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

Federica Barzaghi,Maryam Omrani,Simone Cesaro,Margherita Mauro,Matteo Zoccolillo,Rita Balter,Anastasiia V Bondarenko,Federica Minniti,Massimo Degano,Virginia Vitale,Matteo Chinello,Immacolata Brigida,Michael S Hershfield,Maria Pia Cicalese,Massimiliano De Bortoli,Alessandro Aiuti,Ada Zaccaron,Elisa Bonetti

doi:10.3389/fimmu.2018.02767

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.

Highlights

Deficiency of adenosine deaminase 2 (DADA2) is a genetic autoinflammatory disease caused by autosomal recessive mutations in adenosine deaminase 2 (ADA2) gene, mapped on chromosome 22q11 [1]
We describe a case of ADA2 deficiency presenting as autoimmune lymphoproliferative syndrome (ALPS)-like disease, unresponsive to immunosuppressive therapy, successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT)
Clinical presentation of DADA2 as ALPS-like disease have been reported in two patients [17, 18] who were successfully treated with HSCT and anti-TNF medications respectively

Summary

INTRODUCTION

Deficiency of adenosine deaminase 2 (DADA2) is a genetic autoinflammatory disease caused by autosomal recessive mutations in adenosine deaminase 2 (ADA2) gene, mapped on chromosome 22q11 [1]. Pre-HSCT plasma of the patient was not available but we could assess ADA2 activity in the parents, which resulted lower than healthy controls as expected in carriers, supporting the deleterious effect of the mutations on the protein function. Patient’s ADA2 plasma activity after HSCT was normal, in the absence of clinical manifestations of the disease and in the presence of full donor chimerism (Table 3). These results strongly suggest DADA2 as cause of the hematological manifestations of the patient. She is alive and well 28 months after HSCT enjoying a normal life

Findings

DISCUSSION

ETHICS STATEMENT