title: SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID.
abstract: A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany;
authors.forename: Catharina
authors.initials: C
authors.lastname: Schuetz
authors.forename: Benedicte
authors.initials: B
authors.lastname: Neven
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Dvorak
authors.forename: Sandrine
authors.initials: S
authors.lastname: Leroy
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Ege
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Ansgar S
authors.initials: AS
authors.lastname: Schulz
authors.forename: Manfred
authors.initials: M
authors.lastname: Hoenig
authors.forename: Monika
authors.initials: M
authors.lastname: Sparber-Sauer
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Gatz
authors.forename: Christian
authors.initials: C
authors.lastname: Denzer
authors.forename: Stephane
authors.initials: S
authors.lastname: Blanche
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Biljana N
authors.initials: BN
authors.lastname: Horn
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Friedrich
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004720:Endonucleases; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000209:etiology; D006680:HLA Antigens / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency*; D012307:Risk Factors; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019172:Transplantation Conditioning; D016896:Treatment Outcome
chemical_list: D004268:DNA-Binding Proteins; D006680:HLA Antigens; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C064658:RAG-1 protein; C426344:DCLRE1C protein, human; D004720:Endonucleases