DISEASE CARD

Disease group	Neurocutaneous Disorders
DISEASE NAME	NEUROFIBROMATOSIS Type I
Synonymous	Von Recklinghausen's disease, NF1
Estimated prevalence	1 in 3000 to 4000
OMIM	162200
Inheritance	Autosomal Dominant
Gene (s)	NF1 (613113)

Definition

Neurocutaneous disorders encompass a diverse group of conditions characterized by involvement of both the skin and central nervous system. These disorders often exhibit overlapping signs and symptoms. Among them, the neurofibromatoses stand out as a group of three genetically distinct conditions:

• Neurofibromatosis type 1 (NF1)
• Neurofibromatosis type 2 (NF2)
• Schwannomatosis

All three are associated with a predisposition to developing tumors, distinct dermatologic features (café-au-lait macules (CALMs) and freckling in the axillary or inguinal regions), and systemic involvement. 

 

Neurofibromatosis type 1 (NF1)

This disease was first described by German pathologist Friedrich von Recklinghausen in 1882. NF1 is one of the most common genetic disorders, with a prevalence of 1 in 3,000–6,000 individuals. Approximately 50% of cases are inherited in an autosomal dominant pattern, while 40% arise from spontaneous (de novo) mutations.

NF1 is now recognized as a tumor predisposition syndrome caused by mutations in the NF1 gene, which encodes neurofibromin, a protein critical for regulating RAS-pathway activity and cellular proliferation.¹

 

Clinical Description / Diagnostic criteria

The NIH established diagnostic criteria for NF1 in 1987, which were reaffirmed in 1997 and recently updated in 2021.²

The clinical diagnosis is based on the presence of two or more of the following:

1. CALMs: ≥ 6 with greatest diameter >5mm in prepubertal or ≥15mm in post-pubertal patients

2. Bilateral Freckles (inguinal and axillary)

3. ≥2 neurofibromas (cutaneous and/or subcutaneous), or ≥1 plexiform neurofibroma (PN)

4. ≥2 Lisch nodules (iris), and/or choroidal abnormalities

5. Optic pathway glioma (OPG)

6. Distinctive osseus lesion, i.e. sphenoid wing dysplasia, anterolateral bowing of the tibia, pseudoarthrosis of a long bone

7. One of the following:
   • A heterozygous pathogenic NF1 variant with a variant allele fraction of 50 % in apparently normal tissue
   • A child of a parent, who meets the diagnostic criteria specified in above, merits a diagnosis of NF1 if 1 or more of the criteria, from above, are present

The condition demonstrates 100% penetrance, though its clinical manifestations vary widely between individuals. Clinical evaluation remains crucial for diagnosis given the variability in presentation. Its characteristic features often appear at different stages of life, with some, like CALMs, present at birth, while others, such as tumors, develop later.³

 

Cutaneous manifestations

Café-au-Lait Macules (CALMs)

Café-au-lait macules (CALMs) in NF1 typically exhibit smooth, well-defined borders and uniform pigmentation, varying in size. These lesions are often present from birth or develop within the first year of life. Atypical CALMs, characterized by irregular borders and edges, have also been described.

CALMs can appear anywhere on the body, with a predilection for the torso, buttocks, and lower extremities. In some cases, larger CALMs may overlay a plexiform neurofibroma, particularly when the neurofibroma involves the spinal cord or midline structures.

Most individuals with NF1 exhibit more than five CALMs, and an increased number of lesions correlates with a higher likelihood of an NF1 diagnosis. However, current evidence indicates no relationship between the size of CALMs and the overall severity of the disease.^1,4-5

Freckling

Freckling, particularly in the axillary and inguinal regions, is another critical diagnostic criterion for NF1. These small (1–3 mm), well-defined brown spots typically develop in clusters around 2–3 years of age and are present in 70–80% of adults with NF1. Freckling is the second most common feature of NF1. By the age of 7, approximately 90% of individuals with NF1 exhibit this feature.⁶

