that causes progressive renal failure, deafness, anterior lenticonus or anterior subcapsular cataract, posterior polymorphous dystrophy, and fleck retinopathy. Hematuria begins in childhood. Hypertension and kidney failure occur late in the course of the disease.
Senior-Loken syndrome
Senior-Loken syndrome is an autosomal recessive disease characterized by nephronophthisis, renal failure, and a pigmentary retinal degeneration similar to that of Leber congenital amaurosis (LCA), with a flat electroretinogram (ERG). Children who have received a diagnosis of LCA should undergo renal function studies to rule out Senior-Loken syndrome.
Phakomatoses
The phakomatoses, or neurocutaneous syndromes, are a group of disorders characterized by multiple lesions of 1 or more histologic types that are found in 2 or more organ systems, including the skin and central nervous system (CNS). The lesions are commonly multiorgan hamartomas. Ocular involvement is frequent and may constitute an important source of morbidity as well as provide diagnostic information. Four major disorders have traditionally been designated phakomatoses, all of which have important ocular manifestations:
neurofibromatosis (von Recklinghausen disease) tuberous sclerosis (Bourneville disease)
angiomatosis of the retina and cerebellum (von Hippel–Lindau disease) encephalofacial or encephalotrigeminal angiomatosis (Sturge-Weber syndrome)
Other conditions sometimes classified as phakomatoses include
ataxia-telangiectasia (Louis-Bar syndrome) incontinentia pigmenti (Bloch-Sulzberger syndrome) racemose angioma (Wyburn-Mason syndrome) Klippel-Trénaunay-Weber syndrome
Neurofibromatosis
Patients with neurofibromatosis (NF) manifest characteristic lesions composed of melanocytes or neuroglial cells, both of which are derivatives of neural crest mesenchyme. Although the melanocytic and glial lesions in NF are often called hamartomas, this designation is questionable because most lesions do not become evident until years after birth and many are histologically indistinguishable from low-grade neoplasms originating in the same tissues. NF has 2 forms that are distinguished by differences in genetics, diagnostic criteria, morbidity, and treatment.
Neurofibromatosis 1
Neurofibromatosis 1 (NF1) is the most common single-gene disorder affecting the nervous system. It affects 1 in 3000 to 3500 people and has autosomal dominant inheritance with virtually 100% penetrance. Approximately 50% of cases are sporadic, presumably the result of new mutations. The genetic locus of NF1 is on the long arm of chromosome 17 (17q11.2). The NF1 gene is associated with neurofibromin, which is involved in regulation of cellular proliferation and tumor suppression.
Melanocytic lesions Almost all adults with NF1 have melanocytic lesions involving both the skin and the eye. Café-au-lait spots, the most common cutaneous expression, appear clinically as flat, sharply demarcated, uniformly hyperpigmented macules of varying size and shape. At least a few are usually present at birth; their number and size increase during the first decade of life. Many unaffected individuals have 1–3 café-au-lait spots, but greater numbers are rare except in association with NF.
Clusters of small café-au-lait spots, or freckling, in the axillary or inguinal regions are particularly characteristic of NF1.
Melanocytic lesions of the uveal tract are common ocular manifestations of NF. Iris lesions are small (usually <1 mm), sharply demarcated, dome-shaped excrescences known as Lisch nodules (Fig 28-2). Most Lisch nodules develop between ages 5 and 10 years and are present in nearly all affected adults. An affected adult’s eye typically has dozens.
Figure 28-2 Lisch nodules of iris with neurofibromatosis 1 (NF1). A, Brown iris has lighter-colored Lisch nodules. B, Blue iris has darker-colored Lisch nodules.
Choroidal lesions occur in one-third to one-half of adults with NF1. These hyperpigmented lesions are flat with indistinct borders. Their number varies from 1 to 20 per eye, and each lesion is typically 1–2 times the size of the optic disc. These lesions may be difficult to visualize by conventional fundus examination; near-infrared reflectance imaging has a high sensitivity for detection.
Neither the vision nor the health of the eye is affected by these melanocytic lesions, regardless of their extent. Persons with NF1 are thought to be predisposed to uveal melanoma and to several other malignant neoplasms. However, the prevalence of iris (especially choroidal) tumors is still low.
Glial cell lesions The most common neuroglial lesions in NF1 are nodular and subcutaneous neurofibromas, plexiform neurofibromas, and optic pathway gliomas.
NODULAR NEUROFIBROMAS Among lesions of neuroglial origin in NF1, nodular cutaneous and subcutaneous neurofibromas, or fibroma molluscum, are by far the most common. These lesions are soft, often pedunculated, papulonodules. They typically appear in late childhood and increase in number throughout adolescence and adulthood; nearly all adults with NF1 have at least a few. In some cases, hundreds of these lesions are present, causing considerable disfigurement.
