6 Neurocutaneous Syndromes Maria A. Musarella he neurocutaneous disorders are a group of clinically and Tgenetically heterogeneous diseases that are characterized mainly by harmatomas and tumor growth, involving tissues derived by the embryonic germ layer. Older literature has called these disorders “phakomatoses” (mother-spot). The modern nomenclature and traditional eponyms of these entities are given in Table 6-1. Each of the neurocutaneous diseases is rec- ognized as a distinct clinical disorder. This chapter covers the ophthalmic aspects of these syn- dromes, as well as the numerous and varied multisystemic man- ifestations. Although Proteus syndrome and multiple endocrine neoplasia (MEN) 2B are considered separate from the neurocu- taneous diseases, they are covered here because of the clinical resemblance to classic phakomatoses. NEUROFIBROMATOSIS 1 Historical Perspective Dr. Robert William Smith first described neurofibromatosis 1 (NF1) in 1849 in his treatise on Pathology Diagnosis and Treat- ment of Neuroma.100 However, this work received little atten- tion. Neurofibromatosis is most closely linked with the German pathologist, von Recklinghausen, who described the main fea- tures of this entity in his classic paper of 1882.111 Etiology About 50% of cases of NF1 result from new mutations. The NF1 gene has been mapped to 17q11.2 and positionally cloned. The 291 292 handbook of pediatric eye and systemic disease TABLE 6-1. Neurocutaneous Syndromes. Modern nomenclature Eponyms Neurofibromatosis 1 von Recklinghausen disease Peripheral neurofibromatosis Neurofibromatosis 2 Central neurofibromatosis Tuberous sclerosis Bourneville disease von Hippel–Lindau Disease Ataxia telangiectasia Louis–Bar syndrome Sturge–Weber Encephalotrigeminal angiomatosis Klippel–Trenaunay Angiosteohypertrophy Wyburn-Mason syndrome Racemose angiomatosis Multiple endocrine neoplasia 2B Mucosal neuroma syndrome (Wagenmann–Froboese) Proteus syndrome NF1 gene is one of the largest genes in which mutations lead to a disease in humans. It is approximately 350 kb in size, consists of 60 exons, and encodes for 11 to 13 transcripts with an open reading frame coding for 2818 amino acids.14 In 1990, the NF1 gene and its protein product, neurofibromin, were identified. The gene product is as a tumor suppressor protein.27,42,108 The protein encoded by NF1 has structural and functional similarity to a family of GTPase-activating proteins (GAPs) that down-reg- ulate a cellular proto-oncogene, p21-ras. ras has been implicated in the control of cell growth and differentiation, and the capa- bility of neurofibromin to down-regulate p21-ras suggests that the loss of neurofibromin may lead to uncontrolled cell growth and tumor formation.4,40,73 Incidence NF1 is estimated to affect 1 in 3500 individuals.46 Ophthalmologic FEatures Ophthalmologic features of NF1 are listed in Table 6-2. The most common uveal finding in NF1 is the Lisch nodule, which is a melanocytic harmatoma of the iris.63 These harmatomas appear as elevated, smooth, clear to yellowish or brown, gelati- nous, dome-shaped lesions (Fig. 6-1). Lisch nodules are usually multiple, bilateral, and discrete, measuring up to 2 mm in diam- eter. Lubs and associates examined the prevalence of Lisch nodules in children. Lisch nodules were found in only 5% of NF1 chapter 6: neurocutaneous syndromes 293 in children younger than 3 years of age, 42% among 3- to 4-year- olds, 55% among 5- to 6-year-olds, and in all adults over 21 years of age.66 Lewis and Riccardi reported that Lisch nodules occur in 92% of patients over age 6 years and that the number of Lisch nodules is correlated to the age but not to the number of neu- rofibromas and café au lait spots.59 Thus, Lisch nodules are spe- cific for NF1 but their absence in children does not exclude the diagnosis. Lisch nodules have been described unilaterally