Background/Purpose: The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by biallelic mutations in ADA2. The diagnosis of DADA2 is made by the measurement of very low or absent plasma ADA2 enzymatic activity and on the identification of biallelic loss of function mutations in ADA2.

The clinical phenotype of DADA2 can be simplified into three main subtypes: inflammatory/vascular, immune dysregulation and hematologic. The hematologic manifestations seen in DADA2 can be isolated to a single cell type or be as extensive as total bone marrow failure. Anti-TNF agents have been revolutionary in decreasing the inflammatory and vascular manifestations of disease, but the hematologic manifestations tend to have a lesser robust response necessitating consideration of allogeneic hematopoietic cell transplantation (HCT).

Methods: A retrospective chart review was undertaken for 58 DADA2 patients seen at the NIH Clinical Center.  Those who underwent HCT were further analyzed for a) HCT indication b) type of HCT c) type of conditioning d) post-HCT complications and e) outcome. One patient presented with features suggestive of MonoMac syndrome due to GATA2 deficiency and underwent HCT; diagnosed years later with DADA2. 

Results: The cohort had 6/58 patients who had undergone HCT.  Among the 6 patients, there were a total of 10 HCTs.  Four of the patients underwent HCT at the NIH and 2 were transplanted at other institutions.  The indication(s) for HCT were: trilineage bone marrow failure in 1, immune-mediated neutropenia in 4, and combination pure red cell aplasia and immune-mediated neutropenia in 1. Myeloablative conditioning was used in 1 patient and the others all received varying degrees of reduced-intensity or non-myeloablative conditioning.

There were 3 patients who required multiple HCTs, with 2 patients requiring 2 HCTs and 1 patient receiving 3.  All 3 of the patients who had graft failure had immune-mediated neutropenia as one of their HCT indications.  Pre-HCT bone marrow analysis of these patients revealed large aggregates of T lymphocytes into the marrow and associated maturation arrest of myeloid cells. 

Conclusion: DADA2 is a complex, multisystem disease that has great phenotypic variability.  The diversity of presenting clinical features makes it imperative to promote disease awareness. As there is not an apparent genotype:phenotype correlation to predict disease trajectory, once a diagnosis is made, treatment with anti-TNF agents to reduce a patient’s risk for stroke and may also serve as a bridge to HCT.  For those with disease refractory to anti-TNF agents, HCT is a potential curative option although careful consideration should be taken as our cohort has had multiple graft failures necessitating additional HCTs. Additional research to better understand the mechanisms of disease so targeted treatments can be can be developed and implemented.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/allogeneic-hematopoietic-cell-transplantation-hct-in-the-national-institutes-of-health-nihs-deficiency-of-adenosine-deaminase-2-dada2-patient-cohort/