304 North Cardinal St.
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304 North Cardinal St.
Dorchester Center, MA 02124
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Type 1 neurofibromatosis (NF1), or von Recklinghausen disease, is an autosomal dominant multisystem disorder with highly variable expression. NF1 is caused by pathogenic variants of the neurofibromin gene ( NF1 ) on chromosome 17. The neurofibromin protein is a tumor suppressor. Specifically, NF1 is a GTPase-activating protein that negatively regulates RAS protein signal transduction, which controls the expression of genes involved in apoptosis, the cell cycle, cell differentiation or migration. NF1 pathogenic variants lead to ‘gain of function’ for RAS (as RAS-GTP) with overactivation of the downstream pathways, including the PI3K/AKT/mTOR and Raf/mitogen-activated protein kinase (MAPK)/MEK/ERK pathways, resulting in increased cell growth and potential for malignant transformation. There are five different isoforms of the NF1 gene expressed in different tissues and the variation in phenotype depends on the location, type of variant, and relative amounts of these isoforms expressed.
Cutaneous and ocular lesions are hallmarks. Cutaneous lesions include café au lait spots (CALs), cutaneous neurofibromas (CNs), and plexiform neurofibromas (PNs). Ocular lesions include Lisch nodules (iris hamartomas), optic pathway gliomas (OPGs), and orbital plexiform lesions. CNs may be smaller, benign subcutaneous lesions or larger, plexiform tumors that follow nerves and/or extend into deeper bony and visceral structures. Malignant peripheral nerve sheath tumors (MPNSTs) may develop, particularly within larger plexiform lesions. MPNSTs and vasculopathy are the greatest contributors to mortality in NF1. CALs are typically the first lesions to appear in infancy and early childhood. The paucity of typical lesions in very young children may hamper diagnosis.
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 .
Annual complete cutaneous examinations, particularly in patients with large plexiform lesions
Complete baseline ophthalmologic exam, with slit lamp and dilated fundoscopy. Annual ocular exams to screen for OPGs should be continued through age 8 and every 2 years thereafter from ages 8–18
Skin and eye exams for first-degree relatives (or targeted DNA testing)
Regular developmental assessment in children: evaluation and management of learning disability and attention deficits
Regular blood pressure checks to screen for renal artery stenosis or pheochromocytoma
MRI of brain, optic nerves, and spinal cord with and without contrast based on symptoms and/or focal neurologic signs
MRI or PET scan, with and without contrast, to evaluate deep or changing plexiform neurofibromas
Biopsy or excision of changing or suspicious lesions
Radiographs if osseous involvement is suspected
DNA sequencing of cDNA and genomic DNA (often via panel testing that includes both NF1 and SPRED1 , possibly other RASopathy genes), and deletion/duplication analysis, particularly in young children who do not meet clinical criteria, in those with features of ‘NF1–Noonan syndrome’ and/or cardiac disease and in individuals with reproductive questions. Chromosome microarray analysis may also detect larger genomic deletions that include NF1
Friedman JM. 1998 Oct 2 [Updated 2019 Jun 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews [Internet]. Seattle (WA): University of Washington; 1993–2020. https://www.ncbi.nlm.nih.gov/books/NBK1109 .
This is one of the most comprehensive reviews of NF1, which is frequently updated.
Rauen KA, Alsaegh A, Ben-Shachar S, et al. Am J Med Genet A. 2019; 179: 1091–7.
Denadi R, Buzzo CL, Takata JPL, et al. Ann Plast Surg 2016; 77: 190–4.
In total, 20 patients (mean age 25.8 years, range 5–60) underwent 149 craniofacial soft-tissue surgical procedures to correct facial deformities associated with NF1. All patients underwent procedures for en bloc excision, 60% for facial suspension, 15% for eyebrow suspension, 10% for ear suspension, 45% for lateral canthopexy, and 25% and 5% for shortening of the lower and upper eyelids, respectively. Three patients had surgical complications. The authors concluded that the surgical approach for patients with NF1 should be global, comprehensive, and individualized given the spectrum of soft-tissue deformities.
Lutterodt C, Mohan A, Kirkpatrick N. J Plast Reconstr Aes 2016; 69: 765–9.
Six patients were treated with electrodessication under general anesthesia for an average of three sessions, treating hundreds of lesions per session with minimal complications. Five of six patients preferred electrodessication to surgical excision. The authors proposed that electrodessication is a simple and effective method for treating larger numbers of cutaneous lesions.
Méni C, Sbidian E, Moreno JC, et al. Dermatology 2015; 230: 263–8.
Carbon dioxide laser treatment was well tolerated and resulted in satisfactory patient outcomes in over 106 patients with neurofibromas.