Neurofibromatosis is usually manifested by pigmentation patterns on the skin. In neonates, these appear as evenly pigmented, variously shaped café-au-lait brown macules, which increase in number during the first few years of life [23]. In late adolescence, neurofibromas are found in the skin. Chief complains are cutaneous discoloration or disfigurement, pain, pathologic fractures, and hypertensive headaches due to pheochromocytoma (tumor of the sympathetic paraganglia).

NF1 tumors consist of mast cells, fibroblasts, Schwann cells, and vascular components which develop at any point along a nerve. Three known subtypes of neurofibroma are: cutaneous, subcutaneous, and plexiform. Cutaneous lesions and subcutaneous lesions are in the form of circumscribed nodules, brown or pink or the color of skin, soft or firm to touch, and invaginates when pressed with a finger (a pathognomonic sign). None of these are specific for type 1 neurofibromatosis. 

Plexiform neurofibromas are noncircumscribed, pleomorphic and thick lesions. These are pathognomonic of NF1 [24] and can cause disfigurement by integrating with important supportive structures. Other neural disorders such as malignant peripheral nerve sheath tumors, schwannomas, and granular cell tumors have been associated with NF1 [25].

Although plexiform neurofibromas infiltrate the orbit, temporal region, or eyelids less frequently than optic nerve gliomas, these serve as a potential cause of loss of vision. Strabismus (squinting), proptosis (exophthalmos) and changed globe length are caused by orbitotemporal neurofibromas. Amblyopia (double vision) in young children may result in obstruction of vision secondary to neurofibroma. A study of 21 children with plexiform neurofibroma of the orbitotemporal areas showed 6 cases of lid involvement and 3 with bilateral neurofibromas. Amblyopia was present in 62%, primarily from anisometropia and ptosis (drooping upper eyelid) [26].

Signs and symptoms of neurofibromatosis

Type 1 

Most patients are asymptomatic, if at all, some are with neurologic symptoms or bone deformities. Skin lesions appear in more than 90% of neonates: freckle-like, medium-brown (café-au-lait), macules on the trunk, pelvis, elbows and knees. Present during late childhood are numerous flesh-colored cutaneous tumors, rarely, plexiform neurofibromas appear as an irregularly thickened, grossly deformed structure. Unaffected children may have 2 or 3 café-au-lait macules whereas children with NF1 have as many or more than 6 macules.

Neurologic symptoms and bone abnormalities include:

• Scoliosis
• Pseudoarthrosis 
• Fibrous dysplasia
• Vertical scalloping
• Subperiosteal bone cyst
• Thinning of the long-bone cortex
• Posterior orbital wall is absent, with pulsating exophthalmos

Other clinical findings include: optic glioma and Lisch nodules (iris hamartomas) and changes in arterial walls leading to Moyamoya disease or intracranial artery aneurysms. Children have slightly larger heads and have learning problems. Chronic myelomonocytic leukemia and rhabdomyosarcoma may occur in children and adolescents. Pheochromocytomas affect all ages. Malignant tumors inlcude  supratentorial or brain stem gliomas. Plexiform neurofibromas may transform at any age to malignant peripheral nerve sheath tumors. 

Type 2

Bilateral acoustic neuromas occur in children and young adults, causing hearing loss, instability, headache or facial weakness. Bilateral 8th cranial (vestibulocochlear) nerve masses may be present. Other family members may develop gliomas, meningiomas, or schwannomas.

• Asymptomatic

  All three asymptomatic patients with inhomogeneous lesions were shown to have MPNST. [doi.org]

  We report a case of an asymptomatic swelling of buccal mucosa that simulated the features of neurofibroma on histopathological examination, and the final diagnosis of SCL was made on the basis of immunohistochemical features. [ncbi.nlm.nih.gov]

  […] malignant (MPNST) Types of Schwann cells Axons Disease process Myelinating Covers large diameter PNS axons with myelin - Nonmyelinating Covers small diameter PNS axons with cytoplastic processes Responsible for neurofibromatosis Presentation Symptoms asymptomatic [orthobullets.com]

  Optic gliomas are typically asymptomatic and do not require treatment unless they progressively increase in size. [merckmanuals.com]

