Discussion:
We report a VIAHS ADA2 deficiency diagnosed child with atypical clinical features at disease onset. The clinical description of this girl highlights the variable phenotype associated with ADA2 deficiency due to CECR1 mutations [8]. ADA2 deficiency was first described in two major articles, with fever, visceral and cutaneous lesions compatible with polyarteritis nodosa, and peripheral and central nervous system involvement [8-9]. While the patient in this report eventually demonstrated a comparable spectrum of disease features, she initially presented with a perianal abscess and persistent fever.
ADA2 deficiency should be considered as a differential diagnosis of enlarging cutaneous abscess with no evidence of wound healing in the setting of leukopenia and neutropenia. Our patient exhibited neither hypogammaglobulinemia nor biological markers of autoimmunity (ANA/lupus anticoagulant) nor recurrent infections, even though there was B cell lymphopenia in accordance with the proposed hypothesis that ADA2 deficiency may lead to a defect in memory B cells [4]. Various clinical manifestations of ADA2 deficiency (VAIHS, OMIM#615688) include vasculopathy, skin manifestations, neuropathy, immunodeficiency, and hematology.
Our patient showed a splicing variant c.882-2A>G in ADA2 gene. ADA2 (Adenosine Deaminase 2, OMIM#607575) gene encodes a member of a subfamily of the adenosine deaminase protein family that catalyzes the deamination of adenosine and 2-prime-deoxyadenosine to inosine and deoxyinosine, respectively, and regulates levels of adenosine signaling, cell proliferation and differentiation. Diseases associated with ADA2 include Sneddon syndrome (SNDNS, OMIM#182410), vasculitis, auto-inflammation, immunodeficiency and hematologic defects syndrome (VAIHS, OMIM#615688), Kaposi sarcoma susceptibility, and Diamond-Blackfan anemia 1. The variant c.882-2A>G (ADA2, NM_001282225.2) is reported in ClinVar and Varsome databases as pathogenic for polyarteritis nodosa or VAIHS and has been previously described to resemble ALPS (autoimmune lymphoproliferative syndrome) like phenotype by Alsutlan et al. 2018 (PMID 29271561) [10-11]. There is no precise genotype-phenotype correlation in the reported ADA2 mutations and further studies are needed to evaluate the effects of this mutation on RNA splicing, stability, and translation. Variability in disease severity has been reported even among patients with the same mutation, as previously reported in individuals with homozygous p.Arg169Gln mutation, indicating potential genetic, epigenetic, and environmental factors in determining the severity of the phenotype [2-3, 6].
The use of steroids, Anakinra, Infliximab, and G-CSF was not effective in this condition. Studies have exhibited benefit from the use of anti-TNF agents such as Entracept and Adalimumab, and Thalidomide resulting in complete remission [5]. In addition, the use of fresh frozen plasma (FFP), considered a crucial therapy in DADA2, was also not beneficial, possibly due to the short half-life of ADA2 [9]. Hematopoietic stem cell transplantation (HSCT) with its potential advantages in the cure of the disease and avoidance of long-term cost and toxicity of lifelong anti-TNF therapy [7,11-12] was an option, and HLA typing was done on both parents. However, the current case did not receive HSCT due to complications. HSCT was reported to treat DADA2 effectively [12].
In summary, the classic DADA2 phenotype includes vasculitis, stroke, livedo reticularis, hepatosplenomegaly, hypogammaglobulinemia, and cytopenia and there is high phenotypic variability in DADA2 [10]. Our patient had cutaneous vasculitis and leukopenia, and neutropenia without evidence of lacunar strokes, organomegaly, and dysregulation of immune response rendering diagnosis more challenging. Thus, screening for DADA2 should be considered in the differential diagnosis in children presenting with persistent fever, cytopenia, and non-healing cutaneous lesions. This report renders that marked phenotypic variability can occur, and screening for families should be initiated in those with evidence of ADA2 mutation. Efforts to collect new cases may allow us to close potential diagnostic gaps, straddling the borders of autoinflammation and immunological deficiency [13]. Importantly, although the pathological basis of this severe disease remains unclear, highly promising therapeutic strategies have already emerged.