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Title: Neurofibromatosis

Authors: Emilie Laura Ungricht, Michael Murri, MD.

Photographer:  Dimitrios Malamos, CC BY 4.0 <>, via Wikimedia Commons

Date: 03/25/2021

Keywords/Main Subjects: Neurofibromatosis

Diagnosis: Neurofibromatosis

Neurofibromatosis is a heritable neurocutaneous disorder involving embryonic neuroectoderm. Neuroectoderm derivatives are the most widely affected, including melanocytes, brain, spinal cord, retina, and parts of the ciliary body of the eye.1, 2  There are two distinct subtypes of neurofibromatosis—neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2), each involving different symptoms and with different genetic causes.2,3  Initial signs of neurofibromatosis may present anytime from birth through adolescence and continue to progress through life.3,4


NF1 has an prevalence of 1:2600 to 3000 with approximately half of the cases from familial inheritance and half of the cases from de novo mutations.2, 4-8 NF2 has an incidence of approximately 1:50,000.2,4,7


Both NF1 and NF2 are autosomal dominant diseases with high penetrance.2,7 For NF1, the NF-1 gene located on chromosome 17 codes for neurofibromin, a protein that plays a role in cellular growth regulation.2,7 Studies suggest that the mutations affect the Ras pathway.7,9

NF2 involves autosomal dominant mutations in the NF-2 gene, located on chromosome 22. The protein involved is called merlin or schwannomin and is a tumor suppressor involved in key signaling pathways for cell growth and adhesion.10-11

Clinical Diagnostic Criteria and Clinical Features

The diagnostic criteria vary based on the type of neurofibromatosis and the age of the patient. In NF1, diagnosis requires at least 2 of the following criteria: 2,3,12,13

Lisch nodules (Fig 1) are the most common clinical sign of NF1 and are present in over 94% of patients over the age of 6.14 They are gold to brown hamartomas of the iris that grow up to 2 mm in diameter. These can be visualized with slit-lamp examination.14, 15


Figure 1: Iris with copper-colored Lisch Nodules, a characteristic finding of NF1. Photo taken by Dimitrios Malamos, CC BY 4.0 <>, via Wikimedia Commons


Optic nerve gliomas occur in approximately 15-20% of patients with NF1, predominantly developing prior to the age of 7.16-17 Symptoms vary based on the extent of the tumor, but often result in unilateral proptosis, papilledema, and visual field defects.16

NF1 has additional ocular findings that are not included in the diagnostic criteria, notably retinal tumors. These include retinal astrocytic hamartoma, retinal capillary hemangioblastoma, and vasoproliferative tumors.18 These lesions are often located near or on the optic disc. Adult and pediatric patients may develop glaucoma secondary to plexiform neurofibroma infiltrating the angle or from abnormalities of the trabecular meshwork.18

Additional non-ocular findings associated with NF1 include pheochromocytoma and gastrointestinal neurofibromas.19

NF2 is diagnosed with the Manchester Criteria, which requires one of the following:20

Common ocular findings in NF2 include either cortical or posterior subcapsular cataracts. Retinal hamartomas and Lisch nodule can also be present, but are less common than NF1.20 Symptoms often appear in puberty or early adulthood.

Diagnostic Studies

Based on the high rates of ocular involvement in NF1, patients demonstrating any NF1 findings should have a complete ophthalmologic examination. 23 Evaluation of the optic nerve and its function through afferent pupillary testing, color vision, visual fields, dilated exams, and ocular coherence tomography may help to detect optic nerve gliomas. Slit lamp examination can be used to examine the iris for Lisch nodules, optic disc for retinal tumor evaluation. Intraocular pressure measurements and optic nerve evaluation can help detect glaucoma in NF1. CT scan and MRI are useful in the localization of optic gliomas, although these are not always indicated.23,24 Retinal astrocytomas can be detected via fluorescein angiography, demonstrating hypofluorescence in areas of hyperpigmentation.25

Ocular Management

Management depends on the clinical features. Retinal astrocytomas are often monitored over time and are only treated if they progress to retinal detachment or retinal tears. Treatment involves retinal detachment repair, photocoagulation, or cryopexy depending on extent of the pathology.

Optic nerve gliomas often progress slowly and are only treated if they demonstrate rapid growth. If growth is rapid, the glioma can be surgically resected.16 Depending on the extent of the glioma the surgery can be globe preserving or include enucleation. Unfortunately, visual outcomes do not typically improve with glioma removal. Radiation and chemotherapy have been used with some success.26

For glaucoma associated NF1, medical management is typically attempted first. In cases where this fails, surgical intervention has proven to be effective.27

Cataracts in NF2 are typically followed until they become visually significant. They do not often require early surgical intervention.


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Identifier: Moran_CORE_67595
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