A number sign (#) is used with this entry because vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS) is caused by homozygous or compound heterozygous mutation in the CECR1 gene (ADA2; 607575) on chromosome 22q11.

Mutation in the ADA2 gene can also cause Sneddon syndrome (182410), which shows later onset.

Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits (summary by Zhou et al., 2014 and Navon Elkan et al., 2014). Some patients present with clinical immunodeficiency (van Eyck et al., 2014).

Lee (2018) reviewed the basic biology of ADA2 and the various clinical manifestations of ADA2 deficiency, which include vasculitis affecting small- and medium-sized vessels causing early-onset stroke with subsequent neurologic signs, skin ulcerations resembling polyarteritis nodosa, peripheral neuropathy, immunodeficiency, autoimmune features, and hematologic abnormalities, including anemia and leukopenia. The clinical features are highly pleiotropic, and patients can present with only some of these main features. The hematologic manifestations of the disorder may sometimes resemble Diamond-Blackfan anemia (see, e.g., DBA1, 105650).

Zhou et al. (2014) reported 9 patients from 8 unrelated families who presented with early-onset recurrent ischemic stroke and fever between ages 5 months and 4 years. Three patients also had hemorrhagic stroke. Imaging showed that the strokes occurred in the deep-brain nuclei and brainstem, consistent with small-vessel occlusion. Affected regions included the thalamus, internal capsule, basal ganglia, midbrain, and pons. All patients had variable neurologic manifestations of stroke, such as paraplegia, ataxia, hemiparesis, headache, ophthalmoplegia, aphasia, altered mental status, and cranial nerve dysfunction. One patient had central retinal artery occlusion, and another had left optic nerve atrophy. The levels of acute-phase reactants were markedly increased during febrile episodes. All patients had skin involvement, with livedo racemosa and often with urticarial papules and plaques. Skin biopsy showed neutrophils and macrophages in the interstitium and perivascular T lymphocytes. Other features included hepatosplenomegaly with abnormal liver enzymes, and evidence of a mild immunodeficiency with hypogammaglobulinemia, pancytopenia, and leukopenia. At the onset of stroke, all patients were negative for antiphospholipid antibodies, but lupus anticoagulant developed over time in 5 patients. Aggressive treatment with glucocorticoids, cyclophosphamide, and cytokine inhibitors only partially controlled fever, rash, and acute-phase reactants. Intracranial magnetic resonance angiography was normal in all patients studied, except 1 who had cortical and subcortical lesions and decreased caliber of the right posterior cerebral artery.

Navon Elkan et al. (2014) reported 19 individuals of Georgian Jewish descent with a polyarteritis nodosa vasculopathy. Despite the homogeneous background, there was inter- and intrafamilial variability. Fifteen of the patients were diagnosed before age 10 years, including 6 who were diagnosed in infancy. Four patients with infantile onset had the most severe systemic disease, including ischemia and necrosis, of the fingers and toes. Other variable systemic features included fever, coronary aneurysms, necrotizing vasculitis of the bowel, renal aneurysms and stenosis, and abdominal pain. Several patients had hypertension. Most had skin involvement, with livedo reticularis, rash, purpura, and leukocytoclastic vasculitis or panniculitis on skin biopsy. Neurologic signs and symptoms affected both the central nervous system, manifest as facial palsies and infarcts, and the peripheral nervous system, manifest as neuropathy and foot drop. Laboratory studies showed leukocytosis, thrombocytosis, increased C-reactive protein (CRP; 123260), high erythrocyte sedimentation rate, and sometimes anemia. At the mildest end of the spectrum, 1 patient developed leg ulcers that first appeared at age 59 years. Four German sibs and a Turkish man had a similar disorder with onset in the first decade.

Van Montfrans et al. (2014) reported 2 brothers with ADA2 deficiency confirmed by molecular analysis. One presented at age 6 months with livedo reticularis, hepatosplenomegaly, hypercoagulability, granulocytopenia, and complete red cell aplasia. The other presented at age 6 years with similar features. He also had unexplained fever and had a stroke at age 10 years. Van Eyck et al. (2014) reported 2 affected brothers who presented at 13 and 5 months of age, respectively. The older patient had combined immunodeficiency, cytopenia, and lymphoproliferation. After immunosuppressive and immunoglobulin therapy proved insufficient, he underwent successful hematopoietic stem cell transplantation. The younger patient had a similar phenotype but responded better to immunosuppression therapy. Van Eyck et al. (2014) also reported a Jewish boy with the disorder who presented at age 5 years with recurrent fevers, splenomegaly, lymphadenopathy, anemia, thrombocytosis, and hyperimmunoglobulinemia. Serum IL6 (147620) levels were elevated. These reports emphasized that immunodeficiency and immune dysregulation are part of the phenotypic spectrum of childhood-onset PAN.

