Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry

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.