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Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome

Manfred Hoenig, Chantal Lagresle-Peyrou, Ulrich Pannicke, Luigi D. Notarangelo, Fulvio Porta, Andrew R. Gennery, Mary Slatter, Morton J. Cowan, Polina Stepensky, Hamoud Al-Mousa, Daifulah Al-Zahrani, Sung-Yun Pai, Waleed Al Herz, Hubert B. Gaspar, Paul Veys, Koichi Oshima, Kohsuke Imai, Hiromasa Yabe, Lenora M. Noroski, Nico M. Wulffraat, Karl-Walter Sykora, Pere Soler-Palacin, Hideki Muramatsu, Mariam Al Hilali, Despina Moshous, Klaus-Michael Debatin, Catharina Schuetz, Eva-Maria Jacobsen, Ansgar S. Schulz, Klaus Schwarz, Alain Fischer, Wilhelm Friedrich and Marina Cavazzana on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party

Key Points

  • Compared with other SCID entities, patients with RD have an earlier presentation with bacterial rather than opportunistic infections.

  • Myeloablative agents before transplantation support reliable myeloid engraftment and long-term cure in patients with RD.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

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.

  • Submitted November 2, 2016.
  • Accepted March 13, 2017.
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