Neurofibromatosis (NF) is an autosomal dominant (AD) disease characterized by disordered growth of ectodermal tissues. It is part of a group of disorders called phakomatoses (neurocutaneous syndromes), characterized by benign tumor-like nodules of the eye, skin, and brain. The four disorders designated as phakomatoses are neurofibromatosis (Recklinghausen's disease), tuberous sclerosis (Bourneville's disease), encephalotrigeminal angiomatosis (Sturge-Weber syndrome), and cerebroretinal angiomatosis (von Hippel-Lindau disease). Clinical signs of neurofibromatosis may be present in infancy or not until adulthood in milder forms. There are two subtypes of the syndrome, known as neurofibromatosis type1 (NF-1) and neurofibromatosis type 2 (NF-2).
Friedrich Daniel von Recklinghausen's disease (1882) or NF1 is the more common of the two types of neurofibromatosis, with a prevalence of 1 in 3000 individuals. NF1 shows autosomal dominant (AD) inheritance with almost complete penetrance. The NF1 gene is situated on chromosome 17q11 and about 50% of the patients are found to have new mutations. Neurofibromin, the NF1 gene product, is a guanosine triphosphatase-activating protein abundant in Schwann cells and neurons, with a role in cell proliferation and differentiation. Clinically, NF1 is characterized by skin neurofibromas, café au lait spots, iris tumors (also known as Lisch's nodules), and optic nerve gliomas. A large number of systemic manifestations of NF1 are described, including: visceral involvement (neurofibromas, cardiac rhabdomyoma, carcinoid tumors, malignant nerve sheath tumors, rhabdomyosarcoma), skeletal deformities (sphenoid wing dysplasia, kyphoscoliosis), pheochromocytomas, chronic myelogenous leukemia, mental retardation, learning disabilities, macrocephaly and stenosis of the aqueduct of Sylvius with subsequent obstructive hydrocephalus.
Two or more of the following clinical features are required for the diagnosis of NF-1, as established by the 1987 NIH Consensus Development Conference:
1. Five or more café-au-lait spots more than 5 mm in diameter in pre-pubertal patients; six or more café-au-lait spots more than 15 mm in diameter in post-pubertal patients 2. Two or more neurofibromas of any type, or one plexiform neurofibroma 3. Axillary or inguinal freckling 4. Optic glioma (pilocytic astrocytoma) 5. Two or more Lisch nodules 6. A distinctive osseous lesion (pseudoarthrosis of the tibia or sphenoid wing dysplasia) 7. A first-degree relative diagnosed with NF-1 in accordance with the above criteria
Learning and behavioral disturbances are common in children, and the psychological problems associated with skin manifestations may be severe. Malignant brain tumors, malignant peripheral nerve sheath tumors (MPNST) and childhood leukemia are the main causes of increased mortality in NF1.
NF-2 is a rare disorder, with a prevalence of 1 in 40-50,000 persons, AD inheritance and high penetrance. Wishart first described a case of presumed NF2 in 1882, but the disease was not separated from von Recklinghausen disease until 1987, when different genes on different chromosomes were demonstrated to be involved in the pathogenesis of these disorders. The genetic defect responsible for NF2 is a deletion of a portion of chromosome 22q12, the same chromosomal abnormality found in spontaneous spinal schwannomas. The NF2 gene product is merlin, a protein associated with membrane and cytoskeletal structures. Clinically, NF2 is characterized by bilateral vestibulocochlear schwannomas ("acoustic neuromas"), meningiomas (sometimes multiple), and optic nerve gliomas. The most common tumor associated with the syndrome is the vestibulocochlear schwannoma, encountered in as many as 10% of patients with NF2. Skin findings are essentially absent in this NF2. Clinical presentation is in second or third decade with hearing loss, tinnitus, unsteadiness, headache, or change in vision.
The current case represents a classic ocular presentation of NF1. By the teenage years, Lisch nodules or iris hamartomas are observed in virtually all patient's with NF1, and they are commonly used as diagnostic markers of the disease. Optic gliomas and plexiform neurofibromas are the most common tumors in children with NF1. Many other ophthalmologic lesions have been described in these patients, including choroidal hamartomas, prominent corneal nerves, iris heterochromia, strabismus and neurofibromas of the conjunctiva and ciliary nerves. Combined hamartomas of the retina and retinal pigment epithelium and retinal capillary hemangiomas also occur. Secondary glaucoma due to infiltration of the angle and obstruction of the aqueous flow in the anterior chamber is also seen as a complication of patients with neurofibroma.
This discussion will summarize the most important of these lesions, plexiform neurofibromas and optic pathway gliomas. We will also discuss the pathology associated with glaucoma in general.
Three types of neurofibromas can be encountered in patients with NF1: diffuse, nodular (isolated), and plexiform. Cutaneous neurofibromas are soft, fleshy tumors attached to the skin and they range from small to very large and from several to hundreds in numbers. They can be flat, sessile, or pedunculated. Subcutaneous neurofibromas can often represent a source of pain or pruritus, and can cause serious neurologic compromise. Isolated neurofibromas appear as fusiform swelling of the parent nerve, in contrast to the eccentric location of a schwannoma. Plexiform neurofibromas, pathognomonic to NF1, directly involve nerve plexuses and dorsal nerve roots and must be monitored because they can invade visceral structures. Grossly, plexiform neurofibromas resemble a "bag of worms". Deep plexiform neurofibromas are congential lesions that involve all skin levels from the fascia to the deeper structures and are irregular and noncircumscribed. Malignant transformation occurs in about 5% of plexiform neurofibromas. They show a tendency to develop into malignant peripheral nerve sheath tumors (MPNST), the most common of them being neurofibrosarcoma.
Plexiform neurofibromas are the most common orbital masses found in patients with NF1, and the most severe involvement of the orbit tends to occur in the youngest patients (1). They commonly arise in the lateral portion of the upper eyelid producing a S-shaped configuration of lid, and 25% extend intraorbitally. Although they may be present at birth, signs in a newborn are subtle. The most serious symptom is the development of glaucoma in the ipsilateral eye in up to 50% of the affected patients. Both nodular and plexiform neurofibromas may arise in the orbit, but plexiform neurofibromas are more specifically associated with NF1.
Histologically, neurofibroma consists of a cellular proliferation of randomly arranged spindle-shaped cells with elongated, wavy nuclei. The proliferating cells include Schwann cells and fibroblasts that infiltrate the surrounding tissue and expand nerve branches. A variable amount of background stroma composed of loose fibrosis with admixed areas of myxoid matrix is seen. Mast cells, more readily demonstrated with the Giemsa or toluidine blue stains, are often abundant and can be helpful in the diagnosis. Small axons are frequently seen within the tumor, especially with the use of special stains. Distinguishing a diffuse neurofibroma from benign fibrous proliferations such as myxoid lipoma, nodular fasciitis and focal mucinosis is usually not difficult because the latter lack the wavy appearance of lesional cell nuclei. Nuclear pleomorphism and mitotic activity is unusual in neurofibroma, helping in its differentiation from malignant peripheral nerve sheath tumor.
Plexiform neurofibroma has a characteristic clinical presentation. It is seen only in patients with NF1 and appears on the first decade as an infiltrating lesion involving all aspects of the orbit and producing deformity of the region. Histologic examination reveals an infiltrating tumor, with an organoid growth pattern, with each unit being surrounded by perineurium. Schwann cells, axons and endoneural fibroblasts are seen in the spaces enclosed by perineurium. Diffuse neurofibroma is the rarest type see in the orbit and is not always associated with NF1. It is noncircumscibed and infiltrative into the orbital fat and the extraocular muscles. These lesions show moderate collagenization and are predominantly myxoid, with areas rich in hyaluronic acid. The least likely to be associated with NF1 is the isolated neurofibroma seen in the orbit as a circumscribed mass. The lesion is composed of wavy bundles of peripheral nerve sheath cells with various amounts of collagen and hyaluronic acid deposited in the stroma. Helpful in distinguishing the more heavily collagenized tumors from soft tissue tumors of the orbit and schwannomas are immunohistochemical stains for S100 and neurofilament.
Glaucoma is characterized by elevated intraocular pressure that is sufficient to cause ocular tissue damage; infants are more sensitive to increased intraocular pressure. Glaucoma can lead to diffuse enlargement of the cornea and globe (buphthalmos). There are 3 main types of glaucoma: angle-closure glaucoma, open-angle glaucoma, and congenital glaucoma. Adhesions between the cornea and iris (anterior peripheral synechiae) result in angle closure, which can accelerate progression of glaucoma due to other mechanisms. The elevated intraocular pressure causes degeneration of nerve fibers, probably due to disruption of axoplasmic flow, leading to a cupped excavation of the optic disc; the diameter of the nerve decreases and there is thinning of the nerve fiber layer and the loss of retinal ganglion cells. Congenital glaucoma is associated with systemic disorders such as: Down syndrome, Sturge-Weber syndrome, NF1, chronic uveitis, rubella and developmental disorders of anterior chamber cleavage. It's also associated with various ocular disorders like: aniridia, ectopic lentis, congenital cataract, familial iris hypoplasia, and trauma.
Optic pathway gliomas are often observed in patients with NF1. Generally, they are slow growing and the majority is classified as low-grade pilocytic astrocytomas (grade I). Although they have a low malignant potential, they represent the most important cause of visual disturbance in patients with NF1. Optic gliomas can uni- or bilaterally affect any part of the visual pathway, usually appearing before ten years of age. Bilateral optic nerve tumors are considered pathognomonic of NF1 (4). There is a slight female preponderance of the tumor (5).
Differential diagnosis of optic nerve enlargement should include both neoplastic and nonneoplastic lesions. Neoplastic lesions include: optic glioma, meningioma, neurinoma, hemangioblastoma, metastatic lesions and leukemia. Meningiomas of the optic nerve sheath are seen most often in middle-aged women. In children, they are more common than intracranial meningiomas. Bilateral optic meningiomas are usually associated with neurofibromatosis (10, 11), but bilateral meningiomas in children without neurofibromatosis have also been described (12). Of note is the propensity of optic nerve gliomas to elicit meningothelial hyperplasia, which can complicate intraoperative evaluation in this location.
Histologically, pilocytic astrocytomas of the optic pathway resemble their cerebellar counterparts and have a high propensity for leptomeningeal involvement, although they appear less well circumscribed. The later two characteristics make this tumor more difficult to stage and the evaluation of nerve margins more challenging. The tumor is an astrocytic tumor of low cellularity and a biphasic pattern, composed of compacted bipolar cells associated with Rosenthal fibers and loose textured multipolar cells with eosinophilic granular bodies and microcysts.
Optic gliomas in children with NF1 may regress or show spontaneous involution (9, 16). Also, NF1 patients with optic gliomas have a tendency to develop a second primary neoplasm of the CNS (6,7, 8) found in up to 52% of patients and identified on average four years after the diagnosis of the optic glioma.
In summary, ocular pathology encountered in patients with NF1 is complex, but characteristic. The complexity of the ocular disorders reflects the overall complexity of this disorder and their prognosis reminds us of the high morbidity that these benign lesions have for the NF patients, who have a life expectancy 15 years shorter than the average population.
Contributed by Diana N. Ionescu, MD, Johnathan A. Engh, MD and Charleen T Chu, MD PhD.