PHAKOMATOSES: NEUROFIBROMATOSIS

Neurofibromatosis is a disease that primarily affects nerves of sensation, Schwann cells, and melanocytes. Two genetically distinct forms of neurofibromatosis have been described: type 1 or peripheral (NF1) and type 2 or central (NF2). NF1 is the most common form and

can present at any age.

Symptoms

In NF1, vision loss can occur secondary to optic nerve glioma, menigiomas, glaucoma, or glial hamartomas of the retina. Learning disabilities occur frequently.

For patients with NF2, vision loss can occur secondary to juvenile posterior subcapsular cataracts or meningiomas. Hearing loss and vestibular problems commonly occur in the second to third decade of life.

Clinical Features

Diagnosis of NF1 requires that the patient have two or more of the following: six or more café-au-lait patches (larger than 5 mm in prepubescent patients and larger than 15 mm in postpubescent patients), two or more neurofibromas, one plexiform neurofibroma (s-shaped lid), axillary or inguinal freckling, optic nerve glioma (proptosis), two or more Lisch nodules, sphenoid wing dysplasia (pulsating exophthalmos), and a first-degree relative with NF1.

Posterior segment manifestations described in NF1 include hamartomas of the optic disc, retina, and choroid; retinal hemangioma; congenital hypertrophy of the retinal pigment epithelium; and myelinated nerve fibers. The finding of astrocytic hamartoma is less common in neurofibromatosis compared to tuberous sclerosis.

Diagnosis of NF2 requires that the patient meet the following criteria: bilateral eighth nerve masses; or a first-degree relative with NF2 and either unilateral eighth nerve mass or two of the following: neurofibroma, menigioma, schwannoma, and juvenile posterior subcapsular cataracts. Combined hamartomas of the retinal pigment epithelium and neurosensory retina have been described in patients with NF2.

Ancillary Testing

Magnetic resonance imaging (MRI) and computed tomography (CT) scans are necessary to assess central nervous system disease.

Pathology/Pathogenesis

NF1 is inherited as an autosomal dominant trait with an incidence of one in 3000 live births. The gene for NF1 has been located on chromosome 17q11.2.

NF2 is inherited as an autosomal dominant trait with an incidence of one in 50000 live births. The gene for NF2 has been located on chromosome 22q11.2-q13.1.

Treatment/Prognosis

Most of the intraocular lesions of NF1 are benign and only warrant observation. However, patients with optic nerve gliomas need regular MRIs and visual fields and neuro-ophthalmological follow-up. In patients with NF2, cataract extraction may be necessary to restore visual function in patients with visually significant cataracts.

Systemic Evaluation

Baseline CT/MRI studies are necessary to detect subclinical visual pathway gliomas. Patients should have a cardiac echocardiogram to rule out a cardiac rhabdomyoma. A chest x-ray to rule out cystic lung lesions should be obtained. Patients should also be screened for leukemia, seizures, pheochromocytoma, and other endocrinological abnormalities. Patients with NF1 should also have a baseline neurological evaluation. These screening examinations can be coordinated through the patient’s primary care provider. Patients with NF2 may require otolaryngology consultation for evaluation of hearing loss or abnormal vestibular function.

This patient with neurofibromatosis type 1 demonstrates numerous subcutaneous neurofibromas on her face and neck.

Other common cutaneous manifestations of neurofibromatosis include café-au-lait spots, as seen on the arm of this 13-year-old boy.

The slit lamp examination of the same patient revealed multiple Lisch nodules on the iris surface of each eye.

Fundus photograph of a juxtapapillary combined hamartoma of the retinal pigment epithelium and retina in a patient with neurofibromatosis type 2. The three characteristic findings in this lesion are epiretinal membrane, tortuous retinal vessels, and underlying thickened and/or pigmented retinal pigment epithelium.

Fluorescein angiogram of the combined hamartoma of the retinal pigment epithelium and retina demonstrates markedly tortuous vessels.

Sturge-Weber syndrome consists of a facial cutaneous angioma with an ipsilateral leptomeningeal vascular malformation. The classic findings include cerebral calcifications, seizures, focal neurological defects, and mental deficiency.

Symptoms

Vision loss can occur secondary to glaucoma, amblyopia, cystoid macular degeneration, exudative retinal detachment, or vascular abnormalities of the occipital lobe.

Clinical Features

Sturge-Weber syndrome is a spectrum. Most patients have a forme fruste rather than the full syndrome. The full syndrome consists of facial hemangioma, ipsilateral intracranial hemangioma, ipsilateral choroidal hemangioma, and congenital glaucoma. Developmental delay occurs in up to 50% of patients with leptomeningeal angiomatosis.

Ophthalmic findings in Sturge-Weber syndrome include eyelid hemangiomatosis, prominent conjunctival/episcleral vascular plexi, diffuse choroidal hemangioma with “tomato-catsup fundus,” tortuous retinal vessels, cystoid macular degeneration, exudative retinal detachment, heterochromia iridis, glaucoma, and hyperopic amblyopia.

Systemic findings in Sturge-Weber syndrome include railroad track calcifications of the leptomeninges in the occipital/parietal area, seizures, developmental delay, hypertrophy of the face, hemangiomatosis involvement of airway, and cutaneous hemangiomas.

Ancillary Testing

Glaucoma is a significant cause of vision loss in patients with Sturge-Weber syndrome; therefore, intraocular pressure measurements and visual field testing are essential.

Fluorescein angiography in patients with diffuse choroidal hemangioma may show diffuse leakage. Ultrasonography demonstrates a thickened choroid with medium to high internal reflectivity, and exudative retinal detachments may be detected.

Pathology/Pathogenesis

Sturge-Weber syndrome is not inherited and occurs in one in 50000 live births. There is no race or sex predilection. The lesions in Sturge-Weber syndrome are anomalies of neuroectoderm. Sturge-Weber syndrome is believed to be caused by an abnormality in the early fetal development of the neural crest. The choroidal hemangioma is classified as a mixed hemangioma.

Treatment/Prognosis

If the V1 distribution is not involved there is a low chance of intracranial involvement. Glaucoma in Sturge-Weber syndrome is typically poorly responsive to medications and requires surgical management. Intraoperative complications such as expulsive ocular hemorrhage are common. Hyperopic amblyopia can occur in children with unilateral choroidal hemangioma hence, these patients need careful refraction and amblyopia therapy if warranted. External radiation therapy may be necessary to resolve exudative retinal detachment. Cutaneous hemangiomas can be treated with laser to lessen their appearance and improve cosmesis.

Systemic Evaluation

Patients with Sturge-Weber syndrome should have neurological evaluation. Evaluation of the airway must be performed before performing any surgical intervention.

A 15-year-old boy with Sturge-Weber syndrome demonstrates the “port wine” facial hemangioma.

He had glaucoma refractory to medical management and required surgery. Note the prominently dilated conjunctival and episcleral vessels of his right eye.