Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

Abstract

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.

Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist

“…Lymphopenia, neutropenia, thrombocytopenia (Evans syndrome), lymphoproliferation with/without elevated double negative T-cells (raising a possibility of autoimmune lymphoproliferative syndrome) has also been reported in these patients ( 1 , 18 , 30 , 32 , 46 , 49 – 51 ). In addition to expected bone marrow examination findings of erythroid hyperplasia (with reticulocytosis), features of erythroid hypoplasia or dysplasia (with reticulocytopenia) have also been described in these patients ( 46 , 49 , 50 ). Direct antiglobulin test was also positive in absence of overt hemolysis and PRCA in few patients ( 50 , 52 ).…”

“…ADA2 has been known to itself act as a growth factor ( 7 , 9 ) with a potential to modulate secretion of other growth factors as well. Contemporary evidence also suggests both ADA1 and ADA2 enzymes to play a crucial role in development of progenitor cells in the bone marrow ( 45 , 46 ). The precise contributions of growth factor or ectonucleotidase properties of ADA2 towards development of marrow cells remains to be delineated, resulting in significant gaps in understanding of pathogenesis of marrow hypofunction.…”

“…The precise contributions of growth factor or ectonucleotidase properties of ADA2 towards development of marrow cells remains to be delineated, resulting in significant gaps in understanding of pathogenesis of marrow hypofunction. A possibility of immune-related marrow hypofunction (as a result of autoimmunity) also exists ( 17 , 46 ). Besides ‘central’ (i.e.…”

“…To date, more than a dozen such patients of DADA2 have been reported accompanied with predominant autoimmune cytopenia. In most of these patients the clues for etiological diagnosis have ranged from vasculopathic ulcers ( 30 ), stroke ( 1 ), low IgG/IgM or hypogammaglobulinemia ( 32 , 44 – 48 ), recurrent infections ( 18 , 49 ) including the vaccine pathogens ( 46 ). Lymphopenia, neutropenia, thrombocytopenia (Evans syndrome), lymphoproliferation with/without elevated double negative T-cells (raising a possibility of autoimmune lymphoproliferative syndrome) has also been reported in these patients ( 1 , 18 , 30 , 32 , 46 , 49 – 51 ).…”

“…In most of these patients the clues for etiological diagnosis have ranged from vasculopathic ulcers ( 30 ), stroke ( 1 ), low IgG/IgM or hypogammaglobulinemia ( 32 , 44 – 48 ), recurrent infections ( 18 , 49 ) including the vaccine pathogens ( 46 ). Lymphopenia, neutropenia, thrombocytopenia (Evans syndrome), lymphoproliferation with/without elevated double negative T-cells (raising a possibility of autoimmune lymphoproliferative syndrome) has also been reported in these patients ( 1 , 18 , 30 , 32 , 46 , 49 – 51 ). In addition to expected bone marrow examination findings of erythroid hyperplasia (with reticulocytosis), features of erythroid hypoplasia or dysplasia (with reticulocytopenia) have also been described in these patients ( 46 , 49 , 50 ).…”