Neurofibromatosis (von Recklinghausen disease, central neurofibromatosis, schwannomatosis [neurilemmomatosis])
Neurofibromatosis (Neurofibromatosis type 1 [NF1, von Recklinghausen disease] 237.71, neurofibromatosis type 2 [NF2, central neurofibromatosis] 237.72, schwannomatosis [neurilemmomatosis] 237.73)
Are You Confident of the Diagnosis?
The neurofibromatoses refer to a group of disorders that share a propensity to develop benign tumors of the peripheral nerve sheath. The three well-defined forms of neurofibromatosis include: (1) neurofibromatosis type 1 (NF1); (2) neurofibromatosis type 2 (NF2); and (3) schwannomatosis. Each disorder has a distinct phenotype, but overlap of clinical features may cause diagnostic confusion. Each disorder is due to a different genetic mutation.
What you should be alert for in the history
NF1 should be suspected when a patient presents with multiple cafe-au-lait macules (> 5), multiple neurofibromas (> 2), or a plexiform neurofibroma. NF1 is a multisystem disorder that can affect any organ system. Presentation is highly variable. Because NF1 is autosomal dominant, ask about similar findings in 1st degree relatives. About half of patients will not have a family history. Inquire whether the patient has a history of headaches, pain, hypertension, skin tumors, brain or spinal cord tumors, learning disabilities, attention deficit disorder, seizures, or visual problems.
NF2 and schwannomatosis present primarily with neurological complaints. Patients should be questioned about pain, weakness, headache, paresthesias, tinnitus, hearing loss, vision impairment and vertigo. Family history is also important.
Characteristic features on physical examination
The main cutaneous features of NF1 are multiple (> 5) cafe-au-lait macules, freckling of the axilla and groin (Crowe sign), and neurofibromas (
Multiple cutaneous neurofibromas in an adult with NF1.
Multiple cafe-au-lait macules and early neurofibromas in a child with NF1.
Multiple cafe-au-lait macules in a child with a family history of NF1.
Neurofibromas usually do not appear until puberty. They present as soft, flesh to pink or brown papulonodules. They increase in size and number over time. In contrast, plexiform neurofibromas are usually congenital. Superficial plexiform tumors appear as infiltrated plaques, often with overlying hyperpigmentation or hypertrichosis, that have a ropy feel on palpation. They can become quite large and disfiguring. Other skin findings described in patients with NF1 are juvenile xanthogranulomas (yellow-brown dome-shaped papules), generalized hyperpigmentation, nevus anemicus, and glomus tumors.
Other noncutaneous features may be evident on physical examination. An examination of the skeletal system may show macrocephaly, short stature, facial asymmetry, anterolateral bowing of the long bones (most commonly the tibia), or scoliosis (
Scoliosis and multiple cafe-au-lait macules in a teenager with NF1.
The eyes should be examined to look for proptosis or exopthalmos, which can be a sign of an optic glioma, plexiform neurofibroma involving the orbit or sphenoid wing dysplasia. Lisch nodules are hyperpigmented lesions of the iris that are best seen with slit-lamp examination. When an optic pathway glioma involves the optic chiasm, central precocious puberty may occur due to either infiltration or pressure from the tumor on the hypothalamus. Precocious puberty can also occur in patients with NF1 in the absence of an optic chiasm glioma. Signs of precocious puberty are accelerated growth, breast development, axillary or pubic hair, acne, seborrheic dermatitis or body odor in a young child (< 7 years of age).
Unlike NF1, cutaneous findings are not a predominant feature of NF2, but when present may indicate more severe disease. Cafe-au-lait macules occur at a higher rate in NF2 than the general population, but are not present in large numbers. About half of patients with NF2 have one to five cafe-au-lait macules; < 1% have six or more. Freckling of the axilla and groin does not occur in NF2. Cutaneous tumors occur in about two-thirds of patients. These appear as subcutaneous nodules or discrete, slightly thickened dermal plaques with hypertrichosis and faint hyperpigmentation. Histologically, these are schwannomas, not neurofibromas.