Neurofibromas

Neurofibromas are the most frequent tumors in NF1. These benign peripheral nerve sheath tumors arise from Schwann cells and present as cutaneous, subcutaneous, or plexiform types. Cutaneous neurofibromas typically appear during preadolescence and may number from a few to thousands. Though benign, these soft, fleshy tumors can cause cosmetic concerns and functional impairments. Subcutaneous neurofibromas are commonly firmer and more discrete and occur in about 20% of patients. Hormones such as progesterone may stimulate neurofibroma growth, particularly during puberty or pregnancy.^7-8

 

Ophthalmologic Manifestations

Lisch Nodules

Lisch nodules are melanocytic hamartomas of the iris and are among the most prevalent features of NF1, appearing in nearly all affected individuals. These well-defined, dome-shaped aggregates of melanocytes are typically clear, yellow, or brown. Despite their distinctive appearance, they are asymptomatic and do not affect vision.⁹

Optic Pathway Gliomas (OPGs)

Optic pathway gliomas (OPGs) are benign tumors primarily affecting children under 7 years of age with NF1. These low-grade gliomas, often identified as pilocytic astrocytomas, occur in 15–20% of NF1 patients. They may involve any part of the optic pathway, with 75–85% located in the optic nerves and chiasm. Although most OPGs are asymptomatic, 30–50% may cause visual impairment or precocious puberty due to hypothalamic dysfunction. Common signs include optic nerve pallor, proptosis, edema or atrophy. Younger children (<2 years) and females with post-chiasmal or hypothalamic involvement may face worse outcomes due to more aggressive tumor behavior.^9,10

 

Plexiform Neurofibromas (PNs) and other tumors

Plexiform neurofibromas are present in 26-30% of NF1 patients and can appear at birth or during early childhood. These tumors are hyperpigmented and sometimes covered with terminal hair, when occuring superficial. Internal plexiform neurofibromas can only be detected by MRI. PNs have a 5–15% risk of malignant transformation into aggressive sarcomas, such as malignant peripheral nerve sheath tumors (MPNST). Early diagnosis of MPNST is critical, as these tumors have poor prognosis and high metastatic potential. Unlike MRI and CT, PET can detect cellular changes at early stages of malignancy and distinguish between malignant radiation-induced necrosis and tumors.^{1, 11}

NF1 patients have a significantly elevated cancer risk, with an overall likelihood approximately four times higher than the general population. Specific malignancies inlcude juvenile myelomonocytic leukemia, pheochromocytoma, and various CNS tumors, rhabdomyosarcoma, parathyroid adenomas and gastrointestinal stromal tumors (GISTs). The risk of breast cancer is notably higher, particularly in women under 50. Also other cancers can occur more frequently in this population.¹²

 

Central Nervous System (CNS) Manifestations

NF1 is frequently associated with CNS complications, including vasculopathies, neuroanatomical abnormalities, and neurodevelopmental issues, in addition to optic pathway gliomas (OPGs) and other CNS tumors. Vasculopathies commonly observed in NF1 include arterial stenosis or occlusion, aneurysms, arteriovenous (AV) fistulas, and Moya-Moya syndrome, which increases the risk of ischemic and hemorrhagic stroke.¹³

Focal areas of signal intensity (FASI), previously referred to as Unidentified Bright Objects (UBOs), are T2 hyperintense spots seen on MRI, typically located in the bilateral cerebellar white matter, thalami, basal ganglia, brainstem, or medial temporal lobes. These abnormalities, which often appear during childhood, may be associated with neurocognitive issues. In many cases, they become less prominent or fade by late adolescence. However, FASI can sometimes be mistaken for tumors or overlap with tumor boundaries. Low-grade gliomas may develop within these regions, raising concerns about the potential for tumor formation.¹⁴

 

Bone Abnormalities in NF1

Bone abnormalities are commonly seen in NF1. A characteristic feature of this disorder is macrocephaly, which is typically benign, though head growth should be monitored to detect any signs of increased intracranial pressure due to conditions like aqueductal stenosis or intracranial tumors.

