Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disorder (phakomatosis) characterized by multiple neurofibromas of the skin and nerves, distinctive pigmented spots (café-au-lait spots), and various other manifestations including bone and ocular lesions. The responsible gene, NF1, is located at 17q11.2 and encodes neurofibromin, a tumor suppressor protein.
NF1 is one of the diseases classified as phakomatoses, affecting the skin, nervous system, and eyes simultaneously. It has been determined that NF1 and NF2 are completely different diseases and should not be confused.
Ocular complications include iris Lisch nodules, optic glioma, glaucoma, and eyelid and orbital neurofibromas, which occur with high frequency. In particular, Lisch nodules are found in over 90% of NF1 patients and constitute one of the NIH diagnostic criteria, so ophthalmologists play an important role in the definitive diagnosis of NF1. It is a progressive disease with findings increasing with age, and continuous ophthalmic management from childhood is essential.
NF1 occurs in 1 in 3,000 people. The most common ocular finding is iris Lisch nodules, appearing in over 90% of NF1 patients. Optic glioma occurs in about 15%, and in cases with café-au-lait spots on the eyelids, about 50% have glaucoma.
Subjective symptoms related to ocular complications of NF1 vary depending on the type of lesion involved.
Iris Lisch Nodules
Definition: Melanocytic hamartoma of the iris stroma.
Characteristics: Light brown, well-defined, multiple small nodules. Confirmed by slit-lamp microscopy.
Frequency/Significance: Appears in over 90% of NF1 cases. Presence of two or more fulfills one item of the NIH diagnostic criteria. Does not directly affect vision.
Optic Glioma
Frequency: Occurs in about 15% of NF1 cases (optic pathway glioma).
Course: Often asymptomatic. In progressive cases, optic atrophy leads to visual acuity and visual field defects. Infiltration into the optic chiasm is possible.
Pathology: Low-grade astrocytoma (pilocytic astrocytoma; WHO grade I).
Glaucoma
Frequency: Occurs in 50% of cases with café-au-lait spots on the eyelids. In children, it can cause buphthalmos. Often unilateral.
Pathogenesis: Angle dysgenesis, angle closure due to ciliary body/choroidal thickening, neurofibroma infiltration into the angle, angle structural abnormalities associated with uveal ectropion.
Classification: In the Glaucoma Clinical Practice Guidelines (5th edition), it is classified as “glaucoma associated with congenital systemic disease”1).
Eyelid and Orbital Lesions
Plexiform neurofibroma of the eyelid: Causes mechanical ptosis. May deform the eyelid into a “bag-like” shape.
Orbital tumors: Optic nerve meningioma, optic glioma, intraorbital neurofibroma → proptosis. Diffuse type infiltrates orbital fat and extraocular muscles.
Facial deformity: May be accompanied by orbital and facial bone deformities (e.g., sphenoid dysplasia).
Lisch nodules are melanocytic hamartomas of the iris stroma and do not directly affect vision. However, they are an important finding for the diagnosis of NF1; the presence of two or more nodules fulfills one item (item 5) of the NIH diagnostic criteria.
NF1 is a hereditary disease with an autosomal dominant (AD) inheritance pattern. The responsible gene is the NF1 gene (17q11.2), a large gene consisting of more than 60 exons. The NF1 gene encodes neurofibromin. Neurofibromin functions as a Ras-GTPase activating protein (RasGAP) and is a tumor suppressor gene product that suppresses cell proliferation signals.
Loss of neurofibromin function due to NF1 mutations leads to constitutive activation of the Ras-MAPK pathway. This results in hamartomatous growth in the nervous system, skin, and bones.
Genetic features:
Risk factors for ocular complications:
The diagnosis of NF1 is made according to the NIH diagnostic criteria (at least 2 of 7 items). Ophthalmologists play an important role in evaluating two of these items: Lisch nodules (item 5) and optic glioma (item 4).
