Neuro-oculocutaneous syndromes (phakomatoses) are characterized by systemic hamartomas of the eye, central nervous system (CNS), and skin. Diagnosis is clinical, according to the latest published consensus criteria. Ocular involvement is frequent and can help confirm the specific diagnosis. An overview of these conditions is provided in Table 28-3.
Neurofibromatosis Type 1
Neurofibromatosis type 1 (NF1) is characterized by multiple melanocytic and neuroglial lesions. See Table 28-3 for a list of common features.
Café-au-lait spots, the most common cutaneous expression of NF1, are uniformly hyperpigmented macules of varying size (Fig 28-9). Some are usually present at birth; the number and size increase during the first decade of life. Unaffected individuals may have 1–3 café-au-lait spots, but greater numbers are rare except in association with NF1. Melanocytic lesions of the uveal tract are also common.
Lisch nodules are small (usually <1 mm), sharply demarcated, dome-shaped excrescences of the iris (Fig 28-10). Lisch nodules most often develop between ages 5 and 10 years and are present in nearly all adults with NF1. Multiple flat choroidal lesions 1–2 times the size of the optic disc are common. These lesions are difficult to visualize by conventional fundus examination, but near-infrared reflectance imaging has a high sensitivity for detection. Melanocytic lesions in NF1 do not affect vision.
Table 28-3 Overview and Select Key Features of Neuro-Oculocutaneous Syndromes
Figure 28-9 Multiple café-au-lait spots in an infant with unilateral glaucoma; neurofibromatosis type 1 (NF1) was ultimately diagnosed.
(Courtesy of Arif O. Khan, MD.)
Figure 28-10 Lisch nodules of the iris in 2 patients with NF1. The brown iris has lighter-colored Lisch nodules (A), whereas the blue iris has darker-colored nodules (B).
Nodular cutaneous and subcutaneous neurofibromas, or fibroma molluscum, are by far the most common lesions of neuroglial origin. They typically develop in late childhood.
Plexiform neurofibromas are seen in approximately 30% of cases. These are extensive, soft subcutaneous swellings with indistinct margins, often with hyperpigmentation or hypertrichosis of the overlying skin. Hypertrophy of underlying soft tissue and bone (regional gigantism) is often present. Plexiform neurofibromas develop earlier than nodular lesions, are frequently evident in infancy or childhood, and may cause severe disfigurement and functional impairment. Approximately 10% involve the face, commonly the upper eyelid and orbit (Fig 28-11). Greater involvement of the upper eyelid’s temporal portion results in an S-shaped configuration. Tumor bulk may cause complete ptosis. Glaucoma in the ipsilateral eye is found in up to 50% of cases.
Figure 28-11 Plexiform neurofibroma involving the right upper eyelid, associated with ipsilateral buphthalmos, in a girl with NF1. A, Age 8 months. B, Age 8 years.
Complete excision of an eyelid plexiform neurofibroma is generally not possible. Treatment is directed toward the relief of specific symptoms. Surgical debulking and frontalis suspension procedures can reduce ptosis sufficiently to allow binocular vision. Clinical trials examining use of biologic agents to treat these lesions are under way.
Optic pathway glioma is a low-grade pilocytic astrocytoma involving the optic nerve, chiasm, or both. It is present in approximately 15% of affected patients and is symptomatic in 1%–5% (almost always before age 10 years, after a period of brief rapid enlargement). The efficacy of treatment (ie, chemotherapy, radiation) is unclear because of the condition’s highly variable natural history, including relative stability after rapid growth and spontaneous improvement in a few cases. MRI usually shows cylindrical or fusiform enlargement (Fig 28-12), often with exaggerated sinuousness or kinking, creating an appearance of discontinuity or localized constriction on axial images. In addition to causing bilateral vision loss, tumors involving primarily the chiasm may result in significant morbidity, including hydrocephalus and hypothalamic dysfunction. Chiasmal glioma in patients with NF1 carries a better prognosis than in individuals without NF1.
Other less common neuroglial abnormalities include spinal and gastrointestinal neurofibromas, pheochromocytomas, prominence of corneal nerves (≤20%), localized orbital neurofibromas, and retinal hamartomas.
Jakacki RI, Dombi E, Potter DM, et al. Phase I trial of pegylated interferon-α-2b in young patients with plexiform neurofibromas. Neurology. 2011;76(3):265–272.
Additional manifestations include various benign tumors that involve the skin or the eye (eg, juvenile xanthogranuloma, retinal capillary hemangioma), several forms of malignancy (leukemia, rhabdomyosarcoma, pheochromocytoma, Wilms tumor), bony defects such as scoliosis, pseudarthrosis of the tibia, and hypoplasia of the sphenoid bone (which may cause ocular pulsation). Sphenoid dysplasia may be associated with neurofibromas in the ipsilateral superficial temporal fossa as well as in the deep orbit. Several ill-defined abnormalities of the CNS (macrocephaly, aqueductal stenosis, seizures, and developmental delay) are also seen with greater frequency in patients with NF1. The diagnosis of NF1 should be considered in any child who presents with unilateral glaucoma.
Figure 28-12 Axial MR image of a right optic pathway glioma in a child with NF1.
(Courtesy of Ken K. Nischal, MD.)
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.
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.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.