Scoliosis, either dystrophic or non-dystrophic, affects 10-25% of individuals with NF1, particularly in the cervical and/or thoracic spine. Dystrophic scoliosis, caused by primary bone dysplasia, results in severe spinal curvature and involves multiple vertebral bodies. Scoliosis may also occur due to the presence of paraspinal neurofibromas. If respiratory issues arise, further evaluation is recommended.15

Patients with NF1 often experience impaired bone mineralization, with 48% developing osteopenia and 25% osteoporosis. Their risk of fractures is 3-5 times higher than the general population, possibly due to commonly observed low vitamin D levels in these patients.¹⁶

Long bones, such as the tibia, are particularly fragile, and tibial dysplasia can be congenital, often presenting as anterolateral bowing of the lower leg. Multiple unhealed fractures may result in pseudoarthrosis.

Sphenoid wing dysplasia is a rare but notable feature in about 5% of NF1 patients, typically occurring unilaterally in the peri-orbital region of the face. This condition may be associated with the absence or thinning of the sphenoid wing, as well as the presence of neurofibromas or plexiform neurofibromas (PNs) in the area. Symptoms can include proptosis, and in rare cases, pulsating exophthalmos, which typically occurs without visual impairment. Absence of the sphenoid wing may also lead to herniation of the temporal lobe.^{1, 3}

 

Pathogenesis

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene, a tumor suppressor gene located on the long arm of chromosome 17 (17q11.2). The NF1 gene encodes neurofibromin, a 220 kDa cytoplasmic protein that acts as a negative regulator of the Ras signaling pathway, which is involved in cellular growth and differentiation. Neurofibromin's primary function is to convert the GTP-bound, active form of Ras to its GDP-bound, inactive state, thus inhibiting Ras activation. However, neurofibromin is not produced in astrocytes or Schwann cells, which play key roles in the pathogenesis of NF1-associated tumors. The loss of neurofibromin function due to NF1 mutations leads to uncontrolled Ras activation, enhancing cellular proliferation and survival, thereby contributing to tumorigenesis.¹⁷

The NF1 gene is large, with over 3,000 distinct pathogenic variants reported, including nonsense, missense, splice-site, frameshift, duplication, deletion, microdeletion, and insertion mutations. These variants can affect the expression, structure, or function of neurofibromin, with the majority of missense mutations located within the GTPase-activating protein (GAP)-related domain, which impairs the protein’s ability to regulate Ras activity. Mutations outside of coding regions, such as those affecting RNA processing or stability within regulatory sequences, can also lead to NF1 disease. While the NF1 gene has no defined "hot spots," there are clusters of mutations in specific exons, particularly exons 10a-c and 37.^18-19

Approximately 5-10% of NF1 patients carry deletions or microdeletions of varying sizes. These deletions often include contiguous gene deletions, which result in more severe phenotypic presentations. Patients with larger deletions tend to develop neurofibromas at an earlier age, exhibit a higher tumor burden, and have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs). Additionally, they are more likely to experience learning disabilities, short stature, and dysmorphic features.

The tumorigenesis associated with NF1 follows the “two-hit” hypothesis, which posits that both alleles of the NF1 tumor suppressor gene must be inactivated for tumor initiation. The first “hit” is the germline mutation, which leads to the inheritance of a non-functional NF1 allele. The second “hit” occurs in somatic cells, where a further mutation in the NF1 gene (somatic NF1 mutation) drives tumor formation. Various mechanisms, such as loss of heterozygosity (LOH), frameshift mutations, and DNA methylation defects, have been implicated in the somatic mutations of NF1 that drive tumorigenesis.²⁰

Advancements in molecular testing have facilitated the diagnosis of NF1, with commercially available techniques including next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (aCGH), which provide comprehensive assessments of NF1 mutations.¹

 

Diagnosis

Neurofibromatosis type 1 (NF1) is typically diagnosed based on clinical features, family history, and genetic testing. Early diagnosis of NF1 is crucial for monitoring and managing the various complications associated with the disorder. Regular follow-up with specialists, such as dermatologists, neurologists, ophthalmologists, and orthopedic surgeons, is important for managing symptoms and preventing complications.¹

The diagnostic process may vary depending on the age of the patient and the presentation of symptoms. The diagnosis is often straightforward in individuals who present with the characteristic signs of NF1 and meet the specific diagnostic criteria, but in some cases, genetic testing may be required to confirm the diagnosis. Diagnosing NF1 can be challenging in young patients who present only with CALMs and freckling, especially in the absence of a family history, making molecular testing essential for confirmation.