  A Neurofibroma of Skin may require no treatment, since they are generally asymptomatic. However, in case they are at a body site that causes discomfort and/or present cosmetic worries in the individual, they may be removed. [dovemed.com]

• Soft Tissue Mass

  First, we should keep in mind that this clinical entity is included in the differential diagnosis of soft tissue masses arising from the external nose. [ncbi.nlm.nih.gov]

  tissue mass usually from plexiform neurofibroma 10% of plexiform neurofibromas transform into MPNST associated with loss of expression of CDKN2A or TP53 genes in non-myelinating Schwann cells (that also have biallelic inactivation of NF1) poor prognosis [orthobullets.com]

  Localised neurofibroma is similar to schwannoma, with distinct, fusiform and encapsulated soft tissue masses less than 5 cm in diameter. Most NF1 patients are identified during routine consultation or for verification of a positive family history. [symptoma.com]

• Diarrhea

  Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). [clinicaltrials.gov]

  There was no difference in IBS subtypes; IBS with constipation (patients 21% ( n = 6) and controls 14%( n = 1) ( p = 0.260)), IBS with diarrhea (patients 32% ( n = 9) and controls 57%( n = 4), ( p = 0.790)), mixed IBS (patients 39% ( n = 11) and controls [ojrd.biomedcentral.com]

• Fracture

  The bowing of the tibia makes it more vulnerable to a break, or fracture. Often, this fracture does not heal well due to the deformity of the bone, and may lead to a persistence of the fracture, known as a pseudarthrosis. [orthoinfo.aaos.org]

  Abnormalities in bone development and fractures in children with NF1. Boston Children's Hospital has been named the #1 children's hospital in the nation by U.S. News and World Report for the fifth year in a row! [childrenshospital.org]

  The tumors can grow into the bone, weakening it and making it susceptible to fractures; they can also press on nerves and blood vessels causing neuropathy or loss of blood flow to area of the extremity. [limbpreservation.org]

  Children with NF1 are known to have decreased bone mineral density and increased risk for fractures and should benefit from interventions that increase participation in physical activity. [journals.lww.com]

  Patients may report cutaneous discoloration or disfigurement or more serious physical symptoms (eg, pain caused by neurofibromas, pathologic fractures, hypertensive headaches due to pheochromocytoma). [emedicine.medscape.com]

• Cafe-Au-Lait Spots

  Diagnosis The diagnosis of NF1 is usually made during the first decade of life, based on characteristic skin freckling, cafe-au-lait spots, optic glioma, and/or pseudoarthrosis. [rarediseases.org]

  Carriers of this autosomal dominant trait are prone to the occurrence of benign and malignant tumors which present with cafe-au-lait spots, fibromatous tumors in the skin and Lisch nodules in the eye. [symptoma.com]

  Six or more light brown-colored birthmarks (cafe-au-lait spots) may be located anywhere on the body. The spots usually appear before about 9 years of age. [orthoinfo.aaos.org]

• Facial Pain

  Other symptoms of NF2 include continuous ringing in the ears, headache, facial pain, or weakness, and feeling unsteady or off-balance. Other tumors may involved the lining of the brain (meningiomas) and spinal cord (ependymomas). [kidshealth.org]

  Affected people may also have ringing in the ear(s), headaches, facial pain/numbness, and trouble with their balance. NF1 and NF2 are genetic disorders. A separate abnormal gene causes each form of the disease. [orthoinfo.aaos.org]

• Headache

  Depending on the location and size of the tumors, other symptoms may include problems with balance and walking; dizziness; headache; facial weakness, numbness or pain; ringing in the ears; and/or progressive hearing loss. [cedars-sinai.edu]

  Tinnitus, dizziness, facial numbness, balance problems and chronic headaches may also surface during the teenage years. Numbness may also occur in other parts of the body, due to spinal cord tumors. [genome.gov]

  Chief complains are cutaneous discoloration or disfigurement, pain, pathologic fractures, and hypertensive headaches due to pheochromocytoma (tumor of the sympathetic paraganglia). [symptoma.com]

  The pressure from the tumours on other nerves may also cause headaches or numbness of the face or weakened facial muscles. People who have NF2 may also develop tumours in other body areas, such as the brain and spinal cord. [medbroadcast.com]

