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* Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
Institute for Pathology, University of Freiburg, Freiburg, Germany;
Transfusion Medicine, University Hospital and Institute for Clinical Transfusion Medicine and Immunogenetics, Ulm, Germany;
Institute of Human Genetics, Würzburg, Germany;
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Children’s Hospital, University of Ulm, Ulm, Germany; and
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St. Annastiftskrankenhaus, Ludwigshafen, Germany
DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and 
T cells 10-fold, whereas 
T cells were normal. Spectratyping of all three cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more extensive nucleotide deletions among D and J elements and fewer N nucleotide insertions. Clonal restriction of IgG-expressing, but not IgM-expressing, B cells and the lack of primary and secondary lymph node follicles indicated impaired class switch recombination. Observations in the older sibling showed that this rudimentary immune system was able to mount specific responses to infection. However, partial Ab responses and extensive amplification of T cells could not prevent a life-threatening course of viral and bacterial infections, the development of an EBV-induced lymphoma, and immune dysregulation reflected by severe autoimmune cytopenia. Impaired generation of immune diversity under conditions of limited LigIV activity can cause a human SCID variant with a characteristic immunological phenotype.
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