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.

Figure 1.

May-Grunwald-Giemsa stain of a bone marrow aspirate from a patient with RD (original magnification ×1000, immersion oil, Zeiss Axio Imager M1, AxioCam MRc [Carl Zeiss Microscopy, Jena, Germany]) showing immature lymphoid cells (hematogones) with slim cytoplasm as well as myeloblasts and a dysplastic promyelocyte with nuclear and cytoplasmic vacuoles. In the work-up of the bone marrow with immunostaining and flow cytometry, immature lymphocytes were identified as polyclonal B-cell precursors (flow cytometry of the bone marrow revealed a population of 46% with markers of pre–B cells CD10⁺/CD19⁺/cyIgM⁺/TdT⁺/CD34^–; clonality was tested in a multiplex polymerase chain reaction for the rearranged B-cell receptor heavy chains [data not shown]).

Figure 2.

Genomic map of AK2 isoform B with mutations identified in 29 patients. GenBank reference sequence NM_013411.4 for AK2 complementary DNA, isoform B. The numbers in brackets indicate the frequency of the mutations and whether they were identified as part of a homozygous mutation (*) or a compound heterozygous mutation (#).

Figure 3.

Tree diagrams for patient transplantations. (A) Tree diagram for 14 patients transplanted with T-cell–replete grafts. (B) Tree diagram for 17 patients transplanted with T-cell–depleted grafts. ** indicates dosage not reported; *** indicates targeted Bu 800-1200 µmol/min per L; ^§ indicates treosulfan dosage given in mg/kg; ^§§ indicates busulfan dosage given in mg/m². Bu, busulfan dosage given in mg/kg; Bu based, conditioning regimen contains busulfan; CD45, anti-CD45 antibody; Cy: cyclophosphamide dosage given in mg/kg; Flu, fludarabine dosage given in mg/m²; Mel, melphalan dose given in mg/m²; MFD, matched family donor; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; no cond, no conditioning; pt, patient; RIC, reduced intensity conditioning; TBI, total body irradiation dosage given in Gy; 2nd Tx, second transplant; Treo, treosulfan dosage given in g/m².

Figure 4.

Kaplan-Meier survival estimation with 95% pointwise confidence intervals. Comparison of the survival probability of patients after HSCT with T-cell replete and T-cell depleted grafts.