Case Report: Deficiency in Adenosine Deaminase 2 mimicking a childhood Polyarteritis Nodosa: A case report of two siblings with a novel mutation

Physiopathology and genetics

DADA2 is an autoinflammatory disease caused by a loss-of-function mutation in CECR1, which encodes the ADA2 enzyme. ADA2 is a dimeric enzyme expressed in cells of the myeloid lineage, and monocytes differentiate into macrophages and dendritic cells.² It acts in extracellular space as an endothelial growth factor in.²

Biopsy samples taken from the brain and skin lesions of patients with DADA2 demonstrated significant endothelial damage and increased staining for interleukin-1β, inducible nitric oxide synthase, and TNFα.¹ These findings explain the pro-inflammatory phenotype with endothelial damage and vasculitis.

ADA2 regulates extracellular adenosine levels. Adenosine is known to play a role in the inflammatory responses during acute conditions. ADA2 deficiency causes dysregulation of adenosine levels, leading to chronic inflammation.

NETosis is another mechanism found in DADA2 patients. Indeed, M1 macrophages incubated with NETs from patients with DADA2 release abundant TNFα.

DADA2 phenotypes are associated with mutations inADA2 on chromosome 22q11.1. One hundred fifty-eight mutations were reported in the Infevers database, an online registry of hereditary auto-inflammatory disorder mutations, until March 2025. Of these, 115 mutations were found to be pathogenic/likely pathogenic: 89 substitutions (77, 4%), 21 deletions (18, 3%), four duplications, and one deletion-insertion (del-ins).³ Only one mutation was found in a symptomatic patient of Tunisian origin. This is a substitution for exon 2, c.73G>Tp. (Gly25Cys).

Our patients were homozygous carriers of a previously unreported mutation c.1458–1459insTTGp. (Leu486dup), resulting in different phenotypes, and is classified as of uncertain significance.

Indeed, multiple studies have concluded that there is a large variability in phenotypic manifestations. Differences in phenotypic presentations may occur with the same mutation, including in patients within the same family with the same mutation.⁴ This suggests the involvement of epigenetic and environmental factors that influence the phenotype and severity of the disease.

Diagnosis

Screening for DADA2 is based on two diagnostic methods: measurement of plasma/serum ADA2 activity and genetic testing. To date, no definitive criteria have been established for this condition.

Puietal. suggested an international consensus for screening DADA2.⁵ The DADA2 Consensus Committee, consisting of patient representatives and global experts representing adult and pediatric subspecialties, developed statements for diagnostic testing and screening of DADA2. The diagnosis can be determined by either measurement of ADA2 activity and/or sequencing of the ADA2 gene. Both methods should be used if available.⁵ All patients with DADA2 described to date have very low or undetectable ADA2 catalytic activity in plasma or serum. When available, this method should be performed by a certified laboratory, and normal levels of ADA2 activity are sufficient to rule out diagnosis.⁵

Genetic testing consists of the targeted sequencing of ADA2. DADA2 is diagnosed by the presence of biallelic or likely pathogenic ADA2 variants, as determined by the guidelines established by the American College of Medical Genetics and Genomics.⁵

It is performed either by conventional Sanger sequencing, next-generation sequencing (NGS)-based targeted panels, or exome sequencing.⁶ Small deletions and duplications missed by routine techniques may be detected using multiplex ligation-dependent probe amplification (MLPA) and long-range polymerase chain reaction (PCR).

Patients with monoallelic pathogenic or likely pathogenic ADA2variants are considered carriers.

For patients with monoallelic or biallelic ADA2variants of unknown significance (VUS), measurement of ADA2 enzyme activity should be strongly considered to evaluate the possibility of DADA2.⁵ For Families with a confirmed case of DADA2, screening of siblings should be considered, even in the absence of symptoms, since they are independently at risk and the disease may be, asymptomatic.⁵

Clinical features

The clinical manifestations of DADA2 have varied widely and expanded since 2014. In addition to the pan-like phenotype, autoinflammation, immunodeficiency, hematological involvement, and lymphoproliferation features have been described.⁶ There are also asymptomatic or mildly symptomatic cases.⁶

