Neurofibroma

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Neurofibroma
Neurofibroma02.jpg
Neurofibroma of the skin in a person with neurofibromatosis type I
Specialty Neuro-oncology

A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors (solitary neurofibroma, solitary nerve sheath tumor [1] or sporadic neurofibroma [1] ), while the remainder are found in persons with neurofibromatosis type I (NF1), an autosomal-dominant genetically inherited disease. They can result in a range of symptoms from physical disfiguration and pain to cognitive disability.

Contents

Neurofibromas arise from nonmyelinating-type Schwann cells that exhibit biallelic inactivation of the NF1 gene that codes for the protein neurofibromin. [2] This protein is responsible for regulating the RAS-mediated cell growth signaling pathway. In contrast to schwannomas, another type of tumor arising from Schwann cells, neurofibromas incorporate many additional types of cells and structural elements in addition to Schwann cells, making it difficult to identify and understand all the mechanisms through which they originate and develop. [3]

Types

Neurofibromas have been subdivided into two broad categories: dermal and plexiform. Dermal neurofibromas are associated with a single peripheral nerve, while plexiform neurofibromas are associated with multiple nerve bundles. According to the World Health Organization classification system, dermal and plexiform neurofibromas are grade I tumors. Plexiform neurofibroma are more difficult to treat and can transform into malignant tumors. Dermal neurofibroma do not become malignant.[ citation needed ]

Dermal neurofibroma

Anatomy

Dermal neurofibromas (sometimes referred to as cutaneous neurofibromas) originate in nerves in the skin. Three kinds are distinguished: [4]

  • Discrete cutaneous neurofibromas: Sessile or pedunculated masses on the skin, which are fleshy and non-tender, and can vary in size.
  • Discrete subcutaneous neurofibromas: Lie below and look like bumps on the skin, which can sometimes be tender.
  • Deep nodular neurofibromas: Involving tissues and organs underneath the dermis, but otherwise resembling cutaneous and subcutaneous neurofibromas.

Age of onset

Dermal neurofibroma in a person whose lesions first appeared when he was a teenager Dermal Neurofibroma.jpg
Dermal neurofibroma in a person whose lesions first appeared when he was a teenager

Dermal neurofibromas typically arise in the teenage years and are often associated with the onset of puberty. In people with neurofibromatosis type I, they tend to continue to increase in number and size throughout adulthood, although limits exist as to how big they get, and cases progress at highly variable rates.[ citation needed ]

Medical complications

Dermal neurofibromas can lead to stinging, itching, pain, and disfigurement.[ citation needed ]

No evidence of malignant transformation has been found. [2]

Plexiform neurofibroma

Anatomy

Plexiform neurofibroma of the head and neck, before and after removal Gould Pyle 253.jpg
Plexiform neurofibroma of the head and neck, before and after removal

Plexiform neurofibromas can grow from nerves in the skin or from more internal nerve bundles, and can be very large (with mass in the tens of kilograms). [5] Internal plexiform neurofibromas are very difficult to remove completely because they extend through multiple layers of tissue and the attempt would damage healthy tissue or organs.[ citation needed ]

Age of onset

Image of neurofibroma showing myxoid appearance Neurofibroma -1.jpg
Image of neurofibroma showing myxoid appearance

Plexiform neurofibromas occur earlier in life and are thought to be congenital defects. [4]

Medical complications

Plexiform neurofibroma can cause disfigurement, neurological, and other clinical deficits.[ citation needed ]

Plexiform neurofibromas have the potential to cause severe clinical complications if they occur in certain areas. [6]

About 10% of plexiform neurofibromas undergo transformation into a malignant peripheral nerve sheath tumor. [7] Plexiform neurofibroma is a known precursor for MPNST in NF1 patients. [8] The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A or TP53 gene in nonmyelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.

Cause

This section discusses the tumorigenesis of neurofibroma in terms of genetics, cell signaling, histology and the cell cycle.

Neurofibromin 1 gene

This picture illustrates the structure of the NF1 gene product, neurofibromin 1. This protein is 2818 amino acids long with 3 alternatively spliced exons, 9a, 23a, and 48a. The IRA domains are hypothesized to function as negative regulators of RAS, along with the GRD domain in between them. Neurofibroma.png
This picture illustrates the structure of the NF1 gene product, neurofibromin 1. This protein is 2818 amino acids long with 3 alternatively spliced exons, 9a, 23a, and 48a. The IRA domains are hypothesized to function as negative regulators of RAS, along with the GRD domain in between them.