in seg- mental neurofibromatosis with findings that include café au lait spots confined to one side or segment of the body. Glaucoma is infrequent but may be present at birth or in early childhood. The most common cause is neurofibromatous infiltration and obstruction of the aqueous drainage pathways.39 Neurofibromatous infiltration of the ciliary body may cause sec- ondary angle closure; neovascular and synechiae closure of the angle may occur. Gluacoma is more likely in the presence of a plexiform neuroma of the ipsilateral upper eyelid. Retinal astrocytic hamartomas occur in NF1, sometimes causing retinal dialysis and traction retinal detachment.29 Other retinal manifestations include combined hamartomas of the retina and retina pigment epithelium (RPE), capillary heman- giomas, choroidal neourofibromas, congenital hypertrophy of the RPE, epiretinal membranes, sectoral retinitis pigmentosa, and myelinated nerve fibers. Choroidal neurofibromas are flat yellow and are typically recognized in the posterior pole as single or multiple lesions; these occur in as many as half of affected patients.29 Conjuncti- val hamartomas are painless lesions appearing as salmon-pink growths on the bulbar surface and may infiltrate corneoscleral limbus.48 Prominent corneal nerves have been reported in up to 25% of patients. Plexiform neuromas typically enlarge the upper eyelid with an S-shaped deformity and ptosis (Fig. 6-2).54 These lesions are difficult to excise satisfactorily because they are invested within the lid structures without defined margins. Regrowth is likely following excision. Proptosis in NF1 signals orbital neurofibroma, optic glioma, or congenital absence/dysplasia of the greater wing of the sphe- noid bone.54 In the latter case, pulsatile proptosis may be evident. Optic pathway gliomas are the predominant central nervous system manifestation of NF1 (Figs. 6-3, 6-4). The natural history of the optic gliomas is an area of intense study and great clinical interest. However, the gliomas in NF1 are probably more indolent than sporadic ones.64 Most develop in the first 6 years 294 handbook of pediatric eye and systemic disease TABLE 6-2. Ocular Manifestations of Neurofibromatosis Type 1 (NF1). 1. Orbital General Plexiform neurofibroma Neurilemoma (schwannoma) Proptosis Displacement of the globe Pulsation of the globe synchronous with pulse but no bruit Enlargement of the optic foramen Underdevelopment of the orbital bones Absence of the greater wing of sphenoid Optic nerve gliomas Neurofibromas and the ciliary nerves Lids Ptosis Café au lait spots Plexiform neuromas Neurofibroma of the eyelid 2. Extraocular Conjunctiva Neurofibroma Nodules Thickening of the conjunctival nerves Sclera Nodular swelling of the ciliary nerves 3. Intraocular Anterior segment Nodular swelling of the corneal nerves Medullated/myelinated corneal nerves Posterior embryotoxin Unilateral keratoconus Buphthalmos Dense abnormal tissue in the chamber angle Defects of Schlemm’s canal Focal iris (Lisch) nodules/hamartomas Neurofibroma of the iris Congenital extropion uveae Iris neovascularization Media Cataract (rare) Anterior subcapsular cataract Neurofibroma of the ciliary body Choroid Choroidal ganglioneuromas Diffuse neurofibroma of choroid Diffuse and nodular involvement neurofibroma Uveal malignant melanoma Choroidal nevi Retina Hamartoma of the retina Café au lait spots on the retina chapter 6: neurocutaneous syndromes 295 TABLE 6-2. (continued). Sectoral retinal pigmentation Sectoral chorioretinal scar Myelinated/medullated nerve fibers Typical peripheral retinoschisis Congenital hypertrophy of the retinal pigmented epithelium (RPE) Optic nerve Optic nerve drusen Hamartoma of the optic disc Primary optic atrophy due to tumor pressure Secondary atrophy due to papilledema Glioma of optic nerve head (rare) 4. Other Extraocular muscle palsies Congenