Neurofibromatosis Type 1

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Continuing Education Activity

Neurofibromatosis-1 (NF-1) or Von Recklinghausen disease is one of the inheritable neurocutaneous disorders manifested by developmental changes in the nervous system, bones, and skin. It is an autosomal dominant disorder. Additionally, it is the most common amongst all the hamartoma neoplastic syndromes, including tuberous sclerosis, Gardner, and Cowden syndromes. This activity describes the clinical presentation and management of NF-1 and highlights the role of the interprofessional team in the management of patients with this disease.


  • Discuss the pathophysiology of neurofibromatosis-1.
  • Describe the appropriate examination and workup of neurofibromatosis-1.
  • Review the management of patients with neurofibromatosis-1.
  • Summarize how interprofessional coordinated activity and information sharing can improve patient care and outcomes.


Neurofibromatosis type 1 (NF-1) or Von Recklinghausen disease is one of the inheritable neurocutaneous disorders manifested by developmental changes in the nervous system, bones, and skin. It is an autosomal dominant disorder.[1] Moreover, it is the most common of the hamartoma neoplastic syndromes such as tuberous sclerosis, Gardner, and Cowden syndromes. Other types of neurofibromatosis are neurofibromatosis type 2 and schwannomatosis.[2] Cafe-au-lait macules and neurofibromas are the distinguishing features of neurofibromatosis type 1.


NF-1 is an autosomal dominant disorder. The gene for NF-1 is located on chromosome 17, and it encodes a gene product called neurofibromin.[3][4] Neurofibromin is widely expressed in a variety of tissues. Neurofibromin functions as a tumor suppressor gene by downregulating the rat sarcoma (RAS) gene product. The mutation or deletion of this NF-1 gene results in the phenotypic and genotypic manifestations of the disorder. Penetrance is complete, as it is an autosomal dominant disorder. All generations are involved with no skipping.  Expression of the disorder differs not only from one affected family to another but also between individuals of the same family.[5]


NF-1 is an autosomal-dominant genetic disorder that affects all the offspring of an affected individual. The incidence of NF-1 is noted to be 1 in 2600 to 3000 individuals. There is no predilection for the male or female gender.[6] Fifty percent of the presentations are familial, while the rest of the cases are sporadic. Paternally derived chromosomes are the source of sporadic mutations.[7] The risk of these sporadic mutations is high with advancing paternal age. The incidence of the so-called segmental NF-1, a form that predominantly has skin manifestations, is 1 in 36,000 to 40,000 individuals.[8]


Mutations of the NF-1 gene results in a lack of expression of neurofibromin, thereby promoting tumorigenesis. Neurofibromas develop when both NF-1 alleles get mutated. Neurofibromas embody Schwann cells, perineural cells, mast cells, and fibroblasts. [9] Neurofibromas affecting the skin stem from peripheral nerves and their supporting structures, including neurilemmal cells. The fibroblasts in these neurofibromas are derived from factor XIIIa connective tissue cells, which are HLA-DR-positive in peripheral nerves. Dermal fibroblasts secrete increased amounts of hepatocyte growth factor and stem cell factor, contributing to increased melanin deposition in the epidermis.[10] Café-au-lait spots sometimes contain giant pigment granules found in epidermal cells and melanocytes.


Histopathology of the lesions commonly seen in NF-1 are discussed below:

  • Neurofibroma: These are well-circumscribed spindle cell proliferation, but they rarely are encapsulated. They have a mucinous background and many mast cells. Spindle cells have a wavy appearance. As neurofibromas result from a proliferation of all supporting elements of neural fibers, they may have Schwann cells, perineural cells, and blood vessels. Axons stains show the random distribution of individual axons in neurofibroma. Collagen fibers are interspersed among the spindle cells. Schwann cell is considered to be the main tumor cell, where both NF-1 alleles are lacking.[11]
  • Plexiform neurofibroma: They are thought to be the pathognomonic sign of the disease. Histologically, they show numerous elongated nerve bundles with an abundant myxoid matrix. They are often mixed with diffuse cutaneous neurofibromas that involve the dermis and subcutaneous fat.[12]
  • Cafe-au-lait macules: Histologically, there is an increase in the melanin content of basal keratinocytes and melanocytes. There is also an increase in the number of melanocytes, along with an increase in the amount of melanin. Giant melanosomes or macro melanosomes have been reported.[10]

History and Physical

The course of NF-1 varies considerably in various patients, but most have a benign course of the disease without developing major complications. The variability in presentation appears to be at least partially genetically determined and is unrelated to the unaffected allele. If the clinical presentation is limited to one part of the body, it is called segmental NF-1 (neurofibromatosis type 5) due to mosaic NF-1 gene mutation.[13] If the presentation involves the whole body, it is called generalized NF-1. Cafe-au-lait macules, inguinal and/or axillary freckling, Lisch nodules, and neurofibromas are the initial clinical manifestations of NF-1.[14] Osseous dysplasia and optic glioma usually appear around 1 to 3 years of age. Tumors, both benign and malignant, occur throughout life at an increased rate.[15] Patients with NF-1 may present with the following:[16][17]

