Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency

Abstract

Deficiency of adenosine deaminase type 2 (DADA2) is a rare form of autoinflammatory disorder with limited reported cases. In this paper, we have presented the clinico-immunological, radiological and genetic characteristics of five surviving and three deceased childhood-onset DADA2 patients. We aimed to compare surviving and deceased patients in terms of clinical features and treatment modalities. Moreover, we have evaluated the causes of death in our DADA2 subjects together with the previously reported cases. Demographic features, clinical characteristics, imaging findings, mutations and pharmacological treatments of DADA2 subjects were noted from patient records of pediatric and adult rheumatology clinics in a retrospective and longitudinal nature. Eight patients from seven families were enrolled. While five of them were surviving, three of them had died due to various reasons. Median age of the patients at disease onset and diagnosis was 7 years (range 0.5-13 years) and 14 years (range 5-27 years), respectively. The main clinical manifestations were cutaneous findings (7/8), recurrent low-grade fever (6/8), neurological involvement (6/8) and gastrointestinal involvement (5/8). All patients had increased acute phase reactants at presentation and also during the disease flares. Until the diagnosis of DADA2 was confirmed, five patients have been followed-up with the diagnosis of PAN: two patients both with PAN and FMF, and one patient with CAPS and vasculitis. Demographic, clinical, neurological features and genetic mutations did not differ in surviving and deceased DADA2 patients. Deceased and surviving subjects differed in terms of treatment modalities after the diagnosis of DADA2. Anti-TNF alpha treatment has been initiated in five surviving patients as soon as the diagnosis of DADA2 was established. However, three patients who have died were not able to use sufficient doses of anti-TNF alpha treatment; in one case due to reluctance of patient and in two cases due to establishment of the definite diagnosis by genetic analysis at the same time with the last fatal DADA2 episode. Despite limited number of patients, this case series for the first time compares the phenotypic, genotypic and medication differences between surviving and deceased DADA2 patients. Anti-TNF alpha treatment seems to be efficient and lifesaving in DADA2 patients.

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis

“…The use of steroids in our case was successful in inducing and maintaining remission, although the required dose is usually more than 1 mg/kg of prednisone . The known short‐ and long‐term toxicities of chronic use of steroids preclude it from being the drug of choice for this condition.…”

“…The spectrum of DADA2 phenotype is evolving as more atypical presentations have been reported recently. [7][8][9][10][11][12][13][15][16][17][18] Table 1 summarizes hematological manifestations that were reported in DADA2. In the present case, ALPS-like disorder was the main presentation with absence of signs of vasculitis, livedo reticularis, or stroke, causing a diagnostic challenge that was only resolved after obtaining exome sequencing result.…”

“…Hepatosplenomegaly Common presentation 1,16,22,23 Hypogammaglobulinemia Common presentation 1,22 Hemorrhagic or ischemic stroke Common presentation 1,2,16,22,23 Cytopenia affecting one or more cell lines Common presentation 1,18,23 Evans syndrome One case 1 Atypical diamond blackfan anemia (pure red cell aplasia) Two cases 7,18 Macrophage activation syndrome One case 1 Combined immunodeficiency with lymphoproliferation Three cases 18,20 Common variable immunodeficiency Two cases 12 Autoimmune lymphoproliferative syndrome like Two cases 18 and this study Castleman disease like One case 8 X-linked lymphoproliferative syndrome-like One case 18 The use of steroids in our case was successful in inducing and maintaining remission, although the required dose is usually more than 1 mg/kg of prednisone. 16 The known short-and long-term toxicities of chronic use of steroids preclude it from being the drug of choice for this condition. Anti-TNF medications, etanercept at a dose of 1.6 mg/kg and adalimumab, were successful in maintaining remission in our patient; however, persistent neutropenia was associated with the use of both medications.…”

“…2,7,[16][17][18] Complete response was also described with the use of thalidomide. 16 Methotrexate, azathioprine, rituximab, MMF, cyclophosphamide, and anti-interleukin1 were not effective. 1,2,15 In addition, the short half-life of ADA2 makes fresh frozen plasma an impractical replacement therapy in DADA2.…”

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

“…Treatment of ten individuals with TNF targeting therapy by Levy-Lahad et al led to significant clinical improvement, highlighting the role of this cytokine in disease pathogenesis [84]. The response to TNF directed therapy has since been reproduced [86,87]. In a subsequent study of 48 cases with polyarteritis nodosa associated with livedo reticularis and/or strokes, Gattorno et al performed Sanger sequencing of CECR1 and determined that 15 cases harboured homozygous or compound heterozygous mutations [88].…”