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Severe combined immunodeficiency—molecular pathogenesis and diagnosis
  1. H B Gaspara,
  2. K C Gilmourb,
  3. A M Jonesc
  1. aMolecular Immunology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, bClinical Immunology Laboratory, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children NHS Trust, London, UK, cDepartment of Immunology, Great Ormond Street Hospital for Children NHS Trust
  1. Dr Gasparh.gaspar{at}

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Severe combined immunodeficiencies (SCID) are a heterogeneous group of inherited disorders characterised by profound abnormalities in T, B, and natural killer cell development and function.1 They arise from a variety of molecular defects, and the deficits in both cell mediated and humoral immunity lead to similar presentations in all the defined conditions. Children characteristically present with failure to thrive, recurrent infections, and increased susceptibility to opportunistic infection. The age of presentation is variable but occurs typically between 3 and 6 months when the protective effect of maternally transmitted immunoglobulin has diminished, although atypical and late presentations are well described.

 Over the past 10 years there have been enormous advances in the understanding of the molecular basis of the different forms of SCID (see table 1). These have led to several improvements in diagnosis and management. Firstly, unambiguous assignment of a molecular diagnosis is now possible in many cases. This is particularly important in children who have evidence of combined (cellular and humoral) immunodeficiency, but with “milder” clinical phenotypes than infants with classical SCID. Some of these children are found to have identical molecular defects to those causing SCID, and in these cases the long term outlook is now known to be poor enough to justify bone marrow transplantation (BMT) at an early stage. Secondly, accurate carrier detection and first trimester prenatal diagnosis are possible in any family where the precise mutation has been defined. In some cases prenatal diagnosis of an affected fetus may not lead to termination of pregnancy, but can allow preparation for BMT early in the neonatal period, or even in utero in selected cases.2 Thirdly, knowledge of the genetic defect has allowed a greater understanding of the molecular pathogenesis of the disease with the possibility of designing more rational therapies in some cases, and …

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