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.