Neurofibromatosis (NF) is a neurocutaneous syndrome (phakomatosis) that affects organs derived from the ectoderm (central nervous system, skin, and eyes). It is broadly classified into two types: NF1 and NF2.
NF1 is the most common type. Its prevalence is 1 in 3,000 to 5,000 people, and it shows autosomal dominant inheritance. The responsible gene, NF1, is located on chromosome 17q11.2 and encodes the tumor suppressor protein neurofibromin. Neurofibromin regulates multiple signaling pathways, including the Ras/RAF/MEK/ERK pathway and the Akt/mTOR pathway, and loss of its function leads to tumor formation 1).
Approximately 50% of patients develop the condition due to de novo mutations and have no family history 1). NF1 has nearly complete penetrance, but there is wide phenotypic variability among individuals.
NF2 is less common than NF1, with a prevalence of about 1 in 25,000 people. The responsible gene, NF2, is located on chromosome 22q12 and encodes the protein merlin. Merlin regulates downstream signaling pathways involved in cell proliferation, such as PI3K and MAP kinase.
QHow are NF1 and NF2 different?
A
NF1 is characterized by cutaneous neurofibromas, café-au-lait spots, and Lisch nodules, and is often associated with optic gliomas. NF2 is characterized by bilateral vestibular schwannomas (acoustic neuromas) and frequently accompanied by juvenile cataracts. The responsible genes are located on chromosomes 17 and 22, respectively, and they should be recognized as distinct diseases.
In NF1, ocular symptoms are often subtle. Lisch nodules themselves are asymptomatic. The following symptoms may prompt an ophthalmology consultation:
Vision loss: Progressive visual impairment due to optic glioma. In children, it is often detected through strabismus.
Proptosis: Caused by orbital tumors (plexiform neurofibroma, optic glioma).
Eyelid swelling: Characteristic S-shaped eyelid deformity due to plexiform neurofibroma.
In NF2, symptoms related to vestibular schwannomas such as hearing loss, tinnitus, unsteadiness, and vertigo are predominant. Vision loss is due to cataracts or optic nerve sheath meningioma.
Clinical Findings (Findings Confirmed by Physician Examination)
Lisch nodules: Multiple, well-defined, light brown iris nodules (hamartomas). They are present in over 90% of NF1 patients, and two or more nodules have high diagnostic value. They increase with age and are found in nearly all patients by around age 20.
Optic glioma: Occurs in about 15–20% of cases. It is a benign pilocytic astrocytoma, often developing before age 10. Usually asymptomatic, but may cause optic atrophy and visual impairment.
Eyelid and orbital lesions: Eyelid swelling and ptosis due to plexiform neurofibroma. Orbital bone defects (sphenoid dysplasia).
Retinal findings: Rarely, astrocytic hamartomas are observed. Increased myelinated nerve fibers may also be seen.
Glaucoma: Can be congenital (unilateral) or late-onset. In children, it may cause buphthalmos.
Ocular findings in NF2
Cataract: Juvenile cortical wedge-shaped cataracts are present from birth, with posterior subcapsular opacities progressing later in life.
Retinal findings: Pigment epithelial hamartomas and epiretinal membranes are occasionally seen.
Both NF1 and NF2 show autosomal dominant inheritance.
NF1: Loss-of-function mutation in the NF1 gene at 17q11.2. About 50% are de novo mutations1). Deficiency of neurofibromin leads to constitutive activation of the Ras pathway, resulting in uncontrolled cell proliferation.
NF2: Mutation in the NF2 gene at 22q12. Caused by loss of function of merlin.
Patients with NF1 have an increased risk of developing benign and malignant tumors.
Malignant peripheral nerve sheath tumor (MPNST): Occurs in about 2% of NF1 patients 4). Malignant transformation from plexiform neurofibroma is the main pathway. Rapid growth or new pain may indicate malignancy.
Juvenile myelomonocytic leukemia (JMML): NF1 patients have a 300- to 350-fold higher risk of developing JMML 2). Biallelic inactivation of NF1 is found in 86.1% of JMML cells 2).