The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17qll.2. [9] This gene codes for neurofibromin which is a large 220-250 KDa cytoplasmic protein that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a and 48a) in the encoding gene. The functional part of neurofibromin is a GAP, or GTPase-activating protein. GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling. Loss of RAS control leads to increased activity of other signaling pathways including RAF, ERK1/2, PI3K, PAK and mTOR-S6 kinase. This increased activity of downstream RAS pathways might work together to increase cell growth and survival. [10] Genes that code for proteins that regulate cell growth, such as NF1 and TP53 , are referred to as tumor suppressor genes. Neurofibromin has other growth-regulatory properties besides its ability to regulate RAS activity, but these other functions are poorly understood at this time. [11]

Schwann cells

There are two kinds of Schwann cells, myelinating and nonmyelinating. While myelinating Schwann cells cover large diameter (>1 micrometer) peripheral nervous system (PNS) axons with myelin, nonmyelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes. Nonmyelinating Schwann cells are the neoplastic element in neurofibromas. This conglomeration of nonmyelinating Schwann cells and axons is called a Remak bundle.[ citation needed ]

While nonmyelinating Schwann cells are the origin of neurofibromas, the mutations that make them susceptible to this transformation occur in Schwann cell precursors during early nerve development. Mutated nonmyelinating Schwann cells do not form normal Remak bundles. Instead, they fail to properly surround and segregate target axons. It is unknown at this time why, if both types of Schwann cells exhibit bilallelic inactivation of the NF1 gene, only the nonmyelinating variety give rise to neurofibromas. [12]

Loss of tumor suppressor function

Neurofibromas arise from nonmyelinating Schwann cells that only express the inactive version of the NF1 gene, which leads to a complete loss of expression of functional neurofibromin. While one defective allele may be inherited, loss of heterozygosity (LOH) must occur before a neurofibroma can form; this is called the 'two-hit hypothesis'. This LOH happens by the same mechanisms, such as oxidative DNA damage, that causes mutations in other cells.[ citation needed ]

Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, it begins to proliferate rapidly. This condition is called hyperplasia, which is cell growth beyond what is normally seen. However, despite increased numbers of nonmyelinating Schwann cells, there is no neurofibroma yet. In order for the neurofibroma to develop, cells that are heterozygous for the NF1 gene must be recruited to the site. It has been hypothesized that the proliferating nonmyelinating Schwann cells secrete chemoattractants such as the KIT ligand, and angiogenic factors such as the heparin-binding growth factor midkine. These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplastic lesions created by the nonmyelinating Schwann cells. These cell types include fibroblasts, perineurial cells, endothelial cells, and mast cells. The mast cells then secrete mitogens or survival factors that alter the developing tumor microenvironment and result in neurofibroma formation.[ citation needed ]

Dermal and plexiform neurofibromas differ in later development stages, but the details are unclear at this point. [10]

Diagnosis

Histopathology of neurofibroma: A spindle cell lesion composed of slender fibroblast-like cells with storiform pattern and very low amount of stroma. Histopathology of neurofibroma.jpg
Histopathology of neurofibroma: A spindle cell lesion composed of slender fibroblast-like cells with storiform pattern and very low amount of stroma.

Dermal neurofibromas may be 2 to 20 mm in diameter, is soft, flaccid, and pinkish-white, and frequently this soft small tumor can be invaginated, as if through a ring in the skin by pressure with the finger, a maneuver called "button-holing". [14] : 619 

A blood test for protein melanoma inhibitory activity may be used to detect the presence of neurofibromas. [15] [16]

A biopsy can be used for histopathology diagnosis.

Treatments

Dermal neurofibroma

Dermal neurofibromas are not usually surgically removed unless they are painful or disfiguring, because there are generally so many of them and they are not dangerous.

CO2 lasers have been used to remove dermal neurofibromas. In a paper titled Hypertrophic Scars After Therapy with CO2 Laser for Treatment of Multiple Cutaneous Neurofibromas Ostertag et al. said this about treatment by laser: "The cosmetic disfigurement is the most important issue in the decision to treat cutaneous symptoms of neurofibromatosis. Treating patients with extensive neurofibromas with [a] CO2 laser is still the best choice. However, it is strongly advised that a test treatment be performed to judge the effectiveness of the procedure and whether the developed scar is an acceptable trade-off." [17]

Plexiform neurofibroma

Surgery

As of 2002, the primary treatment option for plexiform neurofibroma was surgery. [18]

Removal of plexiform neurofibromas is difficult because they can be large and cross tissue boundaries. However, besides pain, plexiform neurofibromas are sometimes removed due to the possibility of malignant transformation.

