID, and we discuss how we have integrated gene therapy into our treatment strategy. We aim to use matched related and unrelated donors (including cord blood) whenever possible and have limited the use of mismatched haploidentical donors. Wherever possible, we attempt to transplant SCID patients without the use of cytoreductive conditioning, but it is clear that this is only successful for specific SCID forms and, although survival is good, in specific patients there are ongoing humoral defects. Advances in understanding the genetic basis of disease also mean that we increasingly tailor transplant protocols to the specific SCID form. Numerous multicenter studies have identified the factors determining successful outcome, and survival for SCID has shown great improvement. Allogeneic hematopoietic stem cell transplantation is an extremely effective way of restoring immunity in these individuals. Severe combined immunodeficiency (SCID) arises from different genetic defects associated with lymphocyte development and function and presents with severe infections.
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