To date, more than 600 cases of DADA2 have been reported. This disease seems to be more common in Caucasians and South Asians. The age of presentation ranges from at birth to 59 years.^2,6 The age of onset is mostly pediatric; however, adult presentation (between 18 and 59 years) has been well documented.⁶

The first case described a PAN-like phenotype.¹ The most common clinical manifestations are cutaneous, neurological, and recurrent fevers. Second, the gastrointestinal, renal, cardiac, and pulmonary systems.⁶

The most common skin manifestation is livedo reticularis/racemose.^2,6 Skin vasculitis can present as subcutaneous nodules (including erythema nodosum), purpuric lesions, Raynaud’s phenomenon, skin ulcers, mouth and genital ulcers, urticarial rash and digital gangrene, as well.⁷

Neurological involvement is common and may be a form of disease.⁸ Neurological manifestations may affect both the central nervous system (CNS) and/or the peripheral nervous system (PNC).^6,8 Stroke, particularly ischemic stroke, is the most common neurological manifestation.^1,8 In a review of neurological manifestations of DADA2, including 628 patients, Dzhusandet al.⁸ reported that strokes accounted for 77.5% of all neurological events. Other neurological symptoms include mononeuropathies and polyneuropathies; focal neurological deficits including cranial nerve paralysis; ophthalmological findings such as strabismus, optic neuritis, uveitis, loss of vision, seizures, headache; and other a specific symptoms such as vertigo and amnesia.^6,8 Approximately3% of the patients reviewed had neurocognitive disorders, including isolated cognitive impairment, isolated memory disturbance, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), isolated persistent irritability, and isolated difficulties in concentration.⁸ This is particularly interesting, as neurocognitive disorders may be the sole manifestation of DADA2 and should be examined in a pediatric population in whom cognitive disorders are possibly misdiagnosed.

MRI is the preferred imaging modality, and reveals that ischemic strokes are preferentially localized in the brain stem, thalamus, basal ganglia, internal capsule, and other deep cerebral structures. The Negativity of MRI does not exclude the diagnosis, as there were cases of neurological signs with a mild or transient character (transient ischemic attacks (TIA)), or even cases of MRI-negative infarcts.⁸ Hemorrhagic strokes were described in 11% of cases, mostly in lobar locations. However, basal ganglia,⁸ subdural,¹ and intraventricular hemorrhage may occasionally occur. They may be complicated by the use of antiplatelet agents and anticoagulants in patients with a history of ischemic stroke.⁶ Other MRI abnormalities may include brain atrophy, vessel wall enhancement, posterior reversible encephalopathy syndrome (PRES) pattern, optic atrophy, aneurysms, arterial stenosis, and microhemorrhage.⁸

Renal involvement presents as hypertension, renal infarcts, kidney artery aneurysms and glomerulonephritis.⁹ Testicular involvement, including pain or swelling, is reported to be one of the features similar to PAN. Gastrointestinal involvement mimics the gastrointestinal features of PAN. Abdominal pain can be a unique symptom of mesenteric ischemia and may lead to bowel perforation if it is not diagnosed at time.⁹ Stenosis and aneurysms of the celiac and mesenteric arteries, as described in the first patient, have been reported.¹⁰ Cardiac involvement appears as dilated cardiomyopathy, coronary aneurysms, and focal myocarditis.⁹

Most patients with a vasculitic phenotype fulfill the criteria for PAN, including angiographic and histopathological features.¹¹ However, patients with DADA2 are relatively younger than those with PAN and are more likely to have renal and neurological involvement, especially strokes. Other DADA2 phenotypes include Sneddon’s syndrome, antiphospholipid antibody syndrome, and Behçet’s disease.⁸

Hematological involvement is well-documented and may occur solely or in combination with other DADA2 phenotypes. Anemia is common and results from erythroid hypofunction. It presents as moderate anemia of nutritional etiology, autoimmune hemolytic anemia, or severe refractory anemia similar to pure red cell aplasia (PRCA) and Diamond Blackfan anemia (DBA).¹²

Other hematological cytopenia include leukopenia, neutropenia, thrombocytopenia, and pancytopenia. Autoimmune cytopenia, including Coombs positive test with or without hemolytic anemia and immune thrombocytopenia,⁶ and features of hemophagocytic lymphohistiocytosis have also been reported.¹

Recurrent non-infectious fever is common. Other symptoms suggestive of autoinflammatory syndrome include recurrent episodes of arthralgia/arthritis and myalgias/myositis. Positive Anti-nuclear antibodies and few cases with anti-neutrophil cytoplasmic antibodies (ANCA) and antiphospholipid antibodies were noted, without a clear significance yet.