The following examples show that plexiform neurofibromas can form anywhere and can make surgical resection difficult:

  • A large plexiform neurofibroma in the leg of a 6-year-old male. The authors state: "Our case was operated, as both the cutaneous and deep branches of the peroneal nerve were involved causing pain and numbness in the leg, and because there was a possibility for malignant transformation, as growth in the mass was realized by the family members of the patient." The authors also note, "However, complete resection is quite difficult due to invasion of the tumor into the surrounding soft tissues." [19]
  • A neurofibroma on the left ventricle. The neurofibroma was removed and the patient's mitral valve had to be replaced. [20]
  • A 14-year-old girl with NF1 was diagnosed with a neurofibroma involving her bladder, a rare location. [21]

Radiation

Once a plexiform neurofibroma has undergone malignant transformation, radiation and chemotherapy can be used as treatment. However, radiation is generally not used as a treatment for plexiform neurofibromas because of concerns that this could actually promote malignant transformation. There has even been a documented case of a Schwannoma being induced from a neurofibroma due to radiation therapy. [22]

Medications

ACE inhibitors have been proposed as a novel treatment of neurofibromas. ACE inhibitors are currently used to treat hypertension and congestive heart failure, to avert remodeling and reinfarction after myocardial infarction, and to ameliorate diabetic nephropathy and other renal diseases. ACE inhibitors work by indirectly down regulating TGF-beta, which is a growth factor that has been shown to influence the development of tumors. [23]

No effect

Pirfenidone inhibits fibroblast growth. Studies showed no improvement over controls.

Tipifarnib (also known as drug R115777) inhibits the activation of RAS. This drug is a Farnesyltransferase inhibitor which inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. It successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two after showing no improvement over controls. [24] [25]

Research

The many drug therapies under study for neurofibromas [26] [27] are in various stages of research; more time will be required to determine if these are viable options for the treatment of neurofibromas.

Sirolimus, a compound that inhibits mTOR signalling, is being studied to treat plexiform neurofibromas. [28] [29]

The combination of erlotinib with sirolimus was studied to treat low-grade gliomas. [30]

Early research has shown potential for using the c-kit tyrosine kinase blocking properties of imatinib to treat plexiform neurofibromas. [31] [32] [33]

Peginterferon alfa-2b is being studied to treat plexiform neurofibromas. [34] [35] [36] [37]

Sorafenib is being studied for treatment of unresectable plexiform neurofibroma and low-grade astrocytomas. [38] [39] [40]

In vitro , tranilast, inhibits growth of neurofibroma cells. [41]

Gene therapy for the neurofibromin 1 gene represents the ultimate solution to preventing the cluster of maladies which are enabled by the mutation. [42] [43] As of 2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate NF1 tumor model. [44]

See also

Related Research Articles

<span class="mw-page-title-main">Neurofibromatosis</span> Three genetic disorders involving benign tumors of the nervous system

Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin or surrounding bone. Although symptoms are often mild, each condition presents differently. Neurofibromatosis type I (NF1) is typically characterized by café au lait spots, neurofibromas, scoliosis, and headaches. Neurofibromatosis type II (NF2), on the other hand, may present with early-onset hearing loss, cataracts, tinnitus, difficulty walking or maintaining balance, and muscle atrophy. The third type is called schwannomatosis and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression.

<span class="mw-page-title-main">Vestibular schwannoma</span> Benign tumor of the vestibulocochlear cranial nerve

A vestibular schwannoma (VS), also called acoustic neuroma, is a benign tumor that develops on the vestibulocochlear nerve that passes from the inner ear to the brain. The tumor originates when Schwann cells that form the insulating myelin sheath on the nerve malfunction. Normally, Schwann cells function beneficially to protect the nerves which transmit balance and sound information to the brain. However, sometimes a mutation in the tumor suppressor gene, NF2, located on chromosome 22, results in abnormal production of the cell protein named Merlin, and Schwann cells multiply to form a tumor. The tumor originates mostly on the vestibular division of the nerve rather than the cochlear division, but hearing as well as balance will be affected as the tumor enlarges.

