ABSTRACT
Introduction: The number / phenotype of DADA2 continues to expand rapidly though series from Asia are scant. Objectives: Share experience with 10 DADA2 patients (9 unrelated families) identified over 2 years. Methods: We diagnosed the first case in April 2019 following which we recalled and diagnosed 4 more patients on renewed suspicion. In 2, their phenotypes did not match the initial provisional diagnosis of primary CNS vasculitis and inflammatory bowel disease (IBD) respectively while 2 had been treated as classic PAN. 4 patients were diagnosed prospectively on clinical suspicion and 1in whom we suspected syndromic bone dysplasia with inflammatory features was a diagnostic surprise. Results: 7/10 are males. Age of onset ranged from 4 months - 17 years 9 months. Referrals were by varied specialists including primary pediatrician, pediatric hematologist, ophthalmologist, adult neurologist and urosurgeon. Medium-vessel dominated disease was seen in 6 patients and in 3 we suspected a systemic autoinflammatory disease (SAID) {1-febrile relative of a previously diagnosed DADA2 patient, 1-IBD-like with cutaneous vasculitis,1- early onset prolonged fever with granulomatous mediastinal adenitis suspected Blau syndrome} and 1 patient with progressive deforming symmetric inflammatory arthropathy and acquired micrognathia. Cutaneous features were the commonest;seen in 7 patients and stroke was seen in 3. Other systems involved were musculoskeletal (5- including the bone dysplasia mimic described above),renal (4- notable were renal artery stenosis and perinephric hematoma), gastrointestinal (2- notable was bowel perforation), while ocular involvement was seen in 2 (notable being central retinal artery occlusion and episcleritis). Hematological features were seen in 5 and included pure red cell aplasia, persistent leucopenia and thrombocytopenia in 1 patient each and anemia in 2 (notable-unexplained anemia of infancy). None of the patients had exclusive hematological disease or immunodeficiency. 5 were homozygous for p.G47R variant and 2 are compound heterozygous with p.G47R and splice mutation c.753+2T>A and p.G47R and p.H219P respectively. Of those with p.G47R variant 4 belong to Agarwal community in whom endogamy is known. 2 patients born of a first cousin marriage (and even related three generations higher) have a homozygous pathogenic variant p.G358R. The patient with symmetrical skeletal affliction has a homozygous pathogenic variant in p.R169Q. All 4 patients in whom ADA2 enzyme assay was performed were deficient. 4 patients are on etanercept originator molecule and 6 on etanercept biosimilar with treatment duration varying between 2 weeks to 116 months and no drug side effects. 9 patients are in clinical remission off steroids and growing well with no restriction of activities of daily living. 2 have residual hypertension. 1 unvaccinated patient contracted COVID 19 and recovered uneventfully. Conclusion: Since our first case in 2019, DADA2 is now the commonest SAID in our cohort (10/44). Due to its initial presentation to varied specialists we need to spread awareness to increase diagnosis. We report an unusual phenotype mimicking a bone dysplasia and alert colleagues that the classic phenotype originally described is being overshadowed by a wide spectrum. The p.G47R mutation is the commonest in our series and seen in the endogamous Agarwal community. The disease is very responsive to etanercept and treatment is progressively affordable with etanercept biosimilar. Residual hypertension may be seen with renal involvement and 1 patient with COVID19 on etanercept recovered uneventfully.