  Patients may report cutaneous discoloration or disfigurement or more serious physical symptoms (eg, pain caused by neurofibromas, pathologic fractures, hypertensive headaches due to pheochromocytoma). [emedicine.medscape.com]

On CT scan, tumors appear as a circumscribed hypodense mass with minimal contrast enhancement. With MRI lesions are T1 hypointense and T2 hyperintense with varied contrast enhancement. Localised neurofibroma is similar to schwannoma, with distinct, fusiform and encapsulated soft tissue masses less than 5 cm in diameter. Most NF1 patients are identified during routine consultation or for verification of a positive family history. MRI is recommended to establish the diagnosis of NF1 in patients with symptoms and signs of neurologic disorder and particularly in children with glioma, when visual testing is difficult. Acoustic neuromas or meningiomas of NF2 origin can be diagnosed with MRI in conjunction with CT of the petrous ridge, showing typical widening of the auditory canal.

• Mediastinal Mass

  These tumors may also appear as anterior mediastinal masses, sciatic nerve lesions with pelvic extension, and perirectal plexiform and uterine tumors, all leading to sever clinical complications. [atlasgeneticsoncology.org]

Treatment for neurofibroma, if at all, is selective, depending on the type of lesions i.e., localized, diffuse, and plexiform. In patients with severe symptoms, surgical removal or irradiation of the lesions may be required, provided that the possible damage to the involved nerve is taken into consideration.

Lesions not associated with NF1

Surgery is indicated for localized and diffuse lesions. However, since neurofibromas insinuate between nerve fascicles, it is difficult to perform complete excision without damaging the nerve. Deep-seated lesions are managed with the least intrusion on the parent nerve. No recurrence has been reported and malignant transformation is not the usual case [1].

Lesions associated with NF1

Patients with NF1 are treated conservatively (non-surgical) due to the presence of multiple lesions, unless the severity of symptoms require a more radical approach to treatment. Surgical excision of plexiform neurofibromas is difficult leading to incomplete resection and resurrence in most instances. Malignant transformation is likely to occur in plexiform neurofibromas. 

Prognosis in NF1 varies among individuals, given an equally varied course of illness. Life expectancy is 10  to 15 years, malignancy being the principal cause of death. The spectrum of illness includes brain tumors and malignant peripheral nerve sheath tumors. 

Types of neurofibromatosis: 

Neurofibromatosis type 1 (NF1) or von Recklinghausen disease is the most common type of neurofibromatosis, with prevalence rate of 1 in 2500 to 3000 persons worldwide. The disease involves neurologic, cutaneous, bone or soft-tissue structures in the body. NF1 (autosomal, dominant) gene appears on band 17q11.2, encoding for the synthesis of neurofibromin, a tumor suppressor. More than 1000 mutations have been identified, with germ cell mutation in 20 to 50% of cases.

Neurofibromatosis type 2 (NF2) occurs in 10% of neurofibromatosis cases, with prevalence rate of 1 in 35,000 persons. It causes vestibular schwannomas or congenital bilateral acoustic neuromas. NF2 gene appears on band 22q11, encoding for the synthesis of a tumor suppressor, merlin or schwannomin. The trait is inherited from one of the parents. Two hundred mutations have been reported.

Schwannomatosis is a rare disorder, constituting 15 % of neurofibromatosis cases. It occurs in families (that is, several members are affected). Germline mutation in the SMARCB1 gene is located at band 22q11.23, adjacent to the NF2 gene. Two or more schwannomas may be found in peripheral nerves, causing pain.

Neurofibroma affects persons 20 to 30 years old, male and female alike. The world incidence rate of neurofibromatosis type 1 (NF1, peripheral neurofibromatosis or von Recklinghausen disease) is between 1 in 2,500 to 1 in 3,000 individuals [4] [5]. Carriers of this autosomal dominant trait are prone to the occurrence of benign and malignant tumors which present with cafe-au-lait spots, fibromatous tumors in the skin and Lisch nodules in the eye.  

The central or type 2 neurofibromatosis (NF2) is an autosomal dominant gene that is linked to multiple neoplasia syndrome with incidence rate of 1 in 25,000 live births [6]. It is associated with meningiomas of the brain, tumors of the eighth cranial nerve (usually bilateral), and schwannomas of the dorsal roots of the spinal cord. NF2 is distinct from NF1. 

