# Orbital and Lumbosacral Plexiform Neurofibroma with PTPN11 Mutation: A Form of the RASopathy

## TL;DR

A rare case of neurofibromas in a man with a PTPN11 gene mutation expands the known effects of RASopathies beyond typical conditions like NF1.

## Contribution

This case broadens the phenotype spectrum of PTPN11 mutations by linking them to neurofibromas typically seen in NF1.

## Key findings

- A PTPN11 gene mutation (c.836A>G, p.Y279C) was identified in a patient with neurofibromas.
- The patient did not meet diagnostic criteria for NF1 or other RASopathy syndromes like Noonan syndrome.
- The case suggests neurofibromas can occur in RASopathies beyond NF1, highlighting phenotypic overlap.

## Abstract

RASopathies are a group that encompasses a spectrum of related disorders caused by mutations linked to the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), neurofibromatosis-Noonan syndrome (NFNS), Noonan syndrome with multiple lentigines (NSML). Neurofibromas, as a hallmark of NF1, are extremely rare in patients with other RASopathies. Here we present a case of a 39-year-old Chinese male displaying orbital neurofibromas and lumbosacral plexiform neurofibromas. Histopathology of a CT-guided biopsy of the mass revealed it to be a neurofibroma. The targeted sequencing analysis did not find any pathogenic sequence alteration in the NF1 or NF2 causative genes in blood lymphocytes and hypertrophic nerve tissue, and no additional signs of NF1 were detected, thereby not meeting the diagnostic criteria for NF1. However, we identified a heterozygous mutation (c.836A>G, p.Y279C) in the PTPN11 gene, which is one of the key components of the RAS-MAPK signaling pathway and is associated with NS, NFNS, and NSML. Nonetheless, a thorough examination did not reveal any signs of these syndromes in the patient. Consequently, it was inferred that this patient likely falls within the spectrum of the RASopathies. This represents a unique case manifesting as orbital and lumbosacral plexiform neurofibromas carrying a PTPN11 gene mutation, thereby broadening the phenotype spectrum of PTPN11 mutations. Our results also highlight the overlap between RASopathies. Neurofibromas should be considered indicative of a broader spectrum of disorders resulting from mutations in RASopathies other than NF1.