Ebe Schiavo, Italy
University of Florence Department of NEUROFARBA - Section of Child's HealthPresenter of 2 Presentations
MULTIGENICITY OF THE DEFICIT OF THE IMMUNE SYSTEM: NOVEL FRONTIERS OF PRIMARY IMMUNODEFICIENCIES (PIDS).
Abstract
Background and Aims
PIDs are often associated with autoimmunity due to dysregulation of the immune system as a whole. Clinical phenotypes are heterogeneous and often overlapping and, while in most patients a monogenic cause of disease has been identified, recent advancements made in genetic analysis, in particular with the introduction of high throughput techniques, reveal that a polygenic cause is likely. Our aim is to investigate the genetic background of patients with signs of immunedysregulation and autoimmunity, and to evaluate the pathogenicity of gene variants identified through extensive functional studies.
Methods
We selected nineteen patients, referring to the Haemato-Oncology Department of A. Meyer Children’s Hospital, with signs of immunedysregulation and autoimmunity and we performed extended immunophenotyping and Next Generation Sequencing (NGS) analysis of 50 PID-associated genes.
Results
In six patients we identified a single gene as responsible of the clinical feature. In particular, we identified two patients with STAT3 GOF, one with an activating PIK3CD mutation, and three patients harboring mutations in CTLA4, RAG1 and FAS genes, respectively. Most of them also harbor variants in multiple genes and some of these are recurrently mutated in more then one patient: WAS, DOCK8, CASP10, CASP8, NFATC2 and FCGR3A. Further studies are ongoing to validate the effect of gene variants identified.
Conclusions
Our results suggest that the old hypothesis, based on a single gene mutation as cause of disease, should be revised in favor of the concept that "is the sum that causes the effect" and that a different point of view on PIDs seems inevitable.
PEDIATRIC LYMPHOMA: A POSSIBLE WARNING SIGN OF PRIMARY IMMUNODEFICIENCY DISORDERS (PIDDS)?
Abstract
Background and Aims
Non-Hodgkin lymphomas (NHL) account for approximately 6-7% of pediatric cancers and their incidence increases with age. Patients with PIDDs show a higher susceptibility to hematopoietic malignancies, in particular to NHL. Recently new gene defects responsible for PIDDs with lymphoproliferation as a key clinical sign have been identified. Our goal is to investigate possible immune-mediated mechanisms underlying malignant lymphoproliferation in children who did not show other typical symptoms of PIDDs.
Methods
We retrospectively selected and reviewed the clinical history of eight patients with NHL (6 Burkitt lymphoma, 2 large B cell lymphoma and 1 lymphoblastic T cell lymphoma). Immunophenotyping and exome analysis of known PIDDs genes were performed after lymphoma remission.
Results
Six out of eight patients showed a mild hypogammaglobulinemia at time of presentation, not noticed before. Moreover, one patient had history of recurrent respiratory infections, one of hematologic autoimmunity and two of eight were EBV-positive at diagnosis. Preliminary results show an aberrant B cell phenotype in four patients; exome analysis reveals a novel heterozygous genetic variation in IKZF1 gene in one patient with Burkitt lymphoma and autoimmune cytopenia was identified. Concerning the remaining patients, further studies are ongoing.
Conclusions
A detailed review of clinical history of pediatric patients affected from NHL as well as an impaired immunophenotyping can be important indicators of immune-mediated disorder underlying lymphoproliferation and helpful signs of possible PIDDs that should promptly be investigated by genetic analysis. This will allow an appropriate diagnosis and disease management.