Genetic Diagnosis

Genetic testing is the definitive method for diagnosing NF1. Advancements in molecular testing have facilitated the diagnosis, with commercially available techniques including next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (aCGH), which provide comprehensive assessments of NF1 mutations.

Prenatal Diagnosis

For parents with a known family history of NF1, prenatal testing may be an option. Techniques such as chorionic villus sampling (CVS), amniocentesis, and cell-free DNA (cfDNA) testing can be used to detect the presence of NF1 mutations in a fetus. However, the decision to undergo prenatal testing is often complex, given the variability in disease severity and the uncertainities regarding how the condition will manifest in a child.¹

 

Treatment / Management

While there is no cure for neurofibromatosis type 1 (NF1), management of the disease focuses on alleviating symptoms, addressing complications, and improving the quality of life for affected individuals. Given the wide variability in the severity and progression of NF1, treatment plans must be personalized, with a multidisciplinary approach often involving genetic counselors, neurologists, dermatologists, oncologists, orthopedic specialists, pain management experts, and psychologists.

 

Neurofibromas 

In many cases, neurofibromas are asymptomatic and can be monitored for changes in size or symptoms. Surgery is an option if neurofibromas cause significant symptoms, such as pain, nerve compression, or functional impairment. However, surgery may not always be possible, especially for deep or multiple plexiform neurofibromas. Recurrence is common, and careful preoperative planning is necessary to minimize complications. Laser therapy is another treatment method to destroy/shrink the neurofibroma tissue. Most commonly carbon dioxide lasers are being used, leading to cosmetic improvement while being minimally invasive. ²¹

 

Malignant Peripheral Nerve Sheath Tumors (MPNSTs)

MPNSTs are a major cause of morbidity and mortality in NF1 patients. Surgical resection is the primary treatment, though achieving clear margins can be difficult due to the location of the tumors and their tendency to infiltrate surrounding tissues. Chemotherapy and radiation therapy may be used in cases where MPNSTs cannot be completely resected or are metastatic. However, these therapies often have limited success in NF1-related MPNSTs. ^{1, 22}

Emerging treatments for NF1-associated tumors include

• MEK inhibitors: Selumetinib has shown promise in reducing the size of plexiform neurofibromas and is approved for use in NF1 patients. Other MEK inhibitors like trametinib are also being investigated in clinical trials.
• Tyrosine kinase inhibitors (TKIs) like imatinib are being studied for their potential to target and shrink NF1-associated tumors.
• mTOR inhibitors like rapamycin, everolimus, and sirolimus may help reduce tumor growth by targeting the mTOR signaling pathway, which is often upregulated in NF1-related tumors.

 

Pain Management

Chronic pain, particularly neuropathic pain from neurofibromas, is a major challenge in NF1 management. Pain especially arises from plexiform neurofibromas, which can cause pressure on nerves, leading to discomfort or functional impairment.

Common pharmacological treatments include opioids, which however may not be effective in many cases. Non-opioid analgesics, such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), are used for milder pain. Medications like gabapentin or pregabalin can help manage neuropathic pain, although the response can be variable. Certain tricyclic antidepressants or anticonvulsants (e.g., amitriptyline or carbamazepine) can be useful for managing neuropathic pain. If the pain is directly caused by plexiform neurofibromas or other tumors, surgical resection may alleviate symptoms, although recurrence of pain may occur if tumors return.

New treatments for pain, such as CRMP2 regulation using synthetic peptides, are being researched. Additionally, MEK inhibitors like selumetinib have been reported to reduce pain intensity along with their tumor-shrinking effects.^{1, 23}

 

Orthopedic Management

NF1 is often associated with various musculoskeletal complications, including scoliosis, osteoporosis, and bone dysplasias. Mild cases of scoliosis can be monitored with regular imaging and physical exams. For moderate scoliosis, a brace may help prevent further progression of the curvature. Severe or rapidly progressive scoliosis may require spinal surgery, such as spinal fusion, to correct the curvature and prevent further complications.