Spinal tumors are neoplasms located in either the vertebral column or the spinal cord. There are three main types of spinal tumors classified based on their location: extradural and intradural. Extradural tumors are located outside the dura mater lining and are most commonly metastatic. Intradural tumors are located inside the dura mater lining and are further subdivided into intramedullary and extramedullary tumors. Intradural-intramedullary tumors are located within the dura and spinal cord parenchyma, while intradural-extramedullary tumors are located within the dura but outside the spinal cord parenchyma. The most common presenting symptom of spinal tumors is nocturnal back pain. Other common symptoms include muscle weakness, sensory loss, and difficulty walking. Loss of bowel and bladder control may occur during the later stages of the disease.

<span class="mw-page-title-main">Neurofibromatosis type I</span> Type of neurofibromatosis disease

Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system human disorder caused by the mutation of neurofibromin 1 (NF-1). NF-1 is a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system that can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.

<span class="mw-page-title-main">Malignant peripheral nerve sheath tumor</span> Cancer of the connective tissue surrounding peripheral nerves

A malignant peripheral nerve sheath tumor (MPNST) is a form of cancer of the connective tissue surrounding peripheral nerves. Given its origin and behavior it is classified as a sarcoma. About half the cases are diagnosed in people with neurofibromatosis; the lifetime risk for an MPNST in patients with neurofibromatosis type 1 is 8–13%. MPNST with rhabdomyoblastomatous component are called malignant triton tumors.

<span class="mw-page-title-main">Neurofibromatosis type II</span> Type of neurofibromatosis disease

Neurofibromatosis type II is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, and peripheral nerves. The types of tumors frequently associated with NF2 include vestibular schwannomas, meningiomas, and ependymomas. The main manifestation of the condition is the development of bilateral benign brain tumors in the nerve sheath of the cranial nerve VIII, which is the "auditory-vestibular nerve" that transmits sensory information from the inner ear to the brain. Besides, other benign brain and spinal tumors occur. Symptoms depend on the presence, localisation and growth of the tumor(s). Many people with this condition also experience vision problems. Neurofibromatosis type II is caused by mutations of the "Merlin" gene, which seems to influence the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. Historically the underlying disorder has not had any therapy due to the cell function caused by the genetic mutation.

Phakomatoses, also known as neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses are single-gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance.

<span class="mw-page-title-main">Schwannomatosis</span> Rare genetic disorder

Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, and other neurological complications, excluding hallmark signs of NF. The exact frequency of schwannomatosis cases is unknown, although some populations have noted frequencies as few as 1 case per 1.7 million people.

<span class="mw-page-title-main">Schwannoma</span> Benign nerve-sheath tumor composed of Schwann cells

A schwannoma is a usually benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves.

<span class="mw-page-title-main">Neurofibromin</span> Mammalian protein found in humans

Neurofibromin (NF-1) is a protein that is encoded in humans, in the NF1 gene. NF1 is located on chromosome 17. Neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

<span class="mw-page-title-main">Tipifarnib</span> Chemical compound

Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.

<span class="mw-page-title-main">Granular cell tumor</span> Medical condition

Granular cell tumor is a tumor that can develop on any skin or mucosal surface, but occurs on the tongue 40% of the time.

A nerve sheath tumor is a type of tumor of the nervous system which is made up primarily of the myelin surrounding nerves. From benign tumors like schwannoma to high grade malignant neoplasms known as malignant peripheral nerve sheath tumors, peripheral nerve sheath tumors include a range of clearly characterized clinicopathologic entities. A peripheral nerve sheath tumor (PNST) is a nerve sheath tumor in the peripheral nervous system. Benign peripheral nerve sheath tumors include schwannomas and neurofibromas.

Malignant triton tumor (MTT) is a relatively rare, aggressive tumor made up of both malignant schwannoma cells and malignant rhabdomyoblasts. It is classified as a malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation.

<span class="mw-page-title-main">Legius syndrome</span> Medical condition

Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. It was first described in 2007 and is often mistaken for neurofibromatosis type I. It is caused by mutations in the SPRED1 gene. It is also known as neurofibromatosis type 1-like syndrome.

<span class="mw-page-title-main">Selumetinib</span> Chemical compound

Selumetinib (INN), sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves. It is taken by mouth.

Within medical ophthalmology, Intraocular schwannoma, also termed uveal schwannoma, is a type of schwannoma found in the eye. These tumors are almost always benign in nature and while malignant forms have been documented in other areas of the body, this has not been reported in the uveal region. Composed of Schwann cells, these masses are generally slow growing and can be found in the peripheral nerve tract, often around the head and neck.

