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

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.

Recent advances in understanding the pathogenesis and management of reticular dysgenesis

“…Additionally, a markedly reduced expression of the erythroid marker hbae1.1 was noted, supporting the idea that erythropoiesis defects are intrinsic to Ak2 deficiency in this model. The observation of a large fraction of anaemic RD patients at birth complements these observations (Hoenig et al , ). Furthermore, Rissone et al () showed that increased oxidative stress and reactive oxygen species (ROS) production results in cell death and apoptosis and that Ak2 deficiency causes a progressive reduction of haematopoietic stem and progenitor cells by this mechanism.…”

“…Upon differentiation, fibroblast‐derived induced pluripotent stem cells (iPSCs) from an AK2‐deficient patient recapitulated the promyeloid block that can be observed in the bone marrow of patients (Lagresle‐Peyrou et al , ; Hoenig et al , ). This block is imitated in colony‐forming assays with bone marrow mononuclear cells originating from RD patients (Lagresle‐Peyrou et al , ).…”

“…Other possible explanations include reversions of AK2 mutations in non‐haematopoietic bystander cells in the bone marrow or genetic constellations beyond AK2 which can compensate partially for the AK2 deficiencies. Profound sensorineural hearing loss, which persisted after successful transplantations of haematopoietic stem cells, was documented for 20 patients with an RD phenotype (Guilcher et al , ; Hoenig et al , ). Al‐Mousa et al () reported on four patients sharing an Ala182Asp mutation and the milder phenotype of a combined immunodeficiency with normal neutrophil and lymphocyte counts.…”

HCT for SCID: one size does not fit all

“…Although long-term survival after HCT was 68%, graft failure or persistence/recurrence of agranulocytosis was the predominant cause of treatment failure. 1 Myeloablative transplant conditioning regimens and transplantation of T-cell-replete grafts were associated with best outcomes.…”

“…1 The SCIDs are phenotypically and genotypically heterogeneous, and RD is considered 1 of the most severe forms. 2,3 RD is inherited as an autosomal recessive disorder and accounts for ,2% of SCID and classed as T-, B-, and natural killer-deficient SCID.…”