Advances in genetic and molecular understanding of Omenn syndrome - implications for the future

Abstract

ABSTRACTIntroduction: Omenn syndrome is a rare form of leaky severe combined immunodeficiency, characterized by a widespread thickened exfoliating, protein-losing erythrodermic rash, with scaling with severe alopecia associated with widespread lymphadenopathy and hepatosplenomegaly. Unravelling the pathophysiology has revealed new understandings of the immune system.Areas covered: The description of the clinical phenotype was followed by case descriptions of the immunopathology, description of the genetic defects and realization that Omenn syndrome was a form of severe combined immunodeficiency, with features of severe autoimmunity due to a loss of central and peripheral tolerance. Differences in recombinase activity lead to variable immunological and clinical phenotypes.Expert opinion: As Omenn syndrome is a form of severe combined immunodeficiency, universal introduction of newborn screening will have a significant impact on outcome, as earlier diagnosis will favor better transplant results. Natural killer cells display an immature phenotype, contain a higher content of perforin and demonstrate enhanced degranulation which may mediate allograft rejection, and so addition of serotherapy directed against Natural Killer cells to conditioning protocols may improve outcome. Finally, murine models utilizing genetic correction of autologous stem cells have demonstrated efficacy in curing disease and clinical trials are now in progress.