Adenosine Deaminase 2 Deficiency L95.5

Vasculitis, auto-inflammation, immunodeficiency, and hematologic deficiency syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable. Most patients have features of systemic vasculitis associated with vasculitic skin ulcerations and recurrent strokes affecting the small vessels of the brain leading to neurologic dysfunction.

Vasculitis, Autoinflammation, Immunodeficiency and Hematologic Defects Syndrome (VAIHS) is caused by a homozygous or compound heterozygous mutation in the ADA2gene/CECR1 gene) on chromosome 22q11.

Recurrent fever, myalgias, inflammatory skin changes resembling polyarteritis nodosa, livedo racemosa. Some patients may have renal and/or gastrointestinal involvement with arterial hypertension, aneurysms or ischemic necrosis of the fingers. Some patients exhibit clinical immunodeficiency (Zhou Q et al. 2014).

Elevated acute phase proteins.

First-line treatment consists of TNF inhibitors and is effective in controlling inflammation and maintaining vascular integrity. Hematopoietic stem cell transplantation (HSCT) has been shown to be successful in a group of patients with hematologic manifestations.

Deficiency of ADA2(DADA2) is the first molecularly described monogenic vasculitis syndrome. Over 60 disease-associated mutations have been identified in all domains of ADA2, affecting catalytic activity, protein dimerization and secretion. Vasculopathies ranging from livedo reticularis to polyarteritis nodosa (PAN) and life-threatening ischemic and/or hemorrhagic strokes dominate the clinical features of DADA2 (Meyts I et al. 2018).

A mutation in the ADA2 gene can also cause Sneddon syndrome (182410), which occurs later in life.

Zhou et al (2014) reported 9 patients from 8 unrelated families who presented with early-onset recurrent ischemic apoplexy and recurrent fever between the ages of 5 months and 4 years. Imaging showed that the strokes occurred in the nuclei of the deep brain and brain stem, suggesting small vessel occlusion. All patients had various neurological manifestations of stroke, including 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. Acute-phase proteins were markedly elevated during febrile episodes. All patients had skin involvement: livedo racemosa and signs of leukocytoclastic vasculitis. Other features were hepatosplenomegaly with abnormal liver enzymes, hypogammaglobulinemia, pancytopenia, and leukopenia. 5 patients developed antiphospholipid antibodies after some time.

Navon Elkan et al (2014) reported 19 individuals of Georgian Jewish descent with polyarteritis nodosa vasculopathy. Despite the homogeneous background, there was inter- and intrafamilial variability. Fifteen of the patients were diagnosed with the disease before the age of 10 years, six of whom were diagnosed in infancy. Four patients with onset in infancy suffered from severe systemic reactions, including ischemia and necrosis of the fingers and toes, recurrent fever, coronary aneurysms, necrotizing vasculitis of the intestine, renal aneurysms and stenoses, and abdominal pain. Several patients had hypertension.

Skin: livedo racemosa, leukocytoclastic vasculitis, panniculitis. Neurologic signs and symptoms involved both the central nervous system, manifesting as facial paralysis and infarcts, and the peripheral nervous system (neuropathy). At the mildest end of the spectrum, one patient developed ulcers crura which first appeared at the age of 59 years.

Laboratory: leukocytosis, thrombocytosis, an elevated C-reactive protein, elevated ESR; less commonly, anemia.

1. Lee PY (2018) Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2. Front Pediat 6: 282.
2. Meyts I et al (2018) Deficiency of adenosine deaminase 2 (DADA2): updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol 38:569-578.
3. Navon Elkan P et al (2014) Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. New Eng J Med 370: 921-931.
4. Van Eyck L et al (2014) Mutant ADA2 in vasculopathies. (Letter) New Eng J Med 371: 478-479.
5. Van Eyck L et al (2014) Mutant ADA2 in vasculopathies. (Letter) New Eng J Med 371: 480.
6. Zhou Q et al (2014) Early-onset stroke and vasculopathy associated with mutations in ADA2. New Eng J Med 370: 911-920.