In NF1, neurofibromin deficiency can lead to spindle cell proliferation and smooth muscle dysplasia in the vessel wall 5). Vascular stenosis, occlusion, aneurysms, pseudoaneurysms, and arteriovenous fistulas have been reported. Vascular rupture is the second most common cause of death in young NF1 patients after malignancy 5).
QIs NF1 inherited? What is the impact on children?
A
NF1 is inherited in an autosomal dominant pattern, with a 50% chance of passing the mutation from an affected parent to a child. However, about half of cases result from a de novo mutation with no family history 1). Penetrance is nearly 100%, but symptom severity varies widely even within families.
Café-au-lait spots must be ≥5 mm before puberty and ≥15 mm after puberty. Since about half of patients with sporadic NF1 mutations do not meet diagnostic criteria by age 1, annual monitoring until around age 8 is recommended 1).
The Japanese Dermatological Association diagnostic criteria (2008) also adopt the same 7 items.
CT: Evaluation of orbital tumors. Useful for confirming cylindrical enlargement of the optic nerve and orbital bone defects.
MRI: Optimal for evaluating optic gliomas. They appear hypointense on T1-weighted images and enhance with Gd-DTPA. Brain MRI shows FASI (focal areas of signal intensity) in over 90% of NF1 patients 8).
Visual evoked potentials (VEP): Used to detect optic nerve damage.
Legius syndrome: Presents with café-au-lait spots and freckling but does not cause neurofibromas.
Noonan syndrome: accompanied by short stature and congenital heart disease.
Tuberous sclerosis: accompanied by retinal astrocytic hamartomas, but no Lisch nodules.
QIf café-au-lait spots are present, is NF1 diagnosed immediately?
A
Café-au-lait spots alone do not confirm NF1. Even healthy individuals may have 1 to 3 café-au-lait spots 1). It is necessary to meet at least 2 of the 7 NIH diagnostic criteria, and in childhood, evaluation is performed through repeated follow-up observations.
There is no curative treatment for neurofibromatosis. The mainstay is symptomatic treatment according to the symptoms of each organ and regular follow-up.
If localized to the intraorbital optic nerve and asymptomatic, regular imaging (MRI) follow-up is the principle.
If there is progressive visual impairment or infiltration into the optic chiasm, chemotherapy (platinum agent + vincristine combination) is considered.
Surgical resection carries a high risk of losing visual function, and indications are carefully determined. Sensitivity to radiotherapy is low.
In recent years, the efficacy of stereotactic radiotherapy such as IMRT (intensity-modulated radiation therapy) and Gamma Knife has been reported.
Complete resection of orbital plexiform neurofibromas is difficult and recurrence is common. The treatment plan is determined by comparing the degree of visual impairment and the loss due to surgery.
In advanced cases, orbital exenteration may be necessary.
Selumetinib: A MEK inhibitor. In 2020, the US FDA approved it for children (aged 2 years and older) with NF1 who have symptomatic, inoperable plexiform neurofibromas.
Mirdametinib: The second MEK inhibitor approved by the FDA in March 2025. It is indicated for pediatric and adult patients with NF1.
Surgery is considered when there is significant impairment of appearance or quality of life. Surgical resection and pathological diagnosis are the standard.
Neurofibromin, the product of the NF1 gene, suppresses Ras activity as a GTPase-activating protein (GAP). Loss-of-function mutations in the NF1 gene lead to constitutive activation of the Ras/RAF/MEK/ERK cascade 1). This explains the tendency to form peripheral nerve sheath tumors and gliomas.
Neurofibromin also participates in the Akt/mTOR pathway and the AC/cAMP pathway, regulating cell proliferation and differentiation in a multifaceted manner 1).
Lisch nodules: These are iris melanocytic hamartomas. Hyperplasia of melanocytes forms nodules.
Optic glioma: A benign tumor (pilocytic astrocytoma) arising from proliferation of glial cells of the optic nerve. It occurs in 15–20% of NF1 patients, and 25–60% of optic gliomas occur in NF1 patients.
Glaucoma: Obstruction of the aqueous humor outflow pathway by plexiform neurofibroma is considered a contributing factor. There are congenital (unilateral) and late-onset types.
