Autoimmune Cytopenia: Genetics and Pathophysiological Mechanism in Pediatric Evans Syndrome (ACTION)

Characterization of the genetic causes, and of the immunopathological clinical and biological manifestations in children with pediatric Evans syndrome included in a prospective national observational cohort of rare diseases.

Study Overview

• Status: Unknown
• Conditions: Evans Syndrome
• Intervention / Treatment: Genetic: blood sample

Detailed Description

Pediatric Evans syndrome (pES) is a rare and severe disease combining immunologic thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA). French patients from the 30 hematologic pediatric centers are from 2004 included in a prospective national OBS'CEREVANCE cohort.

A first pilot study revealed a monogenic cause in 7/18 patients (40%) with mutations in the CTLA-4, LRBA, STAT3 GOF, and KRAS. TNGS or exome studies were performed between 2015 and 2018 inn 80 patients with pSE from the OBS'CEREVANCE cohort. This approach, combined with by immunophenotyping lymphocyte, identified a genetic cause of the disease in 26 patients (32%) (TNFRSF6, CTLA4, LRBA, STAT3 GOF, PIK3CD, RAG1, KRAS) and potential causal mutations in 18 other patients (22%), bringing the proportion of potential single gene cause to 76%.

The central hypothesis of this study is that most, if not all, cases of pSE are related to a monogenic or digenic cause, possibly with the intervention of genetic modifiers such as somatic mutations.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nathalie Aladjidi, M.D; Phone Number: 05 57 82 02 79; Email: nathalie.aladjidi@chu-bordeaux.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient registered in the French national prospective OBS'CEREVANCE cohort
• Diagnosis of pediatric Evans syndrome (PTI+AHAI)
• Age strictly under 18 years at the initial onset
• Child residing in metropolitan France and affiliated to a french health insurance system
• Free, informed, written and signed consent

Exclusion Criteria:

• Evans syndrome secondary to chemotherapy, bone marrow transplantation or organ transplantation.
• Refusal to participate from parents/patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: pediatric Evans Syndrome; Collection of biological samples of children with pSE included in the the OBS'CEREVANCE cohort and their parents, for genetic and functional immunological analyzes.

Genetic: blood sample; A first systematic approach by Targeted-Next Generation Sequencing will be used on the entire cohort of patients with pSE. This step will be performed on a sequencing chip specifically developed to detect anomalies in known genes involved in autoimmunity. In patients for whom no mutations are identified, a whole exome sequencing (WES) approach will be applied to patients and their parents to seek to identify mutations in new genes that may be related to pSE. In patients for whom this WES approach is unsuccessful, the search for somatic lymphocyte mutations, or copy number variants will be performed before considering a complete genome sequencing . If several candidate genes are identified, the clinical data provided by the CEREVANCE and the phenotypic analyses carried out prior to genetic analyses by the CEDI laboratory will guide the choices to prioritize the study of the identified variants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of patients for whom a causal mutation has been identified (known or new)	after the genetic analyzes carried out on all the participants included, may 2022
The number of biological samples collected for PSE children included in the OBS'CEREVANCE cohort and their relatives will be recorded	every 3 months, between may 2019 and may 2022

Secondary Outcome Measures

Outcome Measure	Time Frame
Immunopathological clinical manifestations	after the genetic analyzes carried out on all the participants included, may 2022
Abnormalities of lymphocyte immunophenotyping	after the genetic analyzes carried out on all the participants included, may 2022
The correlation between causal mutations identified with the clinical and immunological phenotype	after the genetic analyzes carried out on all the participants included, may 2022
Physiopathological and potentially therapeutic classification of pES-T	after the genetic analyzes carried out on all the participants included, may 2022

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Collaborators: Institut des maladies génétiques, Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): May 6, 2019
• Primary Completion (Anticipated): May 6, 2022
• Study Completion (Anticipated): May 6, 2022

Study Registration Dates

• First Submitted: April 9, 2019
• First Submitted That Met QC Criteria: April 9, 2019
• First Posted (Actual): April 11, 2019

Study Record Updates

• Last Update Posted (Actual): April 11, 2019
• Last Update Submitted That Met QC Criteria: April 9, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: pediatric Evans Syndrome; genetic causes; immunophenotyping immunologic explorations
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease; Hematologic Diseases; Anemia; Blood Platelet Disorders; Anemia, Hemolytic; Syndrome; Thrombocytopenia; Anemia, Hemolytic, Autoimmune
• Other Study ID Numbers: CHUBX 2018/49

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No