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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4090-4097.
Prepublished online as a Blood First Edition Paper on August 26, 2008; DOI 10.1182/blood-2008-04-153361.
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Submitted April 25, 2008
Accepted August 10, 2008
Clinical and immunological consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency
Carsten Speckmann, Ulrich Pannicke, Elisabeth Wiech, Klaus Schwarz, Paul Fisch, Wilhelm Friedrich, Tim Niehues, Kimberly Gilmour, Karin Buiting, Michael Schlesier, Hermann Eibel, Jan Rohr, Andrea Superti-Furga, Ute Gross-Wieltsch, and Stephan Ehl*
Center for Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg
Institute for Transfusion Medicine, University Hospital Ulm, Ulm
Institute for Pathology, University of Freiburg, Freiburg
Department of Paediatrics and Adolescent Medicine, University Hospital, Ulm, Ulm
Kinderklinik, Helios Kliniken Krefeld, Krefeld
Molecular Immunology Unit, Institute of Child Health, University College London, London
Institute for Human Genetics, University Hospital Essen, Essen
Medical Center, Department of Rheumatology and Immunology, University of Freiburg, Freiburg
Department of Haematology and Oncology, Olgahospital, Stuttgart
* Corresponding author; email: stephan.ehl{at}uniklinik-freiburg.de.
X-linked severe combined immunodeficiency is a life-threatening disorder caused by mutations in the gene encoding the interleukin-2 receptor gamma chain (IL2RG). Hypomorphic mutations and reversion of mutations in subpopulations of cells can result in variant clinical phenotypes, making diagnosis and treatment difficult. We describe a 5 year old boy with mild susceptibility to infection, who was investigated for a mutation in IL2RG due to persistent NK and T cell lymphopenia. A functionally relevant novel T466C point mutation was found in B, NK and epithelial cells, while  / and  / T cells showed the normal gene sequence, suggesting reversion of the mutation in a common T cell precursor. This genetic correction in T cells resulted in a diverse T cell repertoire and significant immunity despite failure to produce specific antibodies linked to an intrinsic defect of mutant B cells. These observations confirm the potential of revertant T cell precursors to reconstitute immune function, but questions remain on the longevity of revertant cells implicating the need for careful follow-up and early consideration of HSCT
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