Ensuring adequate intake of calcium and vitamin D is crucial for bone health. Bisphosphonates, such as alendronate, may be used in patients with significant bone loss to prevent fractures.

 

Neurocognitive and Psychological Support

Many individuals with NF1 experience cognitive and psychological challenges, such as learning disabilities, attention deficit hyperactivity disorder (ADHD), and increased anxiety or depression.Thus, children with NF1 may benefit from individualized educational plans to address learning disabilities or attention issues.

Support groups or counseling for both patients and families can help them cope with the psychosocial impact of NF1, including issues related to body image, self-esteem, and the social stigma of visible symptoms like neurofibromas.

 

Surveillance and Early Detection

Ongoing surveillance is critical, regular MRI and CT scans are used to monitor the size of neurofibromas, detect malignant transformation, and assess other structural changes such as scoliosis or brain lesions.

 

References:

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3. Gutmann DH, Ferner RE, Listernick RH, et al. Neurofibromatosis type 1. Nat Rev Dis Prim, 3 (2017), p. 17004.

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7. Jouhilahti EM, Peltonen S, Callens T, et al. The development of cutaneous neurofibromas.Am J Pathol, 178 (2011), pp. 500-505

8. Ortonne N, Wolkenstein P, Blakeley JO, et al. Cutaneous neurofibromas: current clinical and pathologic issues. Neurology, 91 (2018), pp. S5-S13

9. Cassiman C, Legius E, Spileers W, et al. Ophthalmological assessment of children with neurofibromatosis type 1. Eur J Pediatr, 172 (2013), pp. 1327-1333

10. Shofty B, Ben Sira L, Constantini S. Neurofibromatosis 1–associated optic pathway gliomas. Child's Nerv Syst, 36 (2020), pp. 2351-2361

11. Kamran SC. Howard SA, Shinagare AB. et al. Malignant peripheral nerve sheath tumors: prognostic impact of rhabdomyoblastic differentiation (malignant triton tumors), neurofibromatosis 1 status and location. Eur J Surg Oncol, 39 (2013), pp. 46-52

12. Bergqvist C, A. Servy A, L. Valeyrie-Allanore L, et al. Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis, 15 (2020), p. 37

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14. Pillay-Smiley N, Leach J, Lane A, et al. Evaluating focal areas of signal intensity (FASI) in children with neurofibromatosis type-1 (NF1) treated with Selumetinib on pediatric brain tumor consortium (PBTC)-029B. Cancers (Basel), 15 (2023)

^{15. Crawford AH, Herrera-Soto J. Scoliosis associated with neurofibromatosis. Orthop Clin North Am, 38 (2007), pp. 553-562}

16. Heervä E, Koffert A, Jokinen E, et al. A controlled register-based study of 460 neurofibromatosis 1 patients: increased fracture risk in children and adults over 41 years of age. J Bone Miner Res, 27 (2012), pp. 2333-2337

17. Nordlund M, Gu X, Shipley MT, et al. Neurofibromin is enriched in the endoplasmic reticulum of CNS neurons. J Neurosci Off J Soc Neurosci, 13 (1993), pp. 1588-1600

18. Wang W, Wei C, Cui X, et al. (2021). Impacts of NF1 gene mutations and genetic modifiers in neurofibromatosis type 1. 12, 1–12

19. De Luca A, Bottillo I, Sarkozy A, et al. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet, 77 (2005), pp. 1092-1101

20. Brems H, Beert E, de Ravel T, et al. Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol, 10 (2009), pp. 508-515

21.Group of Neurofibromatosis, Plastic and Reconstructive Surgery Society of Chinese Medical Association. [Expert consensus for full course management of plexiform neurofibroma (2025 edition)]. Zhonghua Yi Xue Za Zhi. 2024 Dec 20;104:1-16. Chinese.

22. Klesse LJ, Jordan JT, Radtke HB, et al. The use of MEK inhibitors in neurofibromatosis type 1 – Associated tumors and management of toxicities. Oncologist, 25 (2020), pp. e1109-e1116.

23. Stech K, Habibi B. Pain related quality of life in neurofibromatosis type 1: A narrative review. Curr Pain Headache Rep, 11 (2024), pp. 1177-1183