Neurofibromas are benign neoplasms consisting of schwann cells, fibroblasts  and abundant WHO grade 1 collagen fibres. In contrast to schwannomas, these are without capsules and can insinuate between nerve fascicles. Neurofibromas can potentially transform into malignant peripheral nerve sheath tumors (MPNST).

NF1 gene encodes for the synthesis of neurofibromin, belonging to a group of GTP-ase-activating proteins (GAPs) and which is found in the brain, thymus, spleen, and kidney [7] [8] [9]. GAPs stimulate intrinsic GTPase activity in the ras p21 family [10] [11] [12] which, in turn, activates the stem cell factor (SCF)/c-kit targeting rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways.

Mutations in the NF1 gene adversely affect the biosynthesis of functional proteins that could inhibit the development of NF1-associated tumors [9]. The NF1 trait varies within and among families [13]. Somatic and germline mutations account for complete loss of neurofibromin as in pseudoarthrosis [14] and neurofibromas [15]. Evidence indicates that NF1 is a tumor suppressor gene.

Neurofibromatosis type 2 (NF2) is attributed to defects in the NF2 gene, located on chromosome 22 [16]. NF2 normal cells produce merlin or schwannomin, a tumor suppressor [17] [18]. Molecular technology has made possible detection of abnormality in NF2 in over 93%  of families [19]. New mutations in NF2 manifested differently (somatic mosaicism) may be difficult to establish unless tumor tissue is analyzed [19] [20] [21] [22].

Mutations in NF2 gene means loss of ability to synthesize merlin. Tumor development presumes that both NF2 alleles are inactivated since tumors cannot develop in normal NF2 cell. An abnormal NF2 allele may be inherited from a heterogeneous parent. Thereafter, somatic mutation which may occur after fertilization, could result in two cell lines (mosaicism), one of which carrying the defective gene.

Neurofibromatosis is not preventable in the usual sense of the word. Even at that, the issue of prevention is an ethical one. It is a decision on whether or not to have a child if there is a potential for passing the hereditary condition based on family history. Nonetheless, genetic testing and counselling is recommended for prospective parents. 

Three types of neurofibromas:

• Localized neurofibroma is the most common type of neurofibroma, constituting 90% of all lesions. Most of these occur as single or solitary lesions which are not implicated in the pathogenesis of neurofibromatosis type 1 (NF1) [1].
• Diffuse neurofibroma presents as plaque-like, thickened, elevated lesions of the skin, 90% of which occur singly and are not associated with NF1 [2].
• Plexiform neurofibroma is pathognomonic of NF1 i.e., indicative of the disease condition caused by neurofibromatosis type 1 and that it is potentially malignant [3]. It involves a long nerve and its branches and extends into surrounding tissue beyond the epineurium.

Based on clinical and genetic origins, neurofibromatosis is further classified into: neurofibromatosis type 1 (NFI), type 2 (NF2) and schwannomatosis. NF1 or von Recklinghausen disease, is the most common type of neurofibroma. It is distinguished by the presence of multiple cafe-au-lait macules and neurofibromas. When confined to one location on the body, it is called segmental NF1.

The term "neurofibromatosis" is generic, that is, referring to several clinically related but genetically distinct disease entities. It is basically associated with the finding of benign or malignant tumors of the central or peripheral nervous system, often presenting with pigmented skin macules and other recognizable diagnostic features. Surgical removal is usually prescribed for benign tumors; radiation or chemotherapy for malignant cases.

Neurofibromas are benign tumors of the peripheral nerve sheath. These occur singly and infrequently, but in association with neurofibromatosis type 1 (NF1). The distinguishing features of NF1 are the multiple café-au-lait macules and concomitant skin tumors. Neurofibromas are the most commonly encountered benign tumors of type 1 neurofibromatosis. These tumors consist of mast cells, fibroblasts, Schwann cells, and vascular elements. Tumors are known to develop at any point along a nerve and have the potential to transform into malignant peripheral nerve sheath tumors (MPNST). At the moment curative treatment is not an option in neurofibromatosis. Research however aims to find appropriate medications to alleviate symptoms and to prevent recurrence. Surgical removal of the tumors provide relief in conjunction with radiation to reduce the size of the tumors. 

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