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Neurofibromatosis - External and Internal Eye
See also in: Overview
Other Resources UpToDate PubMed

Neurofibromatosis - External and Internal Eye

See also in: Overview
Contributors: Nitish Mehta MD, Lowell A. Goldsmith MD, MPH, Brandon D. Ayres MD, Christopher Rapuano MD, Harvey A. Brown MD, Sunir J. Garg MD, Lauren Patty Daskivich MD, MSHS
Other Resources UpToDate PubMed

Synopsis

Neurofibromatosis type 1 (NF1), or von Recklinghausen syndrome, and type 2 (NF2), or central neurofibromatosis, are multisystem genetic disorders arising from loss of function of the neurofibrin gene and subsequent unregulated cell division resulting in the formation of noncancerous tumors known as fibromas. Specifically, mutations of chromosome 17 (NF1) and 22 (NF2) cause loss of function of the tumor suppressor neurofibromin protein, resulting in inability to downregulate the Ras oncogene signal transduction pathway and subsequent continuous activation of antiapoptotic pathways. This summary will primarily cover the ophthalmologic manifestations of NF1 (eg, orbitofacial neurofibromas and optic nerve gliomas) in terms of diagnosis, management, and treatment recommendations.

NF1
Affecting 1 in 3000, NF1 is characterized by hallmark cutaneous, neurologic, bone, soft tissue, and ophthalmologic findings resulting from deregulated growth of neural crest origin cell lines.

Although 100% penetrant by age 5 years and although one-third of affected patients will develop serious complications, NF1's diverse expression makes prognostic information difficult to deliver to patients. About 50% of the cases are familial, with an autosomal dominant expression pattern, and 50% of cases arise from de novo mutations.

Neurofibromatosis is clinically diagnosed via the presence of 2 or more of the following:
  • Six or more café au lait macules greater than 5 mm in prepubertal individuals and greater than 15 mm in diameter in postpubertal individuals
  • Two or more Lisch nodules (iris hamartomas)
  • Two or more neurofibromas of any type or a single plexiform neurofibroma
  • Freckling in the axillary or inguinal region (intertriginous)
  • Optic nerve glioma (in early childhood)
  • Distinctive osseus dysplasia (such as sphenoid or tibial)
  • A first-degree relative with NF1
Affected patients are often born with sphenoid wing dysplasia, long bone bowing, subclinical orbitofacial plexiform neurofibromas, and optic nerve gliomas, and at birth or early childhood develop multiple café au lait macules. In early childhood, patients will develop axillary / inguinal freckling, hypertension, and scoliosis. Patients will further progress to develop multiple cutaneous neurofibromas (peripheral nerve sheath tumors). Optic nerve gliomas and orbitofacial plexiform neurofibromas will slowly progress to become symptomatic by mid to late childhood.

Other malignancies and tumors associated with neurofibromatosis include pheochromocytomas, meningiomas, sarcomas, and gastrointestinal tumors of neuroendocrine origin. Patients may have learning disabilities (30%-50%), skeletal abnormalities, vasculopathies (including heart disease), and endocrinologic abnormalities.

Prompt ophthalmologic screening in patients with café au lait macules is recommended to diagnose NF1 and help prevent vision loss.
  • Optic nerve gliomas are grade 1 pilocytic astrocytomas in NF1 that affect the optic nerve, chiasm, or optic tract. They are the most common intraorbital or cranial manifestation of neurofibromatosis, affecting 30%-40% of patients. Often asymptomatic, they are slow growing, locally invasive, and can progress to produce significant morbidity though rarely mortality. Isolated asymptomatic optic nerve gliomas discovered during screening carry the best prognosis. Involvement of the chiasm, pulsatile proptosis, or extension along the visual pathway carries an unfavorable prognosis. Pulsatile proptosis, or the "Orphan Annie sign," is caused by absence of the sphenoid wing with a herniated encephalocele.
  • Orbitofacial plexiform neurofibromas are in seen in 1%-4% of children with NF1. These are variants of benign peripheral nerve sheath tumors that form tangles of unencapsulated, highly vascular, and infiltrative neural tissue involving the eyelids, temporal region, and orbit and causing physical disfiguration, asymmetric refractive error, and mechanical ptosis with a high incidence of resultant amblyopia. They may degenerate into malignant peripheral nerve sheath tumors such as neurofibrosarcomas. Plexiform neurofibromas of the upper eyelid can be associated with ipsilateral glaucoma.
NF2
NF2, or central neurofibromatosis, is 10 times less common than NF1 and primarily presents with vestibular schwannomas (schwannomas of the 8th cranial nerve), which are frequently bilateral. NF2 presents with fewer café au lait macules, rarely forms Lisch nodules of the iris, and is primarily associated ophthalmologically with juvenile cataracts. Optic nerve meningiomas, retinal hamartomas, and epiretinal membranes are also associated with NF2, and any child with decreased vision or retinal examination abnormalities should undergo ophthalmologic evaluation to distinguish NF1 and NF2 from retinoblastoma.

Codes

ICD10CM:
Q85.01 – Neurofibromatosis, type 1
Q85.02 – Neurofibromatosis, type 2

SNOMEDCT:
19133005 – Neurofibromatosis syndrome

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

NF1
Other conditions with café au lait macules:
  • Legius syndrome – Autosomal dominant NF1-like syndrome with loss of function of Ras regulatory gene SPRED1 with café au lait macules, axillary freckling, and macrocephaly but lacks neurofibromas and central nervous system (CNS) tumors.
  • Constitutional mismatch repair-deficiency syndrome – Homozygous deficiency in 1 of the 4 mismatch repair proteins results in café au lait macules and axillary freckling but presents primarily with hematologic malignances in childhood followed by glioblastomas and colorectal cancer.
  • Noonan syndrome – Characterized by short stature, webbed neck, pulmonic stenosis, and café au lait macules without axillary freckling or Lisch nodules.
  • McCune-Albright syndrome – Premature puberty, bony abnormalities, and large café au lait macules with irregular outline.
The differential diagnosis for NF1 also includes:
NF2
The differential diagnosis for NF2 includes:

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Therapy

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References

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Last Updated:04/11/2022
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Neurofibromatosis - External and Internal Eye
See also in: Overview
A medical illustration showing key findings of Neurofibromatosis (Type 1) : Lisch nodules, Axillary freckles, Smooth papules
Clinical image of Neurofibromatosis - imageId=742400. Click to open in gallery.  caption: 'A close-up of pinkish and brownish papules and nodules (neurofibromas) and light brown patches (confetti and <span>café au lait </span> macules).'
A close-up of pinkish and brownish papules and nodules (neurofibromas) and light brown patches (confetti and café au lait macules).
Copyright © 2023 VisualDx®. All rights reserved.