Abstract
Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children’s Tumor Foundation’s NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.
Highlights
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant genetic disorder affecting 1 in 2500–4000 individuals, characterized by alterations of the neurofibromin (NF1) gene located at 17q11.2 (1)
Our analysis cohort consisted of 2051 patients with a mean age of 42 years, and 67% were female (Methods)
Our data are self-reported, and the French Clinical Research Program Neurofibromatosis type 1 (NF1) database defined learning disability as “referral for remedial education” (24)
Summary
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant genetic disorder affecting 1 in 2500–4000 individuals, characterized by alterations of the neurofibromin (NF1) gene located at 17q11.2 (1). Individuals with NF1 may have significant morbidity from the development of nervous system tumors, including neurofibromas, optic gliomas, and malignant nerve sheath tumors. Affected individuals may experience repeated fractures, cardiac issues, or cognitive disabilities. Among individuals with NF1, the clinical manifestations are highly variable and unpredictable, even among individuals sharing identical genetic NF1 mutations, suggesting an influence of modifiers outside the NF1 locus (2). The prevalence and associations of phenotypic manifestations in NF1 from large adult cohorts are sparse. No investigations have permitted identification of clinically based subtype patterns, and there is a need to understand how genetic variants both inside and outside the NF1 locus influence disease subtypes
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