Neurofibromatosis, type 1

Management Strategy

The diagnosis of NF1 can usually be established by clinical criteria. NF1 variant identification is useful in reproductive counseling, confirming the diagnosis, and differentiating NF1 from other RASopathy-related conditions with overlapping phenotypes. The nature of the variant may also affect the prognosis; large deletions or null mutations may be associated with more severe disease, including more severe intellectual disability and greater tumor burdens. There is variable expression of the phenotype from the genotype. There are also more specific genotype-phenotype correlations. For example, the variant p.Met992del is associated with a milder phenotype without CNs or PNs. Variants at amino acid residue 1809 are not associated with PNs, CNs, or symptomatic OPGs, but can be associated with Noonan-like features and pulmonic stenosis. Missense changes at codons 844-848 are associated with a more severe phenotype including PNs and spinal neurofibromas, OPGs, other malignancies, and bone abnormalities. Approximately 50% of NF1 variants arise as de novo events.

Treatment for NF1 was traditionally limited to surgery but targeted non-surgical treatment approaches that exploit the molecular biology of the NF1 protein are actively being developed. For small, benign CNs causing cosmetic concerns and discomfort, simple excision using a scalpel or punch biopsy is appropriate, but surgery is not practical for large tumors. Unfortunately, surgery is not curative; lesions may continue to progress, requiring repeated procedures.

Treatment of PNs is particularly challenging; these tumors are often highly vascular and invasive. Symptomatic lesions should be evaluated by MRI or PET scans because of the risk for evolution into MPNSTs from the accumulation of additional mutations in TP53 or INK4-ARF ( CDKN2A/B ) tumor suppressor genes. Unexplained pain or rapid growth within a PN and areas displaying necrosis or an unusual appearance on imaging studies merit biopsy to exclude malignant transformation. cDNA gene expression profiling may be useful to help distinguish benign from premalignant and malignant lesions. Sirolimus, which blocks the mTOR pathway, and pegylated interferon-α _2b may slow the progression of PNs via its antiproliferative and immunoregulatory activities.

Other proposed therapeutic agents have included angiogenesis inhibitors and antiinflammatory agents to inhibit cell growth and induce apoptosis, and drugs that target RAS signal transduction. Agents that impact the microenvironment of NF1 tumors via limiting the induction of other signaling pathways and through interactions with other cell lines have been studied, as well as combinations of these agents with mTOR inhibitors. Referral of a patient with aggressive MPNSTs to an oncologist for chemoradiotherapy may be warranted.

Other therapies that have been tried for NF1 include ketotifen and pirfenidone, but neither have shown reproducible efficacy. Statins have also been explored as treatment for NF1-related cognitive difficulties because of their known inhibition of p21Ras/MAPK activity, but studies to date have not verified effectiveness.

MEK inhibitors such as selumetinib resulted in PN shrinkage in 71% of subjects in a phase I study in children with inoperable PNs, leading to the designation of selumetinib as a ‘breakthrough therapy’ for NF1 by the US Food and Drug Administration (FDA). In a recent phase 2 trial with selumetinib, the majority of 50 children with NF1 and inoperable PNs showed long-lasting tumor shrinkage and clinical benefit, including reduced pain related to PNs. Combination approaches using selumetinib with an mTOR inhibitor are also actively under investigation. Information about ongoing clinical trials can be found at https://www.ctf.org/research/clinical-drug-pipeline and www.ClinicalTrials.gov .