ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.

Somatic and germline FOXP3 mosaicism in the mother of a boy with IPEX syndrome

“…Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare monogenic disease caused by mutations of FOXP3 gene located on Xp11.23 with an X-linked recessive inheritance pattern. As the FOXP3 gene is essential for the function of regulatory T cells, its deficiency leads to multisystem autoimmune manifestations [1][2][3]. In the absence of curative treatment with hematopoietic stem cell transplantation, IPEX syndrome is a severe life-threatening disorder, especially for the first 2 years of life [4,5].…”

The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency

“…Type 1 interferons decreases after treatment [ 19 ] and may be useful as a biomarker for DADA2 activity. Additional elevated peripheral cytokines have included IL-6 [ 23 – 25 , 26 •], IL-8 [ 25 ], and IL-10 [ 27 , 28 ] (Fig. 1 ).…”

“…Hematologic and immunodeficiency phenotypes were recognized later, with manifestations appearing to be closely linked. Pure red cell aplasia (PRCA), hemolytic anemia, autoimmune neutropenia, isolated refractory thrombocytopenia, and pancytopenia have all been reported [ 26 •, 27 , 28 , 31 •, 37 •, 49 , 57 , 59 , 60 ]. Bone marrow biopsy in one DADA2 patient with bicytopenia revealed myelofibrosis [ 32 •].…”

Phenocopies: Mimics of Inborn Errors of Immunity

“…More than half of patients with ALPS need immunosuppressive treatment for manifestations of autoimmunity, high-dose systemic steroid schemes are needed for short cycles [15]. The use of medications such as mycophenolatemofetil, azathioprine, methotrexate, 6-mercaptopurine or sirolimus has also been documented, although they are not compatible to control the disease by themselves, so hematopoietic progenitor cell transplantation can be alternative [16] [17]. Rituximab has been used for patients with cytopenias refractory to treatment, although it is advised that the risk of prolonged hypogammaglobulinemia must be assessed in all patients [18].…”