DADA2 is associated with a mild immunodeficiency including humoral immunodeficiency with low immunoglobulin levels (particularly low IgM levels) as the most prevalent abnormality.^6,7,9 Additionally, hypogammaglobulinemia, as described in the second patient, impaired vaccine responses, B cell lymphopenia, and low-switched memory B cells are increasingly being reported. The immunodeficiency phenotype can be misdiagnosed as Common Variable Immunodeficiency (CVID), and the presence of vasculitic features may lead to DADA2 diagnosis.¹²

Splenomegaly with or without hepatomegaly as well as lymphadenopathy are well reported features of DADA2.^7,12 Lymphoproliferation in DADA2 includes T-large granular lymphocytic leukemia (T-LGLL), autoimmune lymphoproliferative syndrome (ALPS)-like disease, and Hodgkin Lymphoma.⁹ A multicentric Castleman’s disease like phenotype was reported as well.¹²

Treatment and outcomes

Lee et al. elaborated consensus statements for the management of DADA2 based on published case series and experts’ opinions.⁵

Unlike in patients with PAN, the efficacy of glucocorticoids in the management of DADA2 flares seems to be limited. Indeed, most patients show a partial response to high doses of glucocorticoids with relapses on tapering or are refractory to steroids.^5,6 Retrospective studies have demonstrated the beneficial role of tumor necrosis factor inhibitors (TNFi) in controlling the inflammatory and/or vasculitic flares of the disease. TNFi have been proven to lower the risk of ischemic and hemorrhagic stroke.⁵ The use of disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, azathioprine, cyclophosphamide, cyclosporine, and tacrolimus, has been described, but their long-term efficacy remains limited. Other biological agents have been used, including biologics targeting interleukin 1 (IL1) and 6 (IL6), with no proven or sustainable efficacy.⁵

Disease flares may occur under TNFi treatment in cases of suboptimal dosing of TNFi, treatment discontinuation, or the development of anti-drug antibodies, such as anti-drug antibodies to infliximab, adalimumab, and golimumab. The use of methotrexate may prevent neutralizing anti-drug antibodies and regulate serum TNFi levels.

Allogenic hematopoietic stem cell transplantation (HSCT) is a proven curative option, especially for patients with hematological manifestations and avasculitic phenotype refractory to immunomodulators. Intravenous immunoglobulin (IVIG) cures are considered in patients with humoral immunodeficiency and recurrent infections.

Our patients were both treated with TNF inhibitors, with no relapse noted during a 2-year follow-up.

Identification of a novel ADA2 variant in these siblings broadens the mutational spectrum of DADA2 and highlights the genetic heterogeneity of the disease. Given the phenotypic overlap with early onset polyarteritis nodosa, misdiagnosis remains a significant risk, potentially delaying targeted therapies, such as anti-TNF agents. While whole exome sequencing enabled the diagnosis in this case, the lack of enzymatic ADA2 activity assays is a limitation, as functional validation is essential to confirm pathogenicity. Further studies are needed to elucidate the impact of specific mutations on ADA2 function and clinical phenotype, and to define standardized diagnostic workflows in resource-limited settings. The identification of this novel mutation may reflect ethnic, genetic, epigenetic, or environmental differences specific to our region. It is plausible that this variant is unique to the Tunisian population. Further studies are needed to explore and validate this hypothesis.

Patient perspective

Feedback from the patients and caregivers was actively sought. Both patients and their parents reported a significant improvement in quality of life after treatment, with better disease control. They expressed high levels of satisfaction, particularly with their ability to attend school regularly, which in turn improved their social interactions and general well-being.