Neurofibromatosis, type 1

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Neurofibromatosis, type 1

Lindsay A. Eminger and Rhonda E. Schnur

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Type 1 neurofibromatosis (NF1) is an autosomal dominant multisystem disorder with highly variable expression. NF1 is caused by mutations of the neurofibromin gene on chromosome 17. The neurofibromin protein is a GTPase-activating protein that, in its normal role, negatively regulates RAS protein signal transduction. NF1 mutations lead to over-activated RAS (RAS-GTP) and subsequently, over-activation of the mTOR (mammalian target of rapamycin) cell signaling pathway. Clinically, this results in excess cell growth and the potential for malignant transformation. The disorder can affect virtually any part of the body, but the most characteristic lesions are cutaneous and ocular. Cutaneous lesions include café au lait spots, neurofibromas, and plexiform neurofibromas. Neurofibromas may be benign subcutaneous lesions or deeper, 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 deeper, plexiform lesions.

Management strategy

The diagnosis of NF1 is established by well-defined clinical criteria. The sensitivity of mutation analysis varies depending on the techniques used, but has greatly improved. Mutation identification is useful in reproductive counseling, in confirming the diagnosis in uncertain cases, and in differentiating NF1 from other conditions with overlapping phenotypes such as the multiple lentigenes syndrome. The nature of the mutation may also affect prognosis; large deletions or null mutations are associated with more severe disease, including more severe intellectual disability and greater tumor burdens.

There is currently no proven medical therapy to prevent or treat neurofibromas, but significant efforts are underway to develop targeted treatment approaches that exploit the molecular biology of NF1. Ketotifen was previously used for pain, tenderness, and pruritus of neurofibromas, but there are no recent large studies using this drug. Otherwise, standard treatment for neurofibromas is limited to surgery. For benign neurofibromas, cosmetic concerns and discomfort are indications for removal. Most neurofibromas are small and can be removed by simple excision using a scalpel or punch biopsy. Although there is little morbidity, surgery is not practical for large tumors.

A wire loop connected to a monopolar diathermy machine in the cutting mode has been used to treat hundreds of small lesions. Hemostasis is readily obtained, healing is by secondary intention, and cosmetic outcome is good. CO2 laser vaporization has been used for small tumors with healing by secondary intention, or for larger tumors in conjunction with primary closure. Hundreds of tumors can be removed in one outpatient session under local anesthesia. Unfortunately, surgery is not curative and lesions may continue to progress, requiring repeated procedures.

Treatment of plexiform neurofibromas is particularly challenging because these tumors are often highly vascular and invasive. Symptomatic lesions are evaluated by MRI or PET scans because of the risk for evolution into MPNSTs. Unexplained pain or rapid growth within a plexiform neurofibroma, and areas displaying necrosis or an unusual appearance on imaging studies, merit biopsy to exclude malignant transformation. cDNA gene expression profiling may be used in the future to help distinguish benign from premalignant and malignant lesions.

Non-surgical treatments for plexiform neurofibromas and MPNSTs are under active investigation. A new generation of therapeutic agents includes angiogenesis inhibitors and anti-inflammatory agents that inhibit cell growth and induce apoptosis. Drugs that target RAS signal transduction or limit RAS post-translational processing, such as farnesyl transferase inhibitors (tipifarnib), are promising. Medications that target the mTOR pathway, including rapamycin, are actively being studied. In addition, agents that impact the microenvironment of NF1 tumors via limiting the induction of other signaling pathways and through interactions with other cell lines are being targeted. For example, the tyrosine kinase inhibitor, imatinib mesylate, targets PDGFRα, c-KIT, and c-ABL and is being studied in phase II clinical trials. Combinations of these agents with mTOR inhibitors are also being studied.

RAS-induced transformation requires isoprenylation (i.e., farnesylation or geranyl-geranylation), which can be blocked by farnesyl transferase inhibitors and by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of cholesterol and isoprenyl groups. Therefore, statins are being explored in the treatment of MPNSTs and NF1-related bone dysplasia and cognitive difficulties because of their known inhibition of p21Ras/mitogen activated protein kinase (MAPK) activity. For tibial pseudoarthrosis, recombinant bone morphogenetic protein (an anabolic agent) and bisphosphonates (anticatabolic agents) have been used in combination to promote healing. Pirfenidone, an antifibrotic agent, may stabilize or reduce the size of neurofibromas. Many of the aforementioned medications are undergoing phase II trials.

For mutations that alter gene splicing, antisense morpholino oligomers can restore splicing at the mRNA level in vitro. Tamoxifen, both in in vitro experiments and in orthotopically xenografted mouse models, inhibits proliferation and survival of MPNST cells, and may be a promising treatment modality.

Referral of a patient with aggressive MPNSTs to an oncologist for chemoradiotherapy may be warranted. Information about ongoing clinical trials can be found at www.ctf.org/research/nf1 and www.ClinicalTrials.gov.

Specific investigations

image Annual complete cutaneous examinations, particularly in those patients with large plexiform lesions

image Complete baseline ophthalmologic exam, with slit lamp and dilated funduscopy. Annual ocular exams in children to screen for optic pathway gliomas should be continued through age 8 and every 2 years thereafter from ages 8 to 18

image Skin and eye exams for first-degree relatives

image Regular developmental assessment in children: evaluation and management of learning disability and attention deficits, as needed

image Regular blood pressure checks to screen for renal artery stenosis or pheochromocytoma

image MRI of brain, optic nerves, and spinal cord with and without contrast should be performed if the patient is symptomatic or has focal neurologic signs

image MRI or PET scan, with and without contrast, for deep or changing plexiform neurofibromas

image Biopsy or excision of changing or suspicious lesions

image Radiographs if osseous involvement is suspected

image DNA analysis, particularly in young children who do not meet clinical criteria, in those with features of the ‘NF1–Noonan syndrome’ and/or cardiac disease (to distinguish NF1 from other disorders with overlapping features), and in individuals with reproductive questions

First-line therapies

image Surgical excision C
image Laser therapy C

Second-line therapies

image Ketotifen B
image Chemotherapy D

Third-line and future therapies

image Imatinib E
image mTOR inhibitor (rapamycin) E
image VEGFR/c-Kit inhibitor (cediranib) E
image Multi-kinase inhibitor (sorafenib) E
image Tamoxifen E
image Antisense morpholino oligomers E
image Statins (simvistatin, lovastin) B
image Farnesyl transferase inhibitor (tipifarnib) C
image Pirfenidone B
image Radiofrequency D

Neurofibromatosis 2011: a report of the Children’s Tumor Foundation Annual Meeting.

Kalamarides M, Acosta MT, Babovic-Vuksanovic D, Carpen O, Cichowski K, Evans DG, et al. Acta Neuropathol 2012; 123: 369–80.

These two multidisciplinary conference summaries describe active ongoing research. Data from included noteworthy studies are described:

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