  • Cafe-au-lait macules: Sharply defined light brown patches vary in size from 0.5 cm to 50 cm; the majority are ten cm or less in size. They are the first feature of the disease and appear in all children affected by the disease. They increase in size and number during the first decade of life. 1 to 3 cafe-au-lait macules are observed in about 15 percent of the normal population. NF-1 is distinguished by having 6 or more cafe-au-lait macules.[18][19]
  • Neurofibromas: Neurofibromas are present in the skin (cutaneous), under the skin (nodular), and along with roots of the nerve (plexiform). Pregnancy is associated with an increase in the number and size of tumors, indicating a hormone-responsive state.[20] Cutaneous neurofibromas are soft lilac-pink tumors, mostly sessile and dome-shaped, while some are pedunculated. Mostly found on trunk and limbs ranging from few millimeters to several centimeters in diameter. In females, they are prominent on the areola of the breast. They are usually benign and pose a cosmetic concern in adults. The plexiform neurofibroma is a diffuse elongated neuroma along the course of the nerve, frequently involving trigeminal and cervical nerves. They are usually present during the first two years of life. On palpation, they have a characteristic "bag of worms" sensation. Pain and expansion of the lesion suggest malignant transformation and are associated with higher morbidity and mortality.[21] Nodular neurofibromas are firm, rubbery, and may cause pain. They do not invade adjacent structures and may become premalignant. 
  • Freckling: Axillary and/or inguinal freckling in patients is usually pathognomonic for NF-1, known as Crowe's sign. Freckles are small and grouped when compared to cafe-au-lait macules. It is present in around 70% of the individuals and appears later than café-au-lait spots by 3 to 5 years. Other intertriginous areas might also be involved.[18]
  • Lisch nodules: Lisch nodules appear as dome-shaped lesions around the iris on slit-lamp-examination. They are present in over 90% of the affected adults and are also known as pigmented iris hamartomas. They are usually asymptomatic but used to confirm the diagnosis in the affected individual and the parent.[22]
  • Skeletal abnormalities: Kyphoscoliosis occurs in 10 to 25 percent of the affected individuals, and high-level lesions may lead to respiratory difficulties.[23] Pseudoarthrosis of the tibia or radius occurs in about 5% of infants with the male predisposition.[24] Sphenoid wing dysplasia is a characteristic abnormality in NF-1, manifesting as an asymmetry of the face. Nonossifying fibromas, short stature, osteopenia, and osteoporosis are other noted osseous abnormalities.
  • Neurological abnormalities: Learning disability, cognitive dysfunction, developmental delay, autism spectrum disorder, attention deficit hyperactivity disorder, macrocephaly, and dural ectasia are reported.[25][26]
  • Malignancies: Neurological tumors consist of optic nerve glioma, astrocytoma, brainstem glioma, and schwannomas. Intracranial tumors can cause headaches and seizures.[27][28] Other malignancies reported to have been associated with the disease are Wilms tumor, rhabdomyosarcoma, malignant peripheral nerve sheath tumors, leukemia, gastrointestinal stromal tumors, pheochromocytoma, retinoblastoma, breast cancer, and malignant melanoma.[29][30] Optic nerve glioma is present in about 15 percent of under 6-year-old children with NF-1.[31] Many children with NF-1 and optic nerve glioma are noted to have normal vision. Puberty may be premature or delayed when optic chiasm is involved due to its effect on the hypothalamus.[32] 
  • Other presentations: Hypertension, congenital heart disease, irritable bowel syndrome, and constipation have been reported with NF-1.[33][34] Papillomatous neurofibromas of the hard palate, tongue, etc., are present in only 5% to 10% of cases.


The diagnosis of NF-1 is mainly clinical, based upon agreed clinical national institutes of health (NIH) criteria which require two or more of the following conditions to be fulfilled[35]:

  • Café-au-lait macules: six or more with the greatest dimension of 5 to 15 mm under normal light
  • Neurofibromas: two or more of any type or one plexiform neurofibroma
  • Freckling: axillary or inguinal
  • Optic gliomas
  • Lisch nodules: two or more
  • Bony lesions: sphenoid dysplasia, pseudoarthrosis, and others
  • Family history: a first-degree relative with the disease.

NIH criteria are both highly sensitive and specific except for young children.[14] Focused symptom assessments of pain, weakness, visual concerns and headaches should be done along with developmental assessment. Physical exam should be emphasized on the skin, eye, skeletal and nervous systems. Slit-lamp examination of the eye is recommended.

