Neurofibromatosis (von Recklinghausen’s syndrome)

DEFINITION/OVERVIEW AND ETIOLOGY

Neurofibromatosis (NF) is an ONCS characterized by multisystem involvement that can lead to a wide variety of clinical symptoms and signs.10–17 von Recklinghausen published a classic monograph on this disease in 1882 and the condition is now known as von Recklinghausen’s syndrome.11 More recently, NF has been subcategorized into type 1 (NF-1) and type 2 (NF-2).12 Since there is some overlap in the two types, they are discussed together in this chapter.

The frequency of a new mutation for NF is estimated to be about 1 in 2,500 to 3,000 births; there appears to be no appreciable predilection for gender.12

NF is transmitted by an AD mode of inheritance with about 80% penetrance. NF-1 is also known as peripheral neurofibromatosis or von Recklinghausen’s syndrome. It is recognized to occur from an abnormality of chromosome 17. NF-2 is called central or bilateral acoustic neurofibromatosis. It is characterized by CNS tumors and early onset of posterior subcapsular cataract, and is

recognized to be related to an abnormality in chromosome 22.12,13

CLINICAL PRESENTATION

NF has the most diverse systemic and ocular findings among the ONCS (Table 19).1–3,12,13

Ocular changes include abnormalities in the uveal tract (80%), eyelid (25%), optic nerve (12%), retina (9%), and conjunctiva (4%).11 The plexiform neurofibroma of the orbit and eyelid produces a typical S-shaped curve to the upper eyelid, a finding that is believed to be highly characteristic of NF-1. Plexiform or localized neurofibroma, histopathologically similar to those that appear on the skin, can also occur in the orbit in patients with NF-1. Neurilemoma (schwannoma) can also develop in the orbit of patients with NF-1 and NF-2. They arise from the Schwann cells of the ciliary nerves.Bilateral schwannoma of the auditory nerves (acoustic

neuroma) is considered to be pathognomonic for NF-2.12

Patients with NF-2 have been recognized to have early onset of posterior subcapsular cataract.12 Patients with NF-1 have an increased incidence of congenital glaucoma. It appears to occur more commonly in patients who have neurofibromatous involvement of the eyelids or ipsilateral facial hemihypertrophy. It can be secondary to obstruction of aqueous outflow by diffuse neurofibromatous thickening of the trabecular meshwork, angle closure from forward displacement of the iris by a ciliary body tumor, or from iris neovascularization.

Uveal tract involvement has been recognized in about 80% of patients with NF.13 Multiple iris hamartomas, known as Lisch nodules, are the most common uveal abnormality in NF-1 (258).13 They first appear in childhood around age 5 years or later as discrete, multiple, lightly pigmented elevations of the anterior border layer. Relatively flat pigmented choroidal lesions, presumably melanocytic hamartomas identical to choroidal nevi, are often seen in NF-1. Some patients with NF have a diffuse thickening of the uveal tract due to an increased number of neurofibromatous and melanocytic elements. Other choroidal tumors that rarely are associated with NF are choroidal melanoma and schwannoma. Most cases of choroidal schwannoma, however, are isolated and not associated with NF-1 or NF-2.15 The retinal findings of NF are less common and include retinal astrocytic hamartoma, retinal vasoproliferative tumor, myelinated nerve fibers, multifocal congenital hypertrophy of the RPE (‘bear tracks’), and a lesion similar to combined hamartoma of the retina and RPE. The latter typically occurs in patients with NF- 2 but can be seen with NF-1. The astrocytic hamartoma is relatively rare in NF but is very common in TSC.

259 Neurofibromatosis.Axial proptosis of left eye due to juvenile pilocytic astrocytoma of optic nerve (optic nerve glioma).

The optic nerve can be involved with pilocytic astrocytoma (glioma) (259, 260) or meningioma.2,3 In patients with pilocytic astrocytoma, the reported incidence of NF has ranged from 9% to 30%.17 Both juvenile pilocytic astrocytoma and meningioma of the optic nerve are benign, slowly progressive lesions that often cause visual loss, proptosis, optic disc edema, retinal venous obstruction, and optic atrophy.

For differential diagnosis, the diffuse hamartomatous thickening of the uveal tract in NF should be differentiated from diffuse uveal melanoma, ocular melanocytosis, and uveal metastases. Other differentiating features are discussed elsewhere.3

OTHER FINDINGS

The CNS manifestations of NF vary with the size and extent of the associated tumors.11 Acoustic neuromas, particularly if bilateral, are considered to be pathognomonic of NF-2. Other NF-2-associated tumors include gliomas in the region of the third ventricle, pituitary tumors, and spinal cord meningiomas.

The most important cutaneous manifestations of NF include subcutaneous benign nerve sheath tumors, pigmented macules (café au lait spots) and nevi.2 Many of these skin lesions become clinically apparent at puberty, although in some instances they have been noted at birth. The benign cutaneous and subcutaneous nerve sheath tumors (neurofibromas and schwannomas) are particularly pronounced in the facial area (260).

260 Axial MRI of patient shown in 249.

T2 weighted image with gadolinium enhancement,showing optic nerve pilocytic astrocytoma.

The pigmented macule (café au lait spot) is characterized clinically as a patch of light brown pigmentation with fairly well-defined borders (261). It can occur anywhere on the skin and can assume a variety of sizes and configurations. Café au lait spots are highly characteristic of NF. Strict criteria should be met before making the diagnosis of NF-1 or NF-2 (Table 20).

A number of other benign and malignant systemic tumors have been associated with NF including malignant peripheral nerve sheath tumors, breast carcinoma, genitourinary tumors, gastrointestinal tumors, and cutaneous melanoma. Patients with NF are recognized to have a slightly higher incidence of pheochromocytoma.

Histopathologically, Lisch nodules are focal aggregates of melanocytes and glial cells on the anterior border layer of the iris. The choroidal hamartoma is similar to the iris lesion histopathologically. The retinal astrocytic hamartoma is apparently identical to that seen with TSC.

MANAGEMENT/TREATMENT

Management of the ocular lesions of NF varies with the location and the extent of the disease. Treatment can be very complex. In general, the fundus tumors including diffuse choroidal hamartoma, retinal astrocytic hamartoma, myelinated nerve fibers, and combined hamartoma of the retina and RPE require no treatment. Choroidal neurilemoma and malignant melanoma are managed with one of several methods, depending on many factors.1