Skin findings are not prominent in schwannomatosis. Cafe-au-lait macules and skin-fold freckling do not occur. Subcutaneous schwannomas present as firm, spherical, often painful nodules. They may string along a peripheral nerve. Plaque-like schwannomas do not occur in schwannomatosis.
The diagnosis of NF1 is made when a person fulfills two of seven diagnostic criteria. The NIH diagnostic criteria of NF1 are: (1) six or more cafe-au-lait macules (5 mm or more before puberty, 15 mm or more after puberty); (2) freckling of the axilla or groin; (3) two or more neurofibromas or one plexiform neurofibroma; (4) two or more Lisch nodules; (5) optic pathway glioma; (6) a distinctive osseous lesion, such as sphenoid wing dysplasia or tibial pseudoarthrosis; and (7) a first-degree relative that fulfills criteria.
Many of the diagnostic criteria are age-dependent. Most patients with NF1 fulfill diagnostic criteria by age 8. Care should be taken when using these criteria in young children. An ophthalmologic evaluation with slit lamp examination is required whenever the diagnosis of NF1 is suspected. Magnetic resonance imaging (MRI) of the brain is not necessary to make a diagnosis. Although it is controversial, most experts do not recommend MRI in an asymptomatic individual. The one exception would be when a reliable ophthalmological examination is not possible.
Genetic testing is available for NF1. The test is positive 95% in patients that meet diagnostic criteria. Genetic testing is most helfpul for confirming a diagnosis in an individual who fulfills one criteria (eg, a young child with no family history of NF1 who presents with six or more cafe-au-lait macules and no other findings) or for prenatal testing. Prognostic information is limited at this time.
Diagnostic criteria are available for NF2. NF2 can be diagnosed in individuals with one of the following: (1) bilateral vestibular schwannomas; OR (2) first-degree relative with NF2 and unilateral vestibular schwannoma; OR (3) first-degree relative with NF2 and any two tumors (meningioma, schwannoma, glioma, neurofibroma) or posterior cataracts; OR (4) unilateral vestibular schwannomas and any two tumors or posterior cataracts; OR (5) multiple meningiomas and any two tumors or cataracts; OR (6) multiple meningiomas and a unilateral vestibular schwannomas.
Schwannomas are the only lesion likely to present in the skin. The diagnosis of a schwannoma can be confirmed with skin biopsy. An MRI of the brain should be done on all individuals suspected of having NF2. Genetic testing is available for NF2. It is positive in 93% of familial cases of NF2 and 70% of sporadic cases. Some cases of sporadic NF2 are caused by somatic mosaicism and can be diagnosed by performing genetic testing on affected tissue.
Diagnostic criteria have recently been proposed for schwannomatosis. Individuals must have at least two nonintradermal schwannomas, absence of vestibular schwannomas on MRI, no family history of NF2, and have no known NF2 germline mutation. Genetic testing for INI1/SMARCB1 is available although sensitivity is low. This test is positive in 33% of familial schwannomatosis and 7% of sporadic cases.
Who is at Risk for Developing this Disease?
NF1 is common, affecting approximately 1 in 3000 persons. Fifty percent of cases are sporadic. An individual with NF1 has a 50% risk of having an affected child with NF1. NF1 is fully penetrant, but highly variable even among family members. This means that a mildly affected person may have a child with severe disease and vice versa. Males and females are affected equally. There is no ethnic or racial predilection. The disease usually becomes apparent in young children.
NF2 affects approximately 1 in 40,000 persons. Fifty percent of cases are sporadic. An individual with NF2 has a 50% risk of having an affected child with NF2. There is no ethnic or racial predilection. The average age of onset of findings is between 18 to 24 years.
The exact frequency of schwannomatosis is unknown, but is thought to be similar to NF2. Most cases are sporadic, but some families exhibit an autosomal dominant inheritance pattern. There is no ethnic or racial predilection. The disease primarily affects adults.
What is the Cause of the Disease?