Neuroradiological findings include neurofibromatosis, bright spots, and a high volume of the brain (megalencephaly).[36] Bright spots are high signal intensity areas identified in T2 weighted magnetic resonance imaging of the brain, often found in the brainstem, cerebellum, and basal ganglia.[37] They are not necessary for the diagnosis of NF-1. Both bright spots and megalencephaly have been associated with variable cognitive dysfunction. 

Genetic testing is not mandatory for the diagnosis. It can be utilized for establishing the diagnosis in questionable presentations, screening of family members, and prenatal screening. Ninety-five percent of mutations can be detected by genetic testing in individuals with NF-1 clinical diagnosis.[38] A negative test does not exclude the disease as mosaicism may be possible, as in segmental NF-1. Affected individuals should receive multidisciplinary care from geneticists, pediatricians, pediatric neurologists, ophthalmologists, psychiatrists, and psychologists to identify the disorder and related complications, provide the treatment, and need psychosocial support and guidance.  

Treatment / Management

There is no definitive treatment for NF-1 as it is a genetic disorder and has multiple manifestations.[1][39][40][41] Treatment is mainly symptomatic for various NF-1 manifestations, for example:

  • Tumors are treated based on the type, involvement of other structures, and associated complications. Radiation therapy in NF-1 is associated with the emergence of secondary tumors, thereby opting for radiation only in essential cases.[42] Cutaneous and nodular neurofibromas are treated when they develop symptoms like pain, increase in size, weakness, vision loss, or cosmetic concerns. Surgery, laser, electrodesiccation are some of the treatment modalities. Gabapentin has sometimes been utilized for pruritus treatment along with neuropathic pain management. In particular, plexiform neurofibromas (PN) are associated with high morbidity and malignant transformation compared to cutaneous and nodular neurofibromas. Compression of the airway or spinal cord and disfigurement are common reasons for surgical removal of plexiform neurofibromas.[43] Selumetinib was approved for use in children 3 years of age and older with PN that cannot be operated on despite having symptoms or noted to be progressing. It is a mitogen-activated protein kinase inhibitor.[44]
  • Optic pathway gliomas and other low-grade gliomas should be closely monitored for symptoms, visual acuity, and size. Chemotherapy with vincristine, carboplatin, and vinblastine is the first-line therapy in children.[45] No precise therapy is identified for adults with gliomas. Biopsy or surgery is reserved for the evaluation of high-grade gliomas. Malignant peripheral nerve sheath tumors are treated with surgery and radiation. Rhabdomyosarcomas are treated with chemotherapy, surgery, and radiation. 
  • Carbon dioxide laser is used to excise most disfiguring neurofibromas, but hypertrophic or atrophic scars may result from the treatment.
  • Seizures or epilepsy should thoroughly be investigated as a neurosurgical intervention is sometimes very beneficial for the patient.
  • Children with learning or cognitive disabilities and neurologic impairment should work closely with speech, occupational, and physical therapists. 
  • Skeletal abnormalities like dysplasias, pseudoarthrosis, and scoliosis might require orthopedic correction.[24][46] Vitamin D and calcium supplementation are recommended for individuals with osteopenia and/or osteoporosis. 
  • Psychotherapy and counseling can assist with psychosocial functioning and boost morale.[47]
  • Follow-up every 12 months is recommended to assess for different complications of the disease.
  • All infants are screened with cranial MRI to look for neurological abnormalities.[48][49][50]
  • Genetic counseling is very important in disease management. Informing the patients about the different complications of the disease is very important. And it should be made very clear to the patients regarding their children that 50% are likely to be affected, and the disease may be severe. First-degree relatives who have no disease manifestations are unlikely to carry the gene, and the risk for their offspring is small but not absent.

Differential Diagnosis

  • Legius syndrome is an autosomal dominant disorder like NF-1 but lacks neurofibromas and nervous system involvement. Cafe-au-lait macules, freckling is noted.[51] Loss of function mutations in SPRED1 protein results in Legius syndrome.
  • Neurofibromatosis type 2. Affected individuals do not exhibit more cafe-au-lait macules, unlike NF-1. There is no evidence of Lisch nodules, cognitive dysfunction, or malignant peripheral nerve sheath tumors. Meningiomas and acoustic schwannomas are highly associated with neurofibromatosis type 2 (NF2). Mutations in the NF2 tumor suppressor gene located on the 22q chromosome cause the disorder.[52]
  • Noonan syndrome. Individuals may exhibit cafe-au-lait macules along with low set ears, hypertelorism, webbed neck, short stature, and pulmonary stenosis. Mutations of the genes involved in RAS and mitogen-activated protein kinase signaling pathway result in the syndrome.[53] 
  • Constitutional mismatch repair-deficiency (CMMR-D) syndrome is an autosomal recessive disorder manifesting cafe-au-lait macules, freckling, and Lisch nodules. CMMR-D is typically associated with brain tumors, colorectal cancer, and hematological malignancies, unlike optic glioma and rhabdomyosarcoma associated with NF-1. Mutations in 1 of the 4 mismatch repair genes cause the syndrome.[54]
  • Other differential diagnoses include McCune-Albright syndrome, Silver-Russell syndrome, phosphatase and tensin homolog (PTEN) hamartoma syndrome, Carney syndrome, ataxia-telangiectasia, Klippel-Trenaunay-Weber syndrome, Turner syndrome, and tuberous sclerosis.[10]