The seven items of the NIH diagnostic criteria are listed below.
| Item | Criteria |
|---|---|
| 1. Café-au-lait spots | Prepubertal: ≥6 spots with maximum diameter ≥5 mm / Postpubertal: ≥6 spots with maximum diameter ≥15 mm |
| 2. Neurofibromas | ≥2 neurofibromas or ≥1 plexiform neurofibroma |
| 3. Axillary or inguinal freckling | Freckling in the axillary or inguinal regions (like lentigines) |
| 4. Optic glioma | Optic pathway glioma |
| 5. Lisch nodules | ≥2 iris nodules |
| 6. Bone lesions | Sphenoid dysplasia, thinning of long bone cortex, etc. |
| 7. Family history | First-degree relatives (parents, siblings, children) with NF1 |
| Lesion status | Follow-up frequency |
|---|---|
| Lisch nodules only (no optic glioma) | Annual regular ophthalmic examination |
| Patients with optic glioma | Regular examination every 3 months |
The diagnosis is made when two or more of the seven NIH diagnostic criteria (café-au-lait spots, neurofibromas, axillary/inguinal freckling, optic glioma, Lisch nodules, bone lesions, family history) are met. Ophthalmologists are responsible for evaluating two items: Lisch nodules (item 5) and optic glioma (item 4).
Glaucoma associated with NF1 is difficult to treat because it develops through a combined mechanism of angle dysgenesis, infiltration of the angle by neurofibromas, and ciliary body/choroidal thickening. It is classified under “glaucoma associated with congenital systemic diseases” in the Glaucoma Clinical Practice Guidelines (5th edition) 1).
The treatment strategy for optic pathway glioma depends on the presence of progression and symptoms.
Glaucoma in NF1 results from a combination of angle dysgenesis, neurofibromatous infiltration of the angle, and ciliary body/choroidal thickening. Therefore, standard pediatric glaucoma surgeries (goniotomy, trabeculotomy) are often ineffective, and orbital lesions may make surgical access difficult.
The NF1 gene is located at 17q11.2 and is a large gene consisting of over 60 exons. It encodes neurofibromin, which functions as a Ras-GTPase activating protein (RasGAP).
Lisch nodules (iris hamartomas): In melanocytes of the iris stroma, NF1 mutation causes Ras overactivation, leading to excessive proliferation of melanocytes. They accumulate as hamartomas in the iris stroma but do not affect visual function.
Optic pathway glioma: NF1 is involved in the growth control of glial cells (especially astrocytes) in the optic nerve and optic pathway. Loss of NF1 function → Ras overactivation → low-grade astrocytoma (pilocytic astrocytoma; WHO grade I). It often progresses slowly and exhibits biological behavior characteristic of NF1-associated tumors.
Pathological classification of neurofibromas: In NF1, loss of heterozygosity (LOH) of NF1 occurs in Schwann cells of peripheral nerves, leading to tumor formation. Morphologically, three types are classified.
Complex mechanisms of glaucoma: Glaucoma in NF1 involves multiple mechanisms.
Café-au-lait spots are pigmented lesions that appear early in life, mainly on the trunk, and reflect melanocyte hyperactivity due to NF1 gene mutations. Diagnostic criteria include six or more spots with a maximum diameter of at least 5 mm before puberty, or six or more spots with a maximum diameter of at least 15 mm after puberty. Freckling in the axillary or inguinal regions, multiple neurofibromas, bone lesions such as sphenoid dysplasia, and neurological findings such as epilepsy and intellectual disability also occur as diverse phenotypes resulting from constitutive activation of the Ras-MAPK pathway.
Selumetinib, a molecular targeted drug that targets MEK1/2 downstream of the Ras-MAPK pathway, was approved by the FDA in 2020 for inoperable plexiform neurofibromas in patients aged 2 years and older. Studies on its efficacy for NF1-associated optic pathway gliomas are also ongoing. For approval and insurance coverage in Japan, it is necessary to check the latest developments.
In 2021, the International NF Diagnostic Criteria Committee revised the NIH criteria. Major changes include the addition of genetic testing (identification of NF1 mutations) to the diagnostic criteria and the addition of choroidal abnormalities detected by near-infrared imaging as a new diagnostic item.
The association between NF1 mutations and childhood glaucoma has been confirmed by genetic studies. Approximately 50% of childhood glaucoma cases with NF1 mutations are reported to be unilateral 2). NF1 has been identified as part of the genetic profile of glaucoma associated with congenital systemic diseases and is an important target in molecular diagnosis of childhood and early-onset glaucoma 2).
