| Summary: | Complete deletion of the <i>NF1</i> 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 <i>NF1</i> locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. <i>NF1</i>-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 <i>versus</i> an NF1 reference population. A deletion of the <i>NF1</i> 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 <i>NF1</i>-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 <i>NF1</i>-deleted group. We described the largest <i>NF1</i>-deleted cohort to date and clarified the more severe phenotype observed in these patients.
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