The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort

Abstract

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort's experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.

Keywords: ADA2; anti-TNF therapy; bone marrow failure; deficiency of adenosine deaminase 2 (DADA2); hematopoietic cell transplantation (HCT); immune dysregulation; lacunar strokes; vasculopathy.

Figure 1

The clinical manifestations of DADA2 are broad and not exclusive. (A) Summary of the clinical manifestations of DADA2, including inflammatory, immune dysregulation and hematologic abnormalities. Patients with DADA2 may exhibit any combination of these abnormalities. (B) Breakdown by phenotype of the 58 individuals enrolled in the NIH cohort. The numbers reflect the number of individuals in the NIH 58 patient cohort who fall into each phenotypic zone. Forty-six of the 58 individuals have clinical manifestations that span more than one of the broader classes (inflammatory, immune dysregulation, hematologic).

Figure 2

The cutaneous manifestations of DADA2. (A) Livedo racemosa on the legs of a 38-year-old. (B) Nodules that when biopsied revealed medium vessel vasculitis in a 58-year-old. (Cutaneous polyarteritis nodosa [PAN]). (C) Raynaud’s phenomenon in a 13-month-old. (D) Acral cyanosis and cutaneous ulcer in a 27-year-old. (E) Verruca vulgaris in a 29-year-old.

Figure 3

The medium vessel vasculitis in DADA2 patients resembles the vasculitis in polyarteritis nodosa. (A) Sections of skin biopsy showing lymphovascular occlusion in medium vessels in the medium-to-deep dermis with inflammatory infiltrate with neutrophils and intravascular thrombi. (B) Vasculitis of a medium sized artery characterized by dense transmural infiltrate of mononuclear cells and neutrophils with karyorrhexis, fibrin deposits in vascular lumen, destruction of vessel walls and dense chronic inflammation surrounding the affected blood vessel. (C) Vasculitis involving smaller blood vessels of the superficial subcutis. This biopsy was interpreted as possible polyarteritis nodosa.

Figure 4

The ischemic strokes in DADA2 may present at an early age and can occur, repeatedly, deep in the brain. (A) Shows the diffusion weighted imaging (DWI) (top) and apparent diffusion coefficient (ADC) (bottom) indicative of acute diffusion restriction (yellow arrows) consistent with a new left-paramedial midbrain infarct. (B) The same study, on T2 images a few cuts above, shows evidence of two prior lacunar strokes on the thalamus (blue arrows). These strokes occurred in a 3 year 11-month-old boy.

Figure 5

Hemorrhagic Strokes in DADA2. (A) Axial susceptibility weighted imaging (SWI) sequence showing right frontal intraparenchymal hemorrhage in a 2 year 5-month-old patient. (B) Axial SWI sequence showing left basal ganglia hemorrhage extending into the right lateral ventricle in same patient, now 2 year 6 months old. Notably, the patient was not on any anticoagulation prior to her hemorrhages.

Figure 6

The distribution of strokes in DADA2. In the cohort of 58 patients, 25 patients amassed a total of 76 lacunar strokes. Their distribution was focused primarily in the deep brain nuclei, brainstem and cerebellum.

Figure 7

Inflammatory Myopathy in a DADA2 Patient. A 2-year-old boy presented with refusal to bear weight. He was febrile and preferred to hold his hips in a flexed position. MRI of the pelvis revealed multiple, diffuse, scattered areas of enhancement on T2 weighted imaging, bilaterally. Subsequent muscle biopsy noted multifocal perivascular inflammation as well as endomysial inflammation with both T and B lymphocytes present. There was also an increased number of eosinophils scattered throughout the biopsy specimen.

Figure 8

The portal hypertension in DADA2 can respond positively to anti-TNF therapy. (A) A 7-year-old patient with marked splenomegaly (16 cm) due to portal hypertension and variceal enlargement of abdominal vessels. (B) The same patient 6 years post initiation of anti-TNF therapy with reduction in spleen size (14.2 cm) and reduced vascular prominence.

Figure 9

Peripheral Vascular Disease in DADA2. (A) 25-year-old with inflamed digits and digital resorption. (B) The same patient, 3 years later status post partial amputation of the left third digit following worsening peripheral vascular disease that resulted in the development of gangrene. (C) Angiogram of a normal hand. (D) Angiogram of this patient prior to the amputation, revealing severe occlusive disease of the palmar and digital arteries. The medium and small vessel involvement most closely resembles thromboangiitis obliterans. (E) Angiogram of a lower extremity in a patient with DADA2 showing a loss of distal vasculature perfusion.

Figure 10

Skin ulceration in DADA2. (A) A 40-year-old developed a well-defined, irregularly shaped ulceration with overlying yellow fibrinous exudate (black arrow). The ulcer was not infected. There had been antecedent trauma 3 months prior with a small skin tear. This lesion developed while on adalimumab and screening for neutralizing antibodies to adalimumab was negative. (B) Distal to the knees there was increasing mottled, somewhat reticular erythema representing livedo racemosa. (C) Further examination revealed multiple hypopigmented atrophic plaques consistent with scars from prior ulcerations (white arrows).

Figure 11

Bone Marrow Findings in DADA2. (A) 16-year-old male with history of DADA2 with severe neutropenia (ANC=0.02 K/uL). The marrow, when stained for MPO shows myeloid hypoplasia with presence of decreased immature myeloid precursors and absence of maturing forms consistent with maturation block or loss of myelocytes, metamyelocytes and neutrophils by immune mechanism. (B) Prominent T-cell aggregates and T-cell infiltrate in marrow when stained for CD3 in the marrow of the 16 y/o male with neutropenia. (C) 11-year-old male with progressive pancytopenia while on TNF inhibition. Bone marrow biopsy revealed marked hypocellularity for age morphologically overlapping with aplastic anemia. There was severe myeloid and erythroid hypoplasia with rare megakaryocyte clusters.

Figure 12

Anti-TNF treatment significantly reduces stroke risk in DADA2. Each bar represents a single patient’s respective anti-TNF treatment intervals and stroke incidence. Prior to starting TNF inhibition (red and yellow) there were a total of 76 strokes in 3,622 cumulative patient-months. No ischemic or hemorrhagic strokes have occurred in 2027 cumulative patient-months during TNF inhibition (blue), whereas 66 strokes were observed in a retrospective matched-pair (yellow) analysis (P < 0.001 by the Exact McNemar test). Overall distribution of stroke incidence by age shown via rug plot.

Figure 13

Anti-TNF agents help to reduce the inflammatory burden in DADA2 patients. Analysis of individual inflammatory burden (ESR, CRP, WBC, hemaglobin, hematocrit, platelet count, and serum iron) was completed both pre- and post-anti-TNF initiation. There were statistically significant decreases in WBC (p=0.01), platelet count (p=0.003), ESR (p=0.007), CRP (p=0.02) as well as statistically significant increases in hemoglobin (p=0.03), hematocrit (p=0.001), and serum iron (p=0.01).

Figure 14

Hepatic transient elastography in patients both pre- and post-initiation of anti-TNF therapy. Patients underwent transient elastography both pre- and post-anti-TNF initiation. Upper limit of normal is defined as 7 kPa. The cohort had a statistically significant decrease in transient elastography scores (p=0.012).