PLEXIFORM NEUROFIBROMAS Plexiform neurofibromas occur in approximately 30% of patients with NF1 and appear clinically as extensive soft subcutaneous swellings with indistinct margins. Hyperpigmentation or hypertrichosis of the overlying skin is common, as is hypertrophy of underlying soft tissue and bone (regional gigantism).
Plexiform neurofibromas develop earlier than do nodular lesions, frequently becoming evident in infancy or childhood, and may cause severe disfigurement and functional impairment. Approximately 10% of plexiform neurofibromas involve the face, commonly the upper eyelid and orbit (Fig 28-3). The greater involvement of the upper eyelid’s temporal portion gives the eyelid margin an S-shaped
configuration. Complete ptosis may result from the increasing bulk and weight of the upper eyelid. Glaucoma in the ipsilateral eye is found in as many as half of cases.
Figure 28-3 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 permit binocular vision. Clinical trials examining use of biologic agents in the treatment of these lesions are under way.
Jakacki RI, Dombi E, Potter DM, et al. Phase 1 trial of pegylated interferon-α-2b in young patients with plexiform neurofibromas. Neurology. 2011;76(3):265–272.
OPTIC PATHWAY GLIOMA This low-grade pilocytic astrocytoma (optic glioma) involves the optic nerve, chiasm, or both and is among the most characteristic and potentially serious complications of NF1. Optic pathway gliomas are present in approximately 15% of patients and are symptomatic (ie, produce significant vision loss, proptosis, or other complications) in 1%–5%.
Magnetic resonance imaging (MRI) is the preferred technique for diagnosis. The orbital portion of an involved optic nerve usually shows cylindrical or fusiform enlargement (Fig 28-4), often with exaggerated sinuousness or kinking, creating an appearance of discontinuity or localized constriction on axial images.
Figure 28-4 Axial magnetic resonance (MR) image of a right optic pathway glioma in a child with NF1. (Courtesy of Ken K.
Nischal, MD.)
Optic gliomas that become symptomatic in patients with NF1 nearly always do so before age 10 years, often following a brief period of rapid enlargement. Even without treatment, some gliomas enter a phase of stability or slower growth, and spontaneous improvement has been documented in a few cases.
Tumors confined to the optic nerve at the time of clinical presentation infrequently extend into the chiasm. Chemotherapy may be effective in halting their growth. Radiation therapy can be useful, especially in cases of sudden vision loss or rapid growth. However, the efficacy of these treatments is difficult to evaluate, even in large studies, because of the widely variable natural history of this disease. Subtotal orbital excision for relief of disfiguring proptosis in a blind eye can be considered.
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 much better prognosis than in individuals without NF.
OTHER NEUROGLIAL ABNORMALITIES There are other, less common neuroglial abnormalities. Abnormal proliferation of peripheral neuroglial or other neural crest–derived cells may occur in deeper tissues and visceral organs as well as in skin (spinal and gastrointestinal neurofibromas, pheochromocytoma). Prominence of corneal nerves, thought to represent glial hypertrophy, may be observed on slit-lamp examination in as many as 20% of cases. In rare cases, a localized neurofibroma develops within the orbit. Retinal hamartomas that are indistinguishable from those seen in tuberous sclerosis have also been reported.
Other manifestations NF1 is associated with an increased (but still generally low) incidence of several conditions that cannot be explained by abnormal proliferation of neural crest–derived cells. These include various benign tumors that involve the skin or the eye (juvenile xanthogranuloma, retinal capillary hemangioma) and several forms of malignancy (leukemia, rhabdomyosarcoma, pheochromocytoma, Wilms tumor). Also relatively common are 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.
Diagnosis and monitoring NF1 is diagnosed by genetic testing or based on clinical findings when 2 or more of the following 7 criteria are met:
1.six or more café-au-lait spots that are >5 mm in diameter in prepubescent children or >15 mm in diameter in postpubescent children
2.two or more neurofibromas of any type or 1 plexiform neurofibroma
3.freckling of axillary, inguinal, or other intertriginous areas
4.optic pathway glioma
5.two or more Lisch nodules of the iris
6.a distinctive osseous lesion, such as sphenoid bone dysplasia or thinning of the long-bone cortex, with or without pseudarthrosis
7.a first-degree relative with NF1, according to the above criteria
Lisch nodules may be used to confirm the presence of NF1 in a patient with café-au-lait spots. They may not be present in affected children, but the absence of such nodules in an adult makes the diagnosis unlikely. Some practitioners recommend neuroimaging to look for optic glioma in all