Clinical Spectrum of Ras-Associated Autoimmune Leukoproliferative Disorder (RALD)
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ORIGINAL ARTICLE
Clinical Spectrum of Ras-Associated Autoimmune Leukoproliferative Disorder (RALD) Quentin Neven 1 & Cécile Boulanger 1 & Annelyse Bruwier 2 & Maëlle de Ville de Goyet 1 & Isabelle Meyts 3,4 & Leen Moens 3 & An Van Damme 1 & Bénédicte Brichard 1 Received: 29 April 2020 / Accepted: 26 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Ras-associated autoimmune leukoproliferative disorder (RALD) is a clinical entity initially identified in patients evaluated for an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. It remains a matter of debate whether RALD is a chronic and benign lymphoproliferative disorder or a pre-malignant condition. We report the case of a 7-year-old girl diagnosed with RALD due to somatic KRAS mutation who progressed to a juvenile myelomonocytic leukemia phenotype and finally evolved into acute myeloid leukemia. The case report prompted a literature review by a search for all RALD cases published in PubMed and Embase. We identified 27 patients with RALD. The male-to-female ratio was 1:1 and median age at disease onset was 2 years (range 3 months–36 years). Sixteen patients (59%) harbored somatic mutations in KRAS and 11 patients (41%) somatic mutations in NRAS. The most common features were splenomegaly (26/27 patients), autoimmune cytopenia (15/16 patients), monocytosis (18/24 patients), pericarditis (6 patients), and skin involvement (4 patients). Two patients went on to develop a hematopoietic malignancy. In summary, the current case documents an additional warning about the long-term risk of malignancy in RALD. Keywords Autoimmunity . KRAS . NRAS . malignancy . Ras-associated autoimmune leukoproliferative disorder
Introduction The autoimmune lymphoproliferative syndrome (ALPS), the most common genetic disorder of lymphocyte apoptosis, is caused by germline or somatic mutations in the gene encoding FAS (a cell-surface receptor from the TNF receptor superfamily), germline mutations in Fas ligand (FASLG), or caspase 10 (CASP10) [1–3]. Patients develop early-onset chronic splenomegaly frequently associated with lymphadenopathy and * Quentin Neven [email protected] 1
Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium
2
Department of Pediatrics, Grand Hôpital de Charleroi, Charleroi, Belgium
3
Laboratory for Inborn Errors of Immunity, Department of Immunology, Microbiology and Transplantation, University Hospitals Leuven, Leuven, Belgium
4
Department of Pediatrics, ERN-RITA Core Center, University Hospitals Leuven, Leuven, Belgium
present a high incidence of autoimmunity (mainly cytopenias) as well as an increased risk for the development of hematological malignancies, including both Hodgkin and nonHodgkin lymphoma [3]. In 2007, Oliveira et al. reported a patient with an ALPS-like disease caused by a somatic mutation in NRAS [4]. Later, two additional patients with similar phenotype of non-malignant ly
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