Neurofibromatosis Type 1 with Plexiform Neurofibroma: A Novel Mutation Uncovered

The objective of this article is to present a classic case of Neurofibromatosis Type 1 (NF1), a multisystemic genetic disorder, in a 16-year-old female who demonstrated hallmark clinical features, including café-au-lait macules, Lisch nodules, and a plexiform neurofibroma. This case also highlights the diagnostic significance of next-generation sequencing (NGS), which identified a novel pathogenic missense variant in the NF1 gene (c.988G>C; p.Ala330Pro).

A 16-year-old female presented with a 5-year history of progressive, painless right upper eyelid swelling and ptosis. Examination revealed more than six café-au-lait macules, palmar freckling, and Lisch nodules in the right eye. A soft, ill-defined mass involving the right upper eyelid was consistent with plexiform neurofibroma. She also experienced multiple transient episodes of loss of consciousness (LOC), though no neurological deficits were observed. Whole exome sequencing (WES) revealed a novel heterozygous missense variant (c.988G>C; p.Ala330Pro) in exon 9 of the NF1 gene, classified as likely pathogenic. The variant was absent from population databases and supported by high REVEL and CADD scores. Surgical excision and ptosis correction were performed, and genetic counselling was initiated for the family.

NF1 is a common autosomal dominant disorder with variable phenotypic expression and a wide range of complications. Plexiform neurofibromas are among the more severe manifestations and carry a risk of malignant transformation. The novel NF1 variant identified in this case affects a highly conserved residue and expands the spectrum of NF1 mutations. The clinical and molecular findings underscore the importance of early genetic testing to guide diagnosis, management, and familial risk assessment. The episodes of LOC raise the possibility of neurovascular involvement, which, while rare, is a recognized complication of NF1.

This case underscored the diagnostic value of combining classical clinical features with molecular analysis in NF1. Early detection of pathogenic mutations, appropriate surgical intervention, and long-term follow-up are essential to reduce complications. Multidisciplinary care and emerging targeted therapies, such as MEK inhibitors, may further improve management and prognosis for patients with complex NF1 manifestations.