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Blood, 1 January 2001, Vol. 97, No. 1, pp. 81-88
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
V(D)J recombination defects in lymphocytes due to
RAG mutations: severe immunodeficiency with a spectrum of
clinical presentations
Anna Villa,
Cristina Sobacchi,
Luigi D. Notarangelo,
Fabio Bozzi,
Mario Abinun,
Tore G. Abrahamsen,
Peter D. Arkwright,
Michal Baniyash,
Edward G. Brooks,
Mary Ellen Conley,
Patricia Cortes,
Marzia Duse,
Anders Fasth,
Alexandra M. Filipovich,
Anthony J. Infante,
Alison Jones,
Evelina Mazzolari,
Susanna M. Muller,
Srdjan Pasic,
Gideon Rechavi,
Maria Grazia Sacco,
Sandro Santagata,
Marlis L. Schroeder,
Reinhard Seger,
Dario Strina,
Alberto Ugazio,
Jouni Väliaho,
Mauno Vihinen,
Larry B. Vogler,
Hans Ochs,
Paolo Vezzoni,
Wilhelm Friedrich, and
Klaus Schwarz
From the Department of Human Genome and Multifactorial
Disease, Istituto di Tecnologie, Biomediche Avanzate, Consiglio
Nazionale delle Ricerche, Segrate (MI); Istituto di Medicina Molecolare
"Angelo Nocivelli," and Clinica Pediatrica, Universita di Brescia,
Italy; Children's Bone Marrow Transplant Unit, Newcastle General
Hospital, Newcastle-upon-Tyne; University of Manchester, Academic
Unit of Child Health, St Mary's Hospital, Manchester, United
Kingdom; Department of Pediatrics, The National Hospital, Oslo,
Norway; Lauterberg Center for General and Tumor Immunology, Hebrew
University-Hadassah Medical School, Jerusalem; Pediatric
Hematology-Oncology, Sheba Medical Center, Tel Hashomer and Sackler
School of Medicine, Tel Aviv University, Tel Aviv, Israel; Queen Silvia
Children's Hospital, Göteborg, Sweden; Department of Pediatrics
and Ulm Germany Transfusion Medicine, University of Ulm, Ulm, Germany;
Pediatric Immunology, Mother and Child Health Institute, Belgrade,
Yugoslavia; University Childrens' Hospital, University of Zurich,
Zurich, Switzerland; Institute of Medical Technology, University of
Tampere, and Tampere University Hospital, Tampere, Finland; Department
of Pediatrics, Child Health Research Center, University of Texas
Medical Branch, Galveston, TX; Department of Immunology, St Jude
Children's Research Hospital, Memphis, TN; Immunobiology Center and
Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York
University, New York, NY; Children's Hospital Medical Center,
Cincinnati, OH; Division of Hematology/Oncology/Immunology, Children's
Cancer Research Center, University of Texas Health Science Center, San
Antonio, TX; Pediatric Rheumatology Division, Emory University School
of Medicine, Atlanta, GA; Department of Pediatrics, University of
Washington School of Medicine, Seattle, WA; and Health Sciences Center,
University of Manitoba, Canada.
Severe combined immunodeficiency (SCID) comprises a heterogeneous
group of primary immunodeficiencies, a proportion of which are due to
mutations in either of the 2 recombination activating genes
(RAG)-1 and -2, which mediate the process of V(D)J
recombination leading to the assembly of antigen receptor genes. It is
reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously
thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one
allele and maintain partial V(D)J recombination activity, which
accounts for the generation of residual, oligoclonal T-lymphocytes; (3)
in a third group of patients, findings were only partially compatible
with OS, and these patients, who also carried at least one missense
mutation, may be considered to have atypical SCID/OS; (4) patients with
engraftment of maternal T cells as a complication of a transplacental
transfusion represented a fourth group, and these patients, who often
presented with a clinical phenotype mimicking OS, may be observed
regardless of the type of RAG gene mutation. Analysis of
the RAG genes by direct sequencing is an effective way to
provide accurate diagnosis of RAG-deficient as opposed to
RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.
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