The outlook for patients with NF-1 is guarded and depends on the severity of the disease, presence of malignancy, and extent of the deformity. Those with mild disease can have a reasonable life expectancy, but those with moderate to severe disease have a poor quality of life.[55] Women with NF-1 related breast cancer have a poor 5-year survival rate and high mortality.[56] Patients with central nervous system tumors are at increased risk for secondary malignancies, mortality, and vascular complications.[57] Malignant peripheral nerve sheath tumors in association with NF-1 have poor overall survival.[29] 


Affected individuals should be followed by multidisciplinary specialists for providing longitudinal care to identify the manifestations early and treat the complications as they arise.[58] Annual surveillance visits for children should include height, weight, head circumference, and blood pressure checks. Eye, skin, skeletal, neurological, developmental, and cognitive assessments are completed during the annual visits. School performance and depression screening are recommended. Any plexiform neurofibroma that grows rapidly, becomes more nodular (deeper involvement), develops more pain, or new neurological deficit should be imaged with magnetic resonance imaging for possible malignant peripheral nerve sheath tumor transformation. Given the breast cancer association with NF-1, women are advised annual mammograms from the age of 30 instead of conventional screening at the age of 40.[56] NF-1 individuals with hypertension, headache, diaphoresis, or palpitations should be evaluated for pheochromocytoma by measuring plasma or urine-free fractionated metanephrines.[59]

Vasculopathy incidence in NF-1 is around 0.4 to 6.4 percent, presenting as essential hypertension, renovascular hypertension, hemorrhagic strokes, aneurysms, or arteriovenous fistulae.[60] Magnetic resonance angiogram, renal angiogram, or computed tomography angiogram should assess the vascular lesions and provide the needed medical and /or surgical therapy to prevent further complications. Toe or fingertip pain is likely due to glomus tumors which may coexist. Severe vascular occlusion of internal carotid arteries, moyamoya disease, and multiple endocrine neoplasias are noted in association with NF-1.[10]

Deterrence and Patient Education

The affected individuals and their families should be made aware of the nature of the disease, manifestations, prognosis, and the possible complications that can develop. Education on the need for periodic surveillance, longitudinal multidisciplinary care aimed for physical and mental wellbeing should be provided. Genetic counseling should be offered prior to conception to provide the required information to the patients and families for making an informed decision.

Pearls and Other Issues

All genetic disorders are rare, and they cause extreme anguish for families. The main aim is to ensure proper diagnosis of the disease and genetic counseling of the affected families to prevent their children from the disease or its complications.

Enhancing Healthcare Team Outcomes

The presentation of patients with NF-1 is extremely variable. Because the disorder affects many organs, it is best managed by an interprofessional team, including clinicians (including physicians, nurse practitioners, and physician assistants), specialty-trained nurses. Primary care physicians, geneticists, pediatric neurologists, ophthalmologists, psychiatrists, psychologists, therapists (physical, occupational, and speech) work collectively as an interprofessional team toward health promotion and maintenance. While the disorder is benign, it is vital that healthcare workers closely monitor patients because many organ systems are involved. To improve patient outcomes, it is important to remember that a few patients may develop neurological tumors. Other malignancies reported to have been associated with the disease are Wilms tumor, rhabdomyosarcoma, leukemia, retinoblastoma, and malignant melanoma. A thorough exam and serial imaging studies are the only way to identify the presence of these lesions.

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Neurofibromas and cafe au lait macules on the back
Neurofibromas and cafe au lait macules on the back
Contributed by Drs. Jason C. Sluzevich, and Thoyaja Koritala

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Cafe au lait macules and neurofibroma on the back
Cafe au lait macules and neurofibroma on the back
Contributed by Drs. Ashley B. Wentworth and Thoyaja Koritala

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Cafe au lait macules on the back
Cafe au lait macules on the back
Contributed by Drs. Ashley B. Wentworth and Thoyaja Koritala

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Axillary freckling in Neurofibromatosis type 1
Axillary freckling in Neurofibromatosis type 1
Contributed by Drs. Jason C. Sluzevich and Thoyaja Koritala
Article Details

Article Author

Abdullah Adil

Article Author

Thoyaja Koritala

Article Editor:

Achint Singh


12/6/2021 10:26:07 AM



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