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

Abstract

Adenosine deaminase-2 (ADA2) deficiency (DADA2) is associated with early onset polyarteritis nodosa and vasculopathy. Classic presentation includes livedo reticularis, vasculitis, and stroke. However, the phenotype and disease severity are variable. We present a 5-year-old female who presented with features that mimicked autoimmune lymphoproliferative syndrome (ALPS) in the absence of classic features of DADA2. Exome sequencing identified a novel homozygous splicing variant in ADA2 c.882-2A > G. Patient responded to anti- tumor necrosis factor medication and is in complete remission. Hematologists should be aware of various hematological presentations of DADA2, including ALPS-like disorder, that might lack vasculitis and livedo reticularis to prevent delay in initiating optimal therapy.

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…Importantly, unlike typical DBA due to mutations in ribosomal proteins or GATA1, there is no increase of ADA1 in red blood cell. Autoimmune hemolytic anemia and thrombocytopenia have also been described . Severe neutropenia has been reported in up to 10% of patients .…”

“…Patients suffering from DADA2 have in fact also presented with a clinical picture mimicking autoimmune lymphoproliferative syndrome (ALPS). Indeed, some patients have autoimmune cytopenia in conjunction with generalized lymphadenopathy and the presence of slightly elevated or normal percentages alpha/beta TCR DN T cells . Another group recently reported a T cell large granular leukemia (T‐LGL) in two patients presenting lymphoproliferation at 8y and 31y, respectively.…”

“…Autoimmune hemolytic anemia and thrombocytopenia have also been described. 68,88 Severe neutropenia has been reported in up to 10% of patients. 4,90,91 The clinical phenotype can be very severe with abscesses.…”

“…In late-onset ADA1 deficiency, recurrent herpes virus infections are also common together with progressive lymphopenia, elevated IgE, and autoimmune phenomena. The autoimmune phenomena in DADA2 are less common but have been noted in some patients in the form of systemic lupus and autoimmune cytopenia 1,68,78,84,88. Transiently positive lupus anticoagulant was present in 10% of patients and increased with age.…”

Monogenic autoinflammatory disorders: beyond the periodic fever

“…Since this time, several reports published suggest that the phenotypic spectrum is broad, and the penetrance of disease is variable, with cytopenias, lymphoproliferative disease and immune deficiencies being reported. [103][104][105][106][107] Although an interferon gene signature has been noted in these patients, 108,109 the response to TNF inhibition has been impressive 101,110,111 and is now recommended therapy. 112 Gain-of-function mutations in TMEM137 encoding the cytosolic innate immune sensor STING result in an autoinflammatory disease characterised by peripheral vascular inflammation, nail dystrophy and interstitial lung disease termed STING associated vasculopathy with onset in infancy (SAVI).…”