NF1 is caused by a germline mutation in the NF1 gene. The NF1 gene is located on chromosome 17q11.2. It encodes for neurofibromin, a tumor suppressor protein. In a normal state, neurofibromin accelerates inactivation of Ras, preventing cellular proliferation. In NF1, neurofibromin levels are reduced, which leads to upregulation of Ras and cellular proliferation. Many of the clinical features of NF1 (including neurofibromas and cafe-au-lait macules) develop only after loss of the second (wild type) NF1 allele. Other genetic and epigenetic events likely contribute to tumor formation, but these are currently not known.
NF2 is caused by a germline mutation in the NF2 gene on chromosome 22q11.2. This gene encodes for merlin (schwannomin), also thought to be a tumor suppressor protein. At least some cases of schwanommatosis are due to germline mutations in INI1/SMARCB1 gene. This gene is located near the NF2 locus on chromosome 22.
Systemic Implications and Complications
NF1 is a multisystem disorder that can involve almost any organ system. The severity of NF1 ranges from mild (primarily skin manifestations, few complications, normal life span) to severe (significant morbidity and life-threatening complications, shortened life span). The potential complications of NF1 are listed below.
Increased risk of malignancy. It is estimated that 7 to 15% of patients with NF1 will develop a malignant peripheral nerve sheath tumor (MPNST). MPNST most commonly develops in a preexisting plexiform neurofibroma. Treatment of these tumors is unsatisfactory and the 5 year survival rate is poor. Patients with NF1 also have an increased incidence of pheochromocytoma, rhabdomyosarcoma, and juvenile chronic myelogenous leukemia. Malignancy is a major cause of mortality in NF1.
Organ system compromise due to presence of a plexiform neurofibroma. Approximately half of patients with NF1 will have a plexiform neurofibroma. Many of these are internal. They can occur in any organ system and cause functional compromise.
Vision loss. Optic pathway gliomas occur in about 15% of patients with NF1. They are generally indolent and asymptomatic; however about 5% result in vision loss. Symptomatic optic pathway gliomas usually present by the age of 6.
Central nervous system (CNS) tumors. Patients with NF1 have a higher risk of developing other CNS tumors, including gliomas and astrocytomas. Complications are related to the location and rate of tumor growth.
Learning disabilities. Most patients with NF1 have a normal IQ, but at least 50% have a specific learning disability. Visual-spatial deficits and poor fine motor skills are common. Attention deficit disorders occur at a higher rate.
Seizures. Seizures occur in about 5% of patients with NF1.
Vasculopathy. Patients with NF1 are at a higher risk for renal artery stenosis, which can lead to hypertension, and coarctation of the aorta. NF1-vasculopathy often causes stenosis or occlusion of major arteries of the brain and heart. Intracranial aneurysms occur at a higher rate in patients with NF1. Vasculopathy is a major cause of mortality in NF1.
Scoliosis. Scoliosis occurs in 10 - 30% of NF1 patients. Dystrophic forms occur, which present at a younger age and are rapidly progressive. Diminshed lung function can occur if scoliosis is severe.
Fractures, with pseudoarthrosis. Dysplasia of the long bones occurs in NF1. The most common site of involvement is the tibia. Affected bones are at an increased risk for fracture. These fractures often heal poorly leading to pseudoarthrosis. Amputation is sometimes necessary.
Generalized osteopenia and osteoporosis. This occurs at a higher rate in the NF1 population.
Precocious puberty. About 3% of patients with NF1 develop precocious puberty. This occurs most commonly in patients with an optic chiasm glioma (due to compromised hypothalmic function).
Unidentified bright objects (UBOs). About 60% of patients with NF1 will have UBOs visible on T2-weighted MRI. These areas appear as hyperintense regions in multiple sites. The clinical signficance of these lesions is unclear. They are currently not included as a diagnostic criterion.
Complications in NF2 are often severe and relate to the occurrence of tumors (typically schwannomas or meningiomas) in the central and peripheral nervous system. NF2 is associated with early mortality. The average age of death in a patient with NF2 is 36 years. The potential complications of NF2 are listed below.