Luis F. Parada is a Colombian developmental biologist and neuroscientist who currently serves as Director of the Brain Tumor Center, Albert C. Foster Chair and American Cancer Society Research Professor at Memorial Sloan Kettering Cancer Center in New York City, New York.

<span class="mw-page-title-main">Brigitte C. Widemann</span> German-American pediatric oncologist

Brigitte C. Widemann is German-American pediatric oncologist. She is chief of the pediatric oncology branch and clinical deputy director of the center for cancer research at the National Cancer Institute. She is also the special advisor to the NCI director for childhood cancer.

<span class="mw-page-title-main">Peripheral nerve tumor</span> Medical condition

Peripheral nerve tumors, also called tumors of peripheral nerves or tumors of the peripheral nervous system, are a diverse category with a range of morphological characteristics and biological potential. They are categorized as either benign or malignant peripheral nerve sheath tumors.

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  24. ↑ Clinical trial number NCT00025454 for "R115777 in Treating Patients With Advanced Solid Tumors" at ClinicalTrials.gov
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  28. ↑ Clinical trial number NCT00652990 for "Sirolimus to Treat Plexiform Neurofibromas in Patients With Neurofibromatosis Type I" at ClinicalTrials.gov
  29. ↑ Clinical trial number NCT00634270 for "A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas (Protocol 102)" at ClinicalTrials.gov
  30. ↑ Clinical trial number NCT00901849 for "Tarceva/Rapamycin for Children With Low-Grade Gliomas With or Without Neurofibromatosis Type 1 (NF1)" at ClinicalTrials.gov
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  33. ↑ "Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas" Archived 2012-04-20 at the Wayback Machine
  34. ↑ Clinical trial number NCT00678951 for "Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults" at ClinicalTrials.gov
  35. ↑ Clinical trial number NCT00396019 for "Study of PEG-Intron for Plexiform Neurofibromas" at ClinicalTrials.gov
  36. ↑ Clinical trial number NCT00846430 for "Medical Treatment of "High-Risk" Neurofibromas" at ClinicalTrials.gov
  37. ↑ "A Phase II Trial of Peginterferon Alpha-2b (Pegintron) for Neurofibromatosis Type 1 Related Unresectable, Symptomatic or Life-Threatening Plexiform Neurofibromas", National Institutes of Health study 08-C-0130
  38. ↑ Clinical trial number NCT00727233 for "Sorafenib in Treating Young Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas That Cannot Be Removed by Surgery" at ClinicalTrials.gov
  39. ↑ Ambrosini G, Cheema HS, Seelman S, Teed A, Sambol EB, Singer S, Schwartz GK (April 2008). "Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells". Molecular Cancer Therapeutics. 7 (4): 890–896. doi:10.1158/1535-7163.MCT-07-0518. PMC   3267321 . PMID   18413802.
  40. ↑ Wu J, Dombi E, Jousma E, Scott Dunn R, Lindquist D, Schnell BM, et al. (February 2012). "Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging". Pediatric Blood & Cancer. 58 (2): 173–180. doi:10.1002/pbc.23015. PMC   3128176 . PMID   21319287.
  41. ↑ Yamamoto M, Yamauchi T, Okano K, Takahashi M, Watabe S, Yamamoto Y (March 2009). "Tranilast, an anti-allergic drug, down-regulates the growth of cultured neurofibroma cells derived from neurofibromatosis type 1". The Tohoku Journal of Experimental Medicine. 217 (3): 193–201. doi: 10.1620/tjem.217.193 . PMID   19282654.
  42. ↑ Wetmore DZ, Garner CC (September 2010). "Emerging pharmacotherapies for neurodevelopmental disorders". Journal of Developmental and Behavioral Pediatrics. 31 (7): 564–581. doi:10.1097/DBP.0b013e3181ee3833. PMC   2967570 . PMID   20814256.
  43. ↑ Gottfried ON, Viskochil DH, Couldwell WT (January 2010). "Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications". Neurosurgical Focus. 28 (1): E8. doi: 10.3171/2009.11.FOCUS09221 . PMID   20043723.
  44. ↑ Muir DF (April 2006). "Angiogenesis and Therapeutic Approaches to NF1 Tumors". University of Florida Gainesville. Archived from the original on March 27, 2012. also available here
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