LAUSR

Background DADA2 is an autoinflammatory disease with autosomal recessive inheritance characterized by a heterogeneous clinical phenotype ranging from multisystemic inflammation (fever, polyarteritis nodosa, cerebral stroke, livedo reticularis etc.) to immune-dysregulation and immunodeficiency. Objectives To extend the clinical spectrum of DADA2 reporting a case of isolated nonspecific systemic inflammatory syndrome associated with signs of immune-dysregulation in a patient with a novel ADA2 mutation. Methods In a patient with nonspecific inflammatory phenotype associated to susceptibility to viral infections, Next Generation Sequencing (NGS) panel was performed; mutations detected were confirmed by Sanger analysis. ADA2 enzymatic activity was analyzed in monocyte isolated from the patient and incubated with adenosine and an ADA1 inhibitor. Results The girl, adopted and of Asian origin, began to suffer from nonspecific systemic inflammatory symptoms (persistent fever and arthralgias) at the age of 6. In past history recurrent respiratory infections and impaired immunological response to viruses (CMV related hepatitis, measles after vaccination) were reported. After few months the patient developed clinical and laboratory findings of HLH (Hemophagocytic Lympho-Histocytosis), confirmed on bone marrow samples; treatment with intravenous (IV) high dose (HD) steroids was started, with prompt response. During steroids tapering fever and systemic inflammation reappeared; anti-IL1 treatment (anakinra) was not effective. Immunologic assessment demonstrated mild hypogammaglobulinemia and moderate NK deficiency on lymphocyte subsets. HD IV Immunoglobulins (IG) (2 g/kg every month) allowed to achieve a complete control of the clinical picture; the frequency of administration was progressively reduced to every 4 months due to persistent wellbeing. At the age of 9, after switching IG to the substitutive dosage, the patient experienced Herpes Zoster virus reactivation (requiring prolonged antiviral treatment), followed by the reappearance of the inflammatory phenotype complicated by HLH with neurological involvement (irritability and lethargy), responsive to HD steroids and IG. A later cerebral MRI evidenced a small gliotic area in left Centrum Ovale. After steroids suspension, monthly HD IV IG administrations maintained clinical remission. Further immunological studies confirmed a reduction of NK cells with normal function. Hereditary HLH, Autoimmune Lympho-Proliferative Syndrome (ALPS) and main primary immunodeficiencies were ruled out. Given the clinical picture, a large NGS diagnostic panel (courtesy by K. Botzug, Vienna) for autoinflammatory diseases and immunodeficiencies was performed revealing the homozygous LEU141PRO ADA2 mutation, confirmed by Sanger analysis. Being this mutation novel, an ADA2 enzymatic activity test was performed revealing a complete loss of ADA2 activity. The parents refused anti-TNF treatment and the patient is still on monthly HD IG with a complete wellbeing after 3 years of follow-up. Conclusion The current report enlarges the clinical spectrum associated with DADA2 to a persistent unspecific inflammatory syndrome, complicated by HLH. This case further emphasizes the possibility that NGS could unravel unusual phenotypes of already known inflammatory syndromes. Even if further reports are required, the response to HD IG observed in the present case it is of interest. Even if anti-TNF is the treatment of choice HD IG could be a possible treatment in DADA2, especially during the acute phase. References [1] Caorsi R, et al. Ann Rheum Dis. 201776(10):1648-1656 Disclosure of Interests Francesca Garbarino: None declared, Roberta Caorsi: None declared, Stefano Volpi: None declared, Alice Grossi: None declared, Isabella Ceccherini: None declared, Marco Gattorno Grant/research support from: MG has received unrestricted grants from Sobi and Novartis