Irish children with DADA2 show varied illness, delayed diagnoses and differing treatments

An Irish case series of four children diagnosed with deficiency of adenosine deaminase 2, or DADA2, shows how the rare inherited disorder can resemble unrelated conditions and range from severe multisystem disease to minimal symptoms. The patients, diagnosed between 2020 and 2024 at the National Centre for Paediatric Rheumatology at Children’s Health Ireland at Crumlin in Dublin, were three boys and one girl aged 3 to 12 years at diagnosis. Two patients remained clinically well on adalimumab, one required a change of tumour necrosis factor inhibitor after developing anti-drug antibodies, and one with severe, refractory haematological manifestations underwent haematopoietic stem cell transplantation. These are observational descriptions of individual cases rather than a trial or population-level estimate of treatment effectiveness.

DADA2 is an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function pathogenic variants in the ADA2 gene. It is characterised by vasculopathy, immune dysregulation and haematological abnormalities, and its reported manifestations include recurrent fever, livedo racemosa, early-onset stroke, immunodeficiency and cytopenias. The paper cites an estimated global prevalence of approximately one in 222,000 people while noting that underdiagnosis is probably substantial. It also states that neurological manifestations affect about 50% of patients and that ischaemic and haemorrhagic strokes are among the most serious complications. The condition can therefore be consequential even when a child initially appears relatively well, as illustrated by the marked differences between two siblings in this series.

The first patient was a 3-year-old boy who developed progressive purpuric skin lesions, high-grade fevers every six to eight hours, drenching night sweats, lethargy, weight loss and joint inflammation. Emergency department visits initially attributed the symptoms to benign causes. A skin biopsy at the referring hospital showed perivascular lymphocytic inflammation with an occasional thrombus. After transfer to the Dublin centre, a multidisciplinary team identified livedoid vasculitic lesions and synovitis of both ankles, the right wrist and the left knee. His erythrocyte sedimentation rate was 33 mm/hr, above the reference range of 1–13 mm/hr, and C-reactive protein was 27 mg/L, compared with a reference range below 4 mg/L.

A repeat skin biopsy showed brisk arteritis in a small- to medium-calibre artery within the subcutaneous fat, together with mild superficial perivascular inflammation and mild neutrophilic panniculitis. This pattern prompted consideration of a monogenic cause of childhood-onset polyarteritis nodosa. ADA2 enzyme activity was 1.4 IU/L, below the reference range of 6.9–59.7 IU/L, and genetic testing confirmed compound heterozygous variants, c.140G>C, p.Gly47Ala, classified as pathogenic, and c.872C>T, p.Ser291Leu, classified as likely pathogenic. Adalimumab produced a rapid clinical response. In 2024, anti-adalimumab antibodies and subtherapeutic drug levels prompted a switch to etanercept with methotrexate, and the patient remained clinically stable thereafter. The case supports testing for DADA2 when a young child has livedo-like skin lesions, systemic inflammation and a polyarteritis nodosa-like biopsy pattern.

The second case demonstrates a 12-year diagnostic journey dominated initially by haematology. A male patient presented at 36 weeks’ gestation with hydrops fetalis and profound anaemia: his haemoglobin was 41 g/L, compared with a reference range of 140–240 g/L. A direct Coombs test was negative and the reticulocyte count was 0.2%, consistent with hypoproliferative anaemia. Clinicians made a working diagnosis of Diamond–Blackfan anaemia, and regular red-cell transfusions with iron chelation were initiated. By age five, the patient had developed recurrent aphthous stomatitis, arthralgia, joint stiffness, Raynaud’s phenomenon, erythema and dryness on the backs of his hands, and aseptic meningitis. Positive antinuclear, anti-dsDNA and anti-Ro antibodies later led to reclassification as atypical systemic lupus erythematosus, and azathioprine plus hydroxychloroquine was started. A renal biopsy in 2017 for intermittent proteinuria was normal.

Further complications included disseminated cytomegalovirus infection with pneumonitis and 10,000 copies/mL of viral DNA, persistent lymphopenia and hypogammaglobulinaemia. These findings prompted concern for an underlying inborn error of immunity, and whole-exome sequencing in 2021 identified a homozygous deletion of exons 4–5 in ADA2. The result supplied one genetic diagnosis for 12 years of apparently disparate findings. Family testing then showed that both parents and one sibling were heterozygous carriers. The case illustrates how unexplained symptoms, unusual complications and an inadequate response to an established diagnosis can justify revisiting the diagnostic formulation, but a single observation cannot establish how commonly such diagnostic revision is needed.

Adalimumab and intravenous immunoglobulin replacement improved this patient’s inflammatory markers, but his dependence on red-cell transfusions persisted. He therefore underwent a mismatched-unrelated-donor, T-cell receptor alpha-beta/CD19-depleted peripheral blood stem cell transplant with CD45RO-positive memory T-cell add-back in early 2024. The post-transplant course was complicated by Escherichia coli sepsis, donor-acquired G6PD deficiency, herpes zoster with post-herpetic neuralgia, and hepatic impairment with suspected portal hypertension. By 2025, he had achieved 100% donor chimerism, transfusion independence and clinical remission. The outcome supports consideration of transplantation in the severe, refractory haematological phenotype described by the authors, but the isolated case does not establish comparative benefit or generalise to all children with DADA2. His evolving illness also shows that an initial haematological presentation may not capture later inflammatory, vasculitic or immune manifestations.