Deficiency of neurofibromin induces spindle cell proliferation in vascular smooth muscle cells and dysplasia of the media and intima 5). This forms the basis for the development of aneurysms, pseudoaneurysms, and arteriovenous fistulas. Vascular wall fragility makes hemostasis difficult after trauma and can lead to fatal hemorrhage 5).
Malignant transformation from plexiform neurofibroma to MPNST is thought to be triggered by biallelic inactivation (second hit) of the NF1 gene 4)8). Histologically, complete loss of H3K27me3 (trimethylation of lysine 27 on histone H3) is considered useful for diagnosing MPNST 4).
In a systematic review by Meyer et al. (2023) analyzing 177 NF1 patients, JMML was the most common leukemia subtype, and patients with NF1 and juvenile xanthogranuloma had an even higher rate of JMML (86.7% vs 55.1%, P=0.024) 2). Biallelic inactivation of NF1 in JMML cells was confirmed in 86.1% of cases.
7. Latest Research and Future Perspectives (Investigational Stage)
Following selumetinib (FDA approved in 2020), mirdametinib received FDA approval in March 2025 for NF1 patients with inoperable plexiform neurofibromas. MEK inhibitors have demonstrated tumor shrinkage effects, expanding treatment options for NF1.
In a pilot study in late 2024, the anti-NGF monoclonal antibody tanezumab was evaluated for chronic pain due to schwannomatosis. In 20 patients, 12-week administration resulted in a 30% reduction in pain scores (VAS scale) with minimal side effects. Schwannomatosis associated with SMARCB1 or LZTR1 mutations currently has no approved treatments, and future developments are anticipated.
Barut et al. (2024) reported a 3-year management of central giant cell granuloma and neurofibroma occurring in the mandible of an NF1 patient8). For CGCG, stepwise treatment was performed: conservative resection → intralesional corticosteroid injection → alveolar process resection, ultimately with no recurrence. Two inactivating mutations of the NF1 gene were detected in the CGCG lesion, confirming the neoplastic nature of NF1-associated CGCG.
Zheng Q, Xia B, Zhao X, et al. Diagnosis of neonatal neurofibromatosis type 1: a case report and review of the literature. BMC Pediatrics. 2023;23:259.
Meyer SN, Vaughn A, Li Y, et al. The association between juvenile xanthogranulomas in neurofibromatosis type 1 patients and the development of leukemia: a systematic review. J Eur Acad Dermatol Venereol. 2023;37(12):e1380-e1383.
Chen N, Li W, Min L, et al. Neurofibromatosis type 1 with huge intrathoracic meningoceles misdiagnosed as pleural effusion: a case report and literature review. J Cardiothorac Surg. 2024;19:303.
Furuzono N, Togami S, Kitazono I, et al. Malignant peripheral nerve sheath tumor of the cervix in an adolescent with neurofibromatosis type 1: a case report and review of literature. J Obstet Gynaecol Res. 2024;50:2372-2376.
Lee J, Kim Y. Life-threatening brachial artery hemorrhage and a lethal outcome in patients with neurofibromatosis type 1: two case reports and a review of the literature. J Int Med Res. 2021;49(6):1-8.
Odongo L, Goebeler M, Kneitz H, et al. Fatal maternal complication due to neurofibromatosis type 1-associated giant pigmented plexiform neurofibromas in pregnancy: a case report and literature review. Afri Health Sci. 2022;22(1):160-163.
Lin HY, Lin CC, Tsai SJ. Neurofibromatosis type 1, severe cervical spinal kyphotic deformity, and vertebral arteriovenous fistula presenting with tetraplegia: case report and literature review. Spinal Cord Ser Cases. 2022;8:78.
Barut O, Mukdad M, Danielsson K, et al. Giant cell granuloma and neurofibroma in the mandible of a patient with neurofibromatosis type 1: a long-term follow-up case report with radiological and surgical aspects and a review of the literature. BMC Oral Health. 2024;24:792.
Copy the article text and paste it into your preferred AI assistant.
Article copied to clipboard
Open an AI assistant below and paste the copied text into the chat box.
