Severe Phenotype in Patients with Large Deletions of NF1
Laurence Pacot, Dominique Vidaud, Audrey Sabbagh, Ingrid Laurendeau, Audrey Briand‐Suleau, Audrey Coustier, Théodora Maillard, Cécile Barbance, Fanny Morice‐Picard, Sabine Sigaudy, Olga O. Glazunova, Léna Damaj, Valérie Layet, Chloé Quēlin, Brigitte Gilbert‐Dussardier, Frédérique Audic, Hélène Dollfus, Anne‐Marie Guerrot, James Lespinasse, Sophie Julia, Marie‐Christine Vantyghem, Magali Drouard, Marilyn Lackmy, Bruno Leheup, Yves Alembik, Alexia Lemaire, Patrick Nitschké, Florence Petit, Anne Dieux Coeslier, Eugénie Mutez, Alain Taı̈eb, Mélanie Fradin, Yline Capri, Hala Nasser, Lyse Ruaud, Benjamin Dauriat, Sylvie Bourthoumieu, David Geneviève, Séverine Audebert‐Bellanger, Mathilde Nizon, Radka Stoeva, G. Hickman, Gaël Nicolas, J. Mazereeuw‐Hautier, A. Jannic, S. Ferkal, Béatrice Parfait, Michel Vidaud, members of the NF France Network, P. Wolkenstein, Éric Pasmant
Abstract
Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.