Authors: Emilie Laura Ungricht, Michael Murri, MD.
Photographer: Dimitrios Malamos, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons
Keywords/Main Subjects: 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
- Skin Findings
- 6 or more café au lait macules, >5mm prepubertal or >15mm post pubertal
- Axillary or inguinal freckles
- 2 or more neurofibromas or 1 plexiform neurofibroma
- Skeletal findings
- Sphenoid dysplasia, tibial pseudoarthrosis or other distinctive bone lesion
- Ocular findings:
- Optic nerve glioma
- 2 or more Lisch nodules (Iris hamartomas)
- Family history of NF1
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
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
- Bilateral vestibular schwannomas in patients <70 years old
- First-degree relative with NF2 and one of the following:
- Unilateral vestibular schwannoma in that relative
- Two of the following: meningioma, cataract, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities
- Unilateral vestibular schwannoma and
- Two of the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
- Multiple meningiomas and one of the following
- Unilateral vestibular schwannoma
- Any two of: schwannoma, glioma, neurofibroma, cataract
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.
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
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.
- Larsen’s Human Embryology(Fifth ed.). Elsevier. 2015. p. 77. ISBN 978-1-4557-0684-6.
- Neurofibromatosis Fact Sheet. (n.d.). Retrieved January 30, 2021, from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Neurofibromatosis-Fact-Sheet
- Neurofibromatosis 1. (2020, June 15). Retrieved January 30, 2021, from https://rarediseases.org/rare-diseases/neurofibromatosis-type-1-nf1/
- Nguyen, T.V., Matthews, M.R., Barrera, F.F. and Browning, J.C. (2012), Multiple Cutaneous Plexiform Schwannomas as Initial Presentation of Neurofibromatosis 2 in a 9‐Year‐ Pediatric Dermatology, 29: 536-538. https://doi-org.ezproxy.lib.utah.edu/10.1111/j.1525-1470.2011.01532.x
- Huson, D. Compston, P. Clark, et al. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet, 26 (1989), pp. 704-711
- Rasmussen SA, Friedman JM. NF1 gene and neurofibromatosis 1.Am J Epidemiol. 2000 Jan 1; 151(1):33-40.
- R. Antonio, E.M. Goloni-Bertollo, L.A. Tridico. Neurofibromatosis: chronological history and current issues. An Bras Dermatol, 88 (2013), pp. 329-343
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- Esposito, Teresa, Piluso, Giulio, Saracino, Dario, Uccello, Rossella, Schettino, Carla, Dato, Clemente, Capaldo, Guglielmo, Giugliano, Teresa, Varriale, Bruno, Paolisso, Giuseppe, Di Iorio, Giuseppe, and Melone, Mariarosa A. B. “A Novel Diagnostic Method to Detect Truncated Neurofibromin in Neurofibromatosis 1.” Journal of Neurochemistry6 (2015): 1123-128. Web.
- Thaxton, Courtney, Bott, Marga, Walker, Barbara, Sparrow, Nicklaus A, Lambert, Stephen, and Fernandez-Valle, Cristina. “Schwannomin/merlin Promotes Schwann Cell Elongation and Influences Myelin Segment Length.” Molecular and Cellular Neurosciences1 (2011): 1-9. Web.
- SCOLES, Daniel R, NGUYEN, Vu D, Yun Qin, SUN, Chun-Xiao, MORRISON, Helen, GUTMANN, David H, and PULST, Stefan.-M. “Neurofibromatosis 2 (NF2) Tumor Suppressor Schwannomin and Its Interacting Protein HRS Regulate STAT Signaling.” Human Molecular Genetics25 (2002): 3179-189. Web.
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