Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome.
Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease. Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011. Age at presentation was <4 weeks in 30 of 32 patients (94%). Grafts originated from mismatched family donors in 17 patients (55%), from matched family donors in 6 patients (19%), and from unrelated marrow or umbilical cord blood donors in 8 patients (26%). Thirteen patients received secondary or tertiary transplants. After transplantation, 21 of 31 patients were reported alive at a mean follow-up of 7.9 years (range: 0.6-23.6 years). All patients who died beyond 6 months after HSCT had persistent or recurrent agranulocytosis due to failure of donor myeloid engraftment. In the absence of conditioning, HSCT was ineffective to overcome agranulocytosis, and inclusion of myeloablative components in the conditioning regimens was required to achieve stable lymphomyeloid engraftment. In comparison with other SCID entities, considerable differences were noted regarding age at presentation, onset, and type of infectious complications, as well as the requirement of conditioning prior to HSCT. Although long-term survival is possible in the presence of mixed chimerism, high-level donor myeloid engraftment should be targeted to avoid posttransplant neutropenia.
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
Manfred
M
Hoenig
Biotherapy Clinical Investigation Center, Hôpital Necker Enfants Malades, Paris, France.
Chantal
C
Lagresle-Peyrou
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.|Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.
Ulrich
U
Pannicke
Division of Immunology, Boston Children's Hospital, Boston, MA.
Luigi D
LD
Notarangelo
Department of Pediatrics, University Hospital, Brescia, Italy.
Fulvio
F
Porta
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.|Department of Paediatric Immunology and Haematopoietic Stem Cell Transplant (HSCT), Great North Children´s Hospital, Newcastle upon Tyne, United Kingdom.
Andrew R
AR
Gennery
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.|Department of Paediatric Immunology and Haematopoietic Stem Cell Transplant (HSCT), Great North Children´s Hospital, Newcastle upon Tyne, United Kingdom.
Mary
M
Slatter
Division of Allergy, Immunology and Bone Marrow Transplant (BMT), UCSF Benioff Children´s Hospital, San Francisco, CA.
Morton J
MJ
Cowan
Pediatric Hematology-Oncology, Hadassah University Hospital, Jerusalem, Israel.
Polina
P
Stepensky
Section of Pediatric Allergy/Immunology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Hamoud
H
Al-Mousa
Department of Pediatrics, Allergy, Immunology and BMT, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia.
Daifulah
D
Al-Zahrani
Division of Hematology-Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
Sung-Yun
SY
Pai
Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
Waleed
W
Al Herz
UCL Great Ormond Street Institute of Child Health, London, United Kingdom.|Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
Hubert B
HB
Gaspar
UCL Great Ormond Street Institute of Child Health, London, United Kingdom.|Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
Paul
P
Veys
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Koichi
K
Oshima
Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Kohsuke
K
Imai
Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isahara, Japan.
Hiromasa
H
Yabe
Department of Allergy and Immunology, Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
Lenora M
LM
Noroski
Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Nico M
NM
Wulffraat
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Karl-Walter
KW
Sykora
Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d´Hebron, Barcelona, Spain.
Pere
P
Soler-Palacin
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Hideki
H
Muramatsu
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia; and.
Mariam
M
Al Hilali
Paediatric Immunology, Haematology and Rheumatology, Assistance Publique - Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.
Despina
D
Moshous
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
Klaus-Michael
KM
Debatin
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
Catharina
C
Schuetz
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
Eva-Maria
EM
Jacobsen
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
Ansgar S
AS
Schulz
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.|Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.
Klaus
K
Schwarz
Paediatric Immunology, Haematology and Rheumatology, Assistance Publique - Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.
Alain
A
Fischer
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
Wilhelm
W
Friedrich
Biotherapy Clinical Investigation Center, Hôpital Necker Enfants Malades, Paris, France.
Marina
M
Cavazzana
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D064591:Allografts; D002648:Child; D036101:Cord Blood Stem Cell Transplantation; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007970:Leukopenia / Q000201:enzymology / Q000235:genetics / Q000401:mortality* / Q000628:therapy*; D008297:Male; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics / Q000401:mortality* / Q000628:therapy*; D015996:Survival Rate; D019172:Transplantation Conditioning; D061349:Unrelated Donors
D000262:Adenylyl Cyclases; C100622:adenylyl cyclase 2