The third patient, a 7-year-old Somali boy, was referred in July 2023 with poor oral intake, weight loss and fatigue. His family had recently arrived in Ireland as refugees and was living in emergency accommodation. Records from earlier evaluations in Sweden, including impressions of IgA vasculitis and possible Kawasaki disease, were unavailable, while language barriers initially limited the history. Interpreter-assisted sessions revealed that recurrent day-on, day-off fevers had begun in February 2023 and became progressively persistent. The rash was longstanding and widespread over the trunk, extremities and plantar surfaces, with hyperpigmentation suggesting chronicity. He also had marked fatigue, leg pain, vomiting, abdominal pain and severe weight loss; his admission weight was 20.9 kg, on the ninth centile.

Laboratory evaluation found a C-reactive protein of 104 mg/L, an erythrocyte sedimentation rate of 47 mm/hr, microcytic anaemia and a faecal calprotectin of 406 μg/g. Bone marrow examination excluded malignancy, while lymphocyte subset testing showed low numbers of T-helper, B and natural killer cells. After discussion across general paediatrics, rheumatology, infectious diseases, dermatology and haematology, the team concluded that IgA vasculitis did not explain the persistent fevers, rash distribution or constitutional severity, broadening the differential diagnosis to include inflammatory bowel disease, malignancy and autoinflammatory disease. ADA2 activity was 0.9 IU/L, and genetic testing confirmed a homozygous c.139G>T, p.Gly47Trp variant, establishing the diagnosis in August 2023. The paper does not claim that the family’s refugee status caused the diagnostic difficulty; instead, it identifies repeated, comprehensive history-taking with skilled interpreters as diagnostically important when communication barriers and fragmented records obscure clinical chronology.

Adalimumab resolved the boy’s fever, and nutritional rehabilitation with nasogastric feeding accompanied his treatment. His weight recovered to the 79th centile by 2025, and he maintained remission on adalimumab. Cascade genetic testing after his diagnosis offered another striking illustration of phenotypic variability. His 2-year-old sister carried the same homozygous p.Gly47Trp variant, and her ADA2 activity was 0.1 IU/L. Yet she had only occasional low-grade fevers, no rash, no significant joint symptoms and no constitutional features. Her growth and development were normal. Subtle laboratory abnormalities included a mildly elevated C-reactive protein of 8 mg/L, lymphocyte counts of 0.36–1.2 × 10⁹/L and IgM of 0.25 g/L, but none had independently prompted investigation before the family study.

Following multidisciplinary discussion and shared decision-making with the family, the younger girl began adalimumab at 20 mg subcutaneously every other week. The decision reflected the recognised risk of neurological complications and the established efficacy of TNF inhibition in reducing vascular events in symptomatic DADA2, while the authors acknowledge that prospective evidence on preventive treatment before a first clinical event is lacking. By 2025, she remained clinically well, her inflammatory markers had normalised and her development was normal. The sibling pair demonstrates that identical homozygous variants can be associated with markedly different clinical severity, but the observations do not identify why the phenotypes differ or establish a general treatment rule for asymptomatic children. The paper suggests that family screening can identify affected relatives before obvious symptoms, while concluding that current evidence is insufficient to support population-based newborn screening.

Across the four patients, diagnostic intervals ranged from three months to 12 years, and initial diagnoses included polyarteritis nodosa, Diamond–Blackfan anaemia, atypical systemic lupus erythematosus and IgA vasculitis. Features that the authors say should prompt consideration of DADA2 include unexplained transfusion-dependent anaemia with reticulocytopenia, cutaneous vasculitis with livedo-like features and subcutaneous nodules, a childhood polyarteritis nodosa-like presentation, recurrent or opportunistic infections, or a relevant family history. Coexisting findings across inflammatory, vascular, haematological and immune domains support measuring plasma ADA2 activity and pursuing ADA2 genetic testing, both of which the paper describes as widely accessible. The series also presents DADA2 as a pan-ethnic disorder that should not be excluded on ethnic grounds. However, it comprises only four patients treated at one tertiary centre, and its diagnostic observations and management outcomes require confirmation in larger multicentre cohorts.

Treatment responses differed with the dominant clinical problem in this series. The two patients with predominantly inflammatory or vasculitic manifestations achieved good control with TNF inhibitors, whereas the child whose disease was dominated by red-cell aplasia remained transfusion-dependent despite improved inflammatory markers and required transplantation. Anti-drug antibody development in the first case added a practical feature to long-term treatment: subtherapeutic adalimumab levels led to a successful switch to etanercept plus methotrexate. At the 2025 follow-up, the two patients continuing adalimumab were clinically stable or in remission, while the transplanted patient had full donor chimerism and transfusion independence. These individual outcomes under different treatment strategies are not comparative efficacy data. Overall, the case series supports early recognition, multidisciplinary review, reconsideration of an established diagnosis when a child’s course changes, careful interpreter-supported assessment and systematic family screening after an index DADA2 diagnosis.

Subject of Research: Clinical presentation, diagnosis and treatment of DADA2 in four paediatric patients

Article Title: Deficiency of adenosine deaminase 2 in paediatric patients: a case series from Ireland

Article References: Almubarak, R., Foley, C., Killeen, O. G., MacDermott, E., & Gallagher, K. (2026). Deficiency of adenosine deaminase 2 in paediatric patients: a case series from Ireland. Frontiers in Pediatrics, 14, Article 1878669. https://doi.org/10.3389/fped.2026.1878669

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1878669

Keywords: DADA2, paediatric rare disease, autoinflammatory disease, diagnostic delay, paediatric vasculitis, TNF inhibitors, stem cell transplantation, family screening, haematological disease, Ireland, Deficiency, adenosine