Sasa et al. (2015) reported a family in which 2 sibs had variable manifestations of ADA2 deficiency. The proband presented in infancy with isolated severe anemia clinically resembling Diamond-Blackfan anemia, but erythrocyte ADA was not obtained. He received a hematopoietic bone marrow stem cell transplant from his apparently unaffected sister. However, red cell engraftment was not achieved, and he underwent a second mismatched successful transplant. His sister later presented at 14 years of age with more diverse clinical symptoms consistent with VAIHS, including anemia, immunodeficiency, aphthous ulcers, and low IgM. Genetic analysis identified compound heterozygous mutations in the ADA2 gene in both sibs. Sasa et al. (2015) emphasized that ADA2 deficiency can present with isolated early-onset anemia resembling DBA.

Van Montfrans et al. (2016) reported 9 patients, ranging in age from 4 to 50 years, from 6 unrelated families in the Netherlands with genetically confirmed ADA2 deficiency. Two sibs (patients 8 and 9) were offspring of a Caucasian mother and a father of Moroccan descent. Although all were homozygous for the same missense mutation in the ADA2 gene (R169Q; 607575.0006), the phenotype varied significantly. The mean age at onset was 2.6 years (range, birth to 8 years), and the presenting symptoms differed for each patient. Presenting symptoms included complicated viral infections, pancytopenia, anemia, thrombocytopenia, hypogammaglobulinemia, stroke, acute myeloid leukemia, and neurologic abnormalities, such as strabismus, ataxia, or behavioral changes. Clinical symptoms were also variable, but were consistent with rheumatic or immunologic disease, including arthralgias, ulcerative skin disease or inflammation, splenomegaly, and hepatomegaly. Most patients had more than one episode of neurologic deterioration manifest as cranial nerve deficits such as hearing loss, vertigo, optic nerve atrophy, oculomotor disturbances, focal signs, ataxia, or seizures. Less common features included recurrent fevers and infections, lymphadenopathy, lymphoproliferation, arthralgias, and oral aphthous ulcers. ADA2 enzyme activity was lower in patients compared to controls, and was the lowest in patients with stroke compared to those without stroke. Treatments included corticosteroids, immunoglobulin supplementation, and immunosuppression. Three patients underwent hematopoietic stem cell transplant with complete resolution of symptoms. Van Montfrans et al. (2016) postulated that the clinical variability in these patients with the same European founder allele likely resulted from environmental factors or other genetic variation.

Van Montfrans et al. (2014) and Van Eyck et al. (2014) independently reported 2 patients with ADA2 deficiency who underwent successful hematopoietic stem cell transplantation, which resulted in resolution of cytopenias, skin lesions, hepatosplenomegaly, and hypercoagulability. Serum ADA2 levels were subsequently normal in both patients. Each patient had an affected sib who responded better to immunosuppressive medical therapy.

Van Eyck et al. (2014) reported a Jewish boy with genetically confirmed ADA2 deficiency who responded favorably to treatment with an IL6 receptor antibody (tocilizumab). Before treatment, this patient had elevated serum IL6 levels and strong expression of IL6 in a lymph node biopsy.

The transmission pattern of polyarteritis nodosa in the families reported by Zhou et al. (2014) and Navon Elkan et al. (2014) was consistent with autosomal recessive inheritance.

In 9 patients from 8 unrelated families with polyarteritis nodosa, Zhou et al. (2014) identified homozygous or compound heterozygous mutations in the CECR1 gene (see, e.g., 607575.0001-607575.0006). All mutations except 1 were missense mutations. The initial mutations were found by whole-exome sequencing, and subsequent mutations were found by candidate gene sequencing. Brain and skin biopsies from patients showed evidence of endothelial damage associated with increased staining for IL1B (147720), TNFA (191160), and inducible nitric oxide synthase (NOS2A; 163730). There was evidence for increased B-cell death and reduced B-cell differentiation compared to controls. Patients had significantly decreased ADA2 activity in plasma, and Western blot analysis showed reduced ADA2 protein levels in cell lysates, consistent with a loss of function. Morpholino knockout of a CECR1 ortholog (cecr1b) in zebrafish resulted in intracranial bleeding that could be rescued by wildtype human CECR1, but not by mutant CECR1. Knockout of cecr1b in myeloid cells resulted in neutropenia. Knockdown of CECR1 using short hairpin RNA (shRNA) in human myeloid cells caused marked impairment of macrophage differentiation and disruption of cocultured monolayers of human microvascular endothelial cells. These defects in monocyte/macrophage differentiation were also seen in patients. Zhou et al. (2014) suggested that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and that ADA2 deficiency may polarize macrophages and monocytes toward proinflammatory cells, resulting in inflammation, endothelial cell damage, and small-vessel vasculopathy.

In 19 patients of Georgian Jewish descent with autosomal recessive polyarteritis nodosa, Navon Elkan et al. (2014) identified a homozygous missense mutation in the CECR1 gene (G47R; 607575.0006). The mutation was found by exome sequencing. Affected members of a German family and a Turkish patient were subsequently found to carry compound heterozygous missense CECR1 mutations (607575.0005; 607575.0007-607575.0009). ADA2 activity was significantly reduced in patient serum samples, and in vitro cellular expression studies showed low amounts of secreted mutant protein, consistent with a loss of function.

Zhou et al. (2014) proposed the name 'deficiency of ADA2' (DADA2) for this disorder encompassing systemic inflammation, vascular pathology, and mild immunodeficiency.