Neurofibromatosis

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Article initiated by:

Jessica Randolph, M.D.

All contributors:

Richard Sofoluke, Paul O. Phelps, MD, FACS, Dr John Davis Akkara (MBBS, MS, FAEH, FMRF), Jessica Randolph, M.D., Michael T Yen, MD

Assigned editor:

Paul O. Phelps, MD, FACS

Review:

Assigned status Up to Date

 by Paul O. Phelps, MD, FACS on April 15, 2024.

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Contributing Editors:	add

Neurofibromatosis (NF) is classified as a neurocutaneous syndrome which are a group of congenital disorders that impact organs which arise from the ectoderm. These organs include the central nervous system, the skin, and the eyes. Neurofibromatosis itself is further distinguished into two classes, NF-1 and NF-2. Both types of neurofibromatosis have differing presentations for ocular pathology which can assist in identifying the specific syndrome type, along with manifestations of disease in other body systems.

Neurofibromatosis

Epidemiology

NF-1 is the more common form of these two neurocutaneous syndromes with an estimated prevalence of 1 per 3000 in the general population. NF-2’s prevalence approximates at 1 per every 25,000 people in the general population.

Etiology & Pathophysiology

Both NF-1 and NF-2 arise through an autosomal dominant fashion, although it is noted in NF-1 up to 42% of affected individuals have de novo mutations versus inheritance from a parent.

In affected individuals there is a mutation in the tumor suppressor gene NF1, located on chromosome 17q11.2, that codes for the protein product neurofibromin which is critical in the regulation of the proto-oncogene Ras. Neurofibromin is expressed heavily in the nervous system which helps explain the disease’s inclination for formation of peripheral nerve sheath tumors and gliomas.

The tumor suppressor gene NF2, located on chromosome 22q12, encodes the protein merlin which acts to regulate various downstream mitogenic signaling pathways including PI3K and MAP kinase who govern cellular proliferation.

Signs and Symptoms

The most prominent features that NF-1 patients typically present with include

• Neurofibromas – benign peripheral nerve sheath tumors that are soft, painless nodules that arise on or underneath the skin
• Café-Au Lait spots – hyperpigmented macules or patches seen in various regions in the body
• Freckling – hyperpigmented areas smaller in size than café-au lait spots most prominent in the axillary and inguinal regions
• Lisch Nodules – pigmented iris hamartomas

Lisch nodules are benign, elevated, tan-colored iris nodules considered pathognomonic of NF-1. Rarely they are also seen in segmental neurofibromatosis and Watson syndrome. They are usually bilateral although unilateral Lisch nodules have also been sparsely reported.

NF-1 can also impact many different areas of the eye though most are rarer than others. These findings include lisch nodules, optic and/or brainstem gliomas, development of glaucoma, astrocytic hamartomas & capillary hemangiomas of the retina, and plexiform neurofibromas.

Common NF-2 features include

• Bilateral vestibular acoustic neuromas
• Early-onset cataracts usually bilateral
• Spinal and cerebral tumors usually meningiomas or ependymomas
• Seizures

In terms of ophthalmologic lesions, cataracts are commonly seen where there may be juvenile cortical wedge cataracts shortly after birth with posterior subcapsular opacities developing later in life. The presence of retinal hamartomas, epiretinal membrane and optic nerve sheath meningiomas may also occur.

Diagnosis

It is important to note that almost half of all patients who have sporadic NF-1 mutations do not meet criteria for diagnosis by the age of 1. If neurofibromatosis type 1 is suspected in these patients, yearly monitoring is required until late childhood as 97% of children with at least 1 feature of NF-1 eventually meet diagnostic criteria by the age of 8.

Neurofibromatosis Type 1	Neurofibromatosis Type 2
Must have ≥2 of the following below	Must have any 1 of the following below
1. ≥6 Café au lait macules > 5mm in diameter if prepubertal and >15mm in postpubertal individuals	1. Bilateral vestibular schwannoma before age 70
2. ≥2 neurofibromas of any type or 1 plexiform neurofibroma	2. Unilateral vestibular schwannoma before age 70 and a first degree relative with NF2
3. Freckling in the axillary or inguinal regio	3. Any 2 of the following – meningioma, nonvestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract and either; (1) 1st degree relative w/ NF2 OR (2) unilateral vestibular schwannoma and negative LZTR1 testing
4. ≥2 Lisch nodules	4 Multiple meningiomas and (1) unilateral vestibular schwannoma OR (2) Any 2 of the following – meningioma, nonvestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract
5 Optic glioma	5. Constitutional or mosaic pathogenic NF2 mutation from blood or by identification of an identical mutation from 2 separate tumors in the same individual
6 Distinctive osseous lesion (sphenoid wind dysplasia, thinning of long bone cortex, etc) with or without pseudoarthrosis
7 First-degree relative with NF1 based on above criteria

Differential diagnosis

It is important to distinguish the two syndromes of neurofibromatosis from each other as they may present with similar symptoms in addition to other clinical conditions such as Legius syndrome, Noonan syndrome and constitutional mismatch repair syndrome.

Management

Current treatment for both NF-1 and NF-2 is directed at the manifestations of disease that arise within the different organ systems. This includes excision or resection of tumors, chemotherapy, radiotherapy, and removal of cataracts. Removal of neurofibromas may also be an option if they cause significant impairment in one’s appearance or quality of life.