Progressive, sensorineural hearling loss. Almost all patients with NF2 develop bilateral vestibular schwannomas. In most patients this leads to hearing loss.
Decreased visual acuity .Decreased vision is caused by posterior capsular catracts or compression of vital ocular structures from intracranial or intraorbital tumors.
CNS tumors. Brain tumors, especially meningiomas, develop at a higher rate in patients with NF2. Meningiomas are a common cause of mortality in these patients.
Neurological deficits. These vary depending on location of schwannomas in various nerves, but functional impairment is common in NF2. Pain is less common. Progressive polyneuropathy is common in patients with multiple spinal cord tumors.
Hydrocephalus. This occurs as a result of obstruction from intracranial tumors.
Mononeuropathy. Mononeuropathy may occur as a facial palsy, squint or hand/foot drop. This is due to proliferation of Schwann cells in a specific nerve. Sometimes this is the earliest sign of NF2.
Schwanommatosis is associated with chronic pain, often intractable. Neurological deficits, such as weakness and sensory deficits, may occur, but are less common than in NF2. The lifespan appears to be normal in patients with schwannomatosis.
Treatment options are summed up in
Treatment options for skin manifestations of NF1
|Neurofibromas (symptomatic or disfiguring)||None||ExcisionCO2 Laser VaporizationElectrosurgical excision||None|
|Cafe-au-lait macules||None||Laser therapyQ-switched Nd:YAG (532 nm, 1064 nm)Q-switched alexandrite (755 nm)Q-switched ruby (694 nm)Copper vapor laser (511 nm)Pigmented lesion dye laser (510 nm)||Sun Protection|
|Plexiform neurofibroma (symptomatic, disfiguring, functional compromise)||MethotrexateInterferon-alphaVincristineThalidomide (all empiric therapies)||Excision||None|
Optimal Therapeutic Approach for this Disease
Associated complications involving the nervous system, eye, bones, and cardiovascular system should be referred to an appropriate specialist. Symptomatic or disfiguring cutaneous neurofibromas are best treated with simple excision. There are reports of CO2 laser vaporization or electrosurgical excision being used for the efficient removal of large numbers of tumors. Hypertrophic scarring is a risk. Clinical trials evaluating topical rapamycin, topical imiquimod, intralesional ranibizumab (VEGF inhibitor), and erbium-YAG laser vaporization for treating cutaneous neurofibromas are ongoing.
Cafe-au-lait spots that are cosmetically distressing can be lightened with a number of pigmented lesion lasers. The Q-switched Nd:YAG (532 nm, 1064 nm), Q-switched alexandrite (755 nm), Q-switched ruby (694 nm), copper vapor laser (511 nm), and pigmented lesion dye laser (510 nm) have all been reported as being efficacious. There are no studies directly comparing these lasers so recommending one over another is difficult. It is important to tell the patient that about half of lesions do not respond to laser treatment and of those that do respond, half recur over time. Multiple treatments are often necessary. Hypo- and hyperpigmentation are risks.
Plexiform neurofibromas, because of their infiltrative nature, are more difficult to completely excise and recurrence is common. Hemorrhage and nerve damage are major risks. Medical treatment of plexiform neurofibromas is empiric. Drugs reported include methotrexate, interferon-alpha, vincristine, and thalidomide. There are multiple ongoing clinical trials evaluating the use of sirolimus (mTOR inhibitor), imatinib (c-kit inhibitor), ranibizumab (VEGF inhibitor), photodynamic therapy, pirfenadone (antifibrotic agent), and sorafenib (tyrosine kinase receptor inhibitor) for progressive or problematic plexiform neurofibromas.
A full physical examination is necessary in all patients when a diagnosis of NF1 is considered. Examination should focus on the skin, eyes, skeletal, nervous, and cardiovascular systems. A complete medical history should be obtained with a focus on features associated with NF1. A complete family history for NF1 is important. It may be helfpul to perform examinations of skin and eye in first-degree relatives. All patients with suspected NF1 need to have an ophthalmologic evaluation with slit lamp examination. MRI scans of the brain are not necessary to establish a diagnosis and are not generally recommended as a screening tool.
If a patient meets NIH diagnostic criteria for NF1, they should be referred to a specialist (usually a geneticist or neurologist) experienced at managing patients with NF1. A list of NF specialists and NF clinics (NF Clinic Network) in the United States is available at
All children should have a developmental assessment prior to starting school. Blood pressure, height, and head circumference should be monitored yearly. MRI scans can define the extent of plexiform neurofibromas and can be used to follow tumor progression. Other studies are indicated as needed if other signs or symptoms arise. Although it is controversial, most NF experts do not recommend MRI scans in an asymptomatic individual.
A high index of suspicion for MPNST is necessary in patients with plexiform neurofibromas. Tumors should be monitored for rapid growth, firm areas in a previously soft tumor or unrelenting pain. Positron emission tomography (PET) scanning using 18-fluorodeoxyglucose has been shown to be helpful in distinguishing benign from maligant areas. A targeted biopsy using the results of the PET scan should be done if there is concern for malignant transformation.
If an infant or young child presents with only multiple cafe-au-lait macules (five or more at least 5 mm in diameter) and no family history of NF1, they should be followed clinically, at least until the age of 8, as if they have NF1 or until another diagnosis becomes apparent. Almost all children with NF1 will meet NIH diagnostic criteria by the age of 8. Genetic testing can be useful in confirming a diagnosis of NF1 earlier. This may alleviate some of the anxiety associated with the “wait and watch” approach. A recently described syndrome due to mutations in SPRED1, Legius syndrome, also presents with multiple cafe-au-lait macules and axillary freckling and may be indistinguishable from NF1 early in life. Genetic testing is available and should be considered in patients with pigmentary features of NF1, but negative NF1 testing.
Genetic counseling is important for patients and their families with NF1. Patients with NF1 need to understand that there is a 50% risk of passing the disease to each offspring. The severity of NF1 is unpredictable and variable, even within the same family. This means that a mildly affected parent can have a child with severe disease and vice versa. Prenatal testing is available if the familial mutation is known, but will not predict the severity of NF1.
All patients suspected of having NF2 or schwannomatosis should be referred to a specialist (usually a geneticist or neurologist) experienced at handling these disorders. Baseline evaluation consists of head MRI, hearing evaluation with brainstem auditory evoked response (BAER), ophthalmolgic examination and full skin examination. These studies are usually repeated annually. Patients with schwannomatosis should be referred to a pain clinic if chronic pain is an issue.
Unusual Clinical Scenarios to Consider in Patient Management
Clinical features of NF1 (typically cafe-au-lait macules, axillary or inguinal freckling, or neurofibromas) localized to a body segment should raise the possiblity of segmental neurofibromatosis. The estimated occurence of segmental NF1 is 1 in 40,000; however, the actual incidence is probably higher. Segmental NF1 is caused by a postzygotic mutation in the NF1 gene. The later the mutation occurs during embryogenesis, the more localized the findings will be. Any combination of skin findings can occur (pigmentary, tumor or both).
Serious complications of NF1 usually do not arise in patients with segmental disease, although rare cases of skeletal dysplasia, optic pathway glioma and MPNST have been reported. The risk of transmitting NF1 to offspring is much lower than 50%, although probably higher than someone without segmental NF1.
Mosaic NF1 also occurs from a postzygotic mutation in the NF1 gene. Mosaic NF1 often presents with more generalized features than segmental NF1. It is thought that in these cases the mutation occurs earlier during embryogenesis. A clue to mosaicism is the finding of sharply demarcated normal areas of skin on examination. Patients with mosaic NF1 tend to have milder disease. Genetic testing from blood is often negative in these patients. Genetic testing from a biopsy of affected tissue (cafe-au-lait macule, neurofibroma) is possible and may identify the post zygotic NF1 mutation. This information can be used for prenatal or preimplantation testing if desired.
Juvenile xanthogranulomas (JXGs) are more common in patients with NF1. JXGs in the setting of NF1 are associated with a higher risk of juvenile myelomonocytic leukemia. Because the overall incidence of this association is low, routine monitoring of a CBC is not recommended. However, physicians should be aware of this association and monitor for signs of leukemia, such as hepatosplenomegaly, lymphadenopathy, pallor and petechiae.
Multiple cafe-au-lait macules and freckling of the axilla or groin were once thought to be pathognomonic for NF1. It is now known that Legius syndrome can present with the same pigmentary features. The phenotype of Legius syndrome is characterized by multiple cafe-au-lait macules, axillary freckling, and macrocephaly. Lipomas, learning disabilities and Noonan-like facies have also been described. Lisch nodules appear to be absent. The more serious tumorigenic manifestations (eg, optic pathway gliomas, plexiform neurofibromas, malignancies) do not appear to occur in patients with Legius syndrome.
Recognizing this disorder may have important prognostic and monitoring implications for patients. It is estimated that 1 - 2% of patients that fulfill NIH diagnostic criteria met solely by pigmentary findings will actually have Legius syndrome. Genetic testing for SPRED1( the gene that causes Legius syndrome) is available.
What is the Evidence?
Neurofibromatosis. vol. 1. 1988. pp. 172-78.(Summarizes the recommendations of the consensus development conference and publishes for the first time the recommened NIH diagnostic criteria. These criteria are used today unmodified with high specificity and sensitivity.)
Boyd, KP, Korf, BR, Theos, A. "Neurofibromatosis type 1". J Am Acad Dermatol. vol. 61. 2009. pp. 1-14.(An updated review article on NF1. The review includes clinical features, molecular genetics, and pathophysiology of NF1.)
Ferner, RE, Huson, SM, Thomas, N, Moss, C, Willshaw, H. "Guidelines for the diagnosis and management of individuals with neuofibromatosis 1". J Med Genet. vol. 44. 2007. pp. 81-8.(This consensus statment from the United Kingdom discusses the diagnostic driteria, major differential diagnosis, clinical manifestations and the present strategies for monitoring and managing NF1 complications.)
DeBella, K, Szudek, J, Friedman, JM. "Use of National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children". Pediatrics. vol. 105. 2000. pp. 608-14.(A retrospective study that evaluated the age of onset of the clinical features used in the NIH Diagnostic Criteria in 1893 patients with NF1. This study also examined at what age a diagnosis of NF1 can be confidently made using these criteria.)
Hersh, JH. "Committee on Genetics. Health supervision for children with neurofibromatosis". Pediatrics. vol. 121. 2008. pp. 633-42.(This article provides guidelines for monitoring and providing intervention in children affected by NF1.)
Theos, A, Korf, BR. "American College of Physicians, American Physiological Society". Ann Intern Med. vol. 144. 2006. pp. 842849.(A detailed review of what is known about the pathophysiology of the various clinical features reported in NF1.)
Ferner, RE. "Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective". Lancet Neurol. vol. 6. 2007. pp. 340-51.(An excellent review article that reviews the clinical features, complications, pathogenesis, and molecular genetics of both NF1 and NF2.)
Listernick, R, Mancini, AJ, Charrow. "Segmental neurofibromatosis in childhood". Am J Med Genet. vol. 121A. 2003. pp. 132-35.(This is a retrospective study that summarizes the clinical features in 39 children with segmental NF1.)
Burgdorf, WH, Zelger, B. "JXG, NF1, and JMML: alphabet soup or a clinical issue". Pediatr Dermatol. vol. 21. 2004. pp. 174-76.(This well-thought out commentary reviews the relationship between NF1, JXG, and JMML. The authors conclude that although the relative risk of JMML in patients with JXG and NF1 is increased, the absolute risk is low.)
MacCollin, M, Chiocca, EA, Evans, DG, Friedman, JM, Horvitz, R. "Diagnostic criteria for schwannomatosis". Neurology. vol. 64. 2005. pp. 1838-45.(This article reviews the key features of schwannomatosis, differentiating it from NF2, and proposes a set of diagnsotic criteria.)
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