Pediatric acute lymphoblastic leukemia (pALL) is the most common childhood malignancy, yet its etiology remains incompletely understood. However, over the course of three waves of germline genetic research, several non-environmental causes have been identified. Beginning with trisomy 21, seven overt cancer predisposition syndromes (CPSs)-characterized by broad clinical phenotypes that include an elevated risk of pALL-were first described. More recently, newly described CPSs conferring high risk of pALL are increasingly covert, with six exhibiting only minimal or no non-cancer features. These 13 CPSs now represent the principal known hereditary causes of pALL, and human pangenomic data indicates a strong negative selection against mutations in the genes associated with these conditions. Collectively they affect approximately 1 in 450 newborns, of which just a minority will develop the disease. As evidenced by tailored leukemia care protocols for children with trisomy 21, there is growing recognition that CPSs warrant specialized diagnostic, therapeutic, and long-term management strategies. In this review, we investigate the evidence that the 12 other CPSs associated with high risk of pALL may also see benefits from specialized care - even if these needs are often incompletely mapped or addressed in the clinic. Given the rarity of each syndrome, collaborative international research and shared data initiatives will be crucial for advancing knowledge and improving outcomes for these patients.

Childhood Leukaemia Investigation Prague Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czechia

Department of Childhood and Adolescent Medicine Rigshospitalet Copenhagen Denmark

Department of Clinical Genetics Rigshospitalet Copenhagen Denmark

Department of Clinical Medicine Faculty of Medicine Copenhagen University Copenhagen Denmark

Department of Genetic Predisposition to Cancer Medical University of Lodz Lodz Poland

Department of Genetics Robert Debré University Hospital APHP Paris France

Department of Genetics University Medical Center Utrecht Utrecht University Utrecht the Netherlands

Department of Pediatric Hematology and Oncology Schneider Children's Medical Center and Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Pediatric Oncology Hematology and Clinical Immunology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany

Department of Pediatrics Oncology and Hematology Medical University of Lodz Lodz Poland

INSERM UMR_S1131 Institut de Recherche Saint Louis Paris France Paris France

Pediatric Hematology and Immunology Department Robert Debré Academic Hospital GHU AP HP Nord Paris Paris France

Princess Máxima Center for Pediatric Oncology Utrecht Netherlands

School of Medicine and Surgery University of Milano Bicocca Milan Italy

Tettamanti Center Fondazione IRCCS San Gerardo dei Tintori Monza Italy

University Paris Cité Paris France

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