children with NF. Others recommend routine examination and reserve the use of neuroimaging for patients who develop abnormalities of vision, pupil function, or optic disc appearance. An appropriate interval for periodic ophthalmic reassessment in childhood is 1–2 years, unless a specific abnormality requires closer observation.
Fisher MJ, Loguidice M, Gutmann DH, et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 2012;14(6):790–797. Epub 2012 Apr 3.
Kalamarides M, Acosta MT, Babovic-Vuksanovic D, et al. Neurofibromatosis 2011: a report of the Children’s Tumor Foundation annual meeting. Acta Neuropathol. 2012;123(3):369–380.
Neurofibromatosis 2
Neurofibromatosis 2 (NF2) is much less common than NF1; it has an incidence of 1:33,000–1:40,000. It is an autosomal dominant condition, and approximately half of all cases show sporadic mutation. The NF2 gene, neurofibromin 2 (merlin), is located on chromosome 22 (22q12.2) and encodes for a cytoskeletal membrane-linking protein. NF2 is diagnosed clinically by the presence of bilateral acoustic neuromas (eighth cranial nerve tumors) or by a first-degree relative with NF2 and presence of a unilateral acoustic neuroma, neurofibroma, meningioma, schwannoma, glioma, or early-onset posterior subcapsular cataract.
Patients with NF2 typically present in their teens or early adulthood with symptoms related to the eighth nerve tumor(s), including decreased hearing or tinnitus. Ocular findings may predate the onset of symptoms. Therefore, the alert ophthalmologist may be able to help identify the potential for CNS tumors before they become symptomatic. The most characteristic ocular finding in NF2 is lens opacity, especially posterior subcapsular cataract or wedge-shaped cortical cataracts. Up to 80% of patients have epiretinal membranes. Less common findings are retinal hamartoma and combined hamartomas of the retina and retinal pigment epithelium (RPE). Lisch nodules of the iris can occur in NF2 but are infrequent.
Tuberous Sclerosis
Tuberous sclerosis (TS), or Bourneville disease, has a reported incidence of approximately 1 in 10,000. Two distinct genes give rise to TS: TSC1 on 9q34 and TSC2 on 16p13.3. Their proteins, hamartin and tuberin, respectively, are tumor suppressors. Transmission as an autosomal dominant trait has been documented in numerous pedigrees, but new mutations account for as many as 80% of cases.
The 3 classic findings, known as the Vogt triad, are cognitive impairment, seizures, and facial angiofibromas, although all 3 are present in only about 30% of patients with TS. This disease is characterized by benign tumor growth in multiple organs, predominantly the skin, brain, heart, kidney, and eye. Clinical features are divided into major and minor features (Table 28-3). Two major or 1 major and 2 minor features are necessary for a definitive diagnosis.
Table 28-4
TS is characterized by several distinct skin lesions. The ash-leaf spot presents in infancy as a
sharply demarcated hypopigmented lesion (Fig 28-5A). Ultraviolet light increases the visibility of these spots in light-skinned people. Facial angiofibromas, often called adenoma sebaceum (Fig 285B), appear in childhood and are present in three-quarters of adults with TS. These lesions are often mistaken for common acne. Subungual and periungual fibromas are also common after puberty. A thickened plaque of skin known as a shagreen patch occurs in approximately one-quarter of cases, typically in the lumbosacral area.
Figure 28-5 Cutaneous lesions of tuberous sclerosis. A, Hypopigmented macule. B, Adenoma sebaceum of the face.
Seizures occur in 80% of patients with TS and may be difficult to control. Severe cognitive impairment is present in 50% of patients, but in others, intelligence may be normal. Characteristic neuroimaging findings include periventricular or basal ganglia calcification (representing benign astrocytomas), and tuberous malformations of the cortex (Fig 28-6). Malignant astrocytomas occur infrequently. Obstruction of the foramen of Munro by tumor may produce hydrocephalus. Cardiac tumors (rhabdomyomas) can lead to early death or severe disability. Bone and kidney lesions are common but usually produce no significant disturbance of function.
Figure 28-6 Brain lesions of tuberous sclerosis. A, Axial computed tomography image showing small periventricular calcifications. B, Axial T2-weighted MRI demonstrating tuberous malformations (arrows).
The most frequent and characteristic ocular manifestation of TS is the retinal phakoma (Fig 28-7). Pathologically, this growth arises from the innermost layer of the retina and is composed of nerve fibers and relatively undifferentiated cells that appear to be of glial origin. The growth is frequently called an astrocytic hamartoma. Phakomas are usually found near the posterior pole and involve the retina, the optic disc, or both. They vary in size from approximately half to twice the diameter of the disc. Vision is rarely affected.
Figure 28-7 Fundus lesions of tuberous sclerosis, left eye. In addition to the large phakoma partially overlying the optic disc, a small hypopigmented lesion (arrow) appears in the temporal macula, and a barely visible second phakoma (arrowhead) partially obscures a retinal blood vessel near the edge of the photograph, directly below the disc. The lesions of tuberous sclerosis can vary considerably in their opaqueness and visibility.
Retinal phakomas have 3 distinct appearances. The first is typically found in very young children; the phakomas are relatively flat with a smooth surface, indistinct margins, and a gray-white color that makes them difficult to detect. The second is a sharply demarcated, elevated, yellow-white, calcified lesion with an irregular surface that has been compared to a mulberry. These lesions are more often found in older patients, on or adjacent to the optic disc. The third type is a transitional lesion that combines features of the first 2.
Phakomas are present in 30%–50% of patients with TS. One to several may be found in a single eye, and 40% are bilateral. There is no evidence that the number of lesions increases with age, but individual tumors have been documented to grow over time. Phakomas are not pathognomonic of TS; they occur occasionally in association with neurofibromatosis and in the eyes of unaffected persons. Retinal lesions are more common in individuals with the TSC2 mutation. Hypopigmented lesions analogous to white spots of the skin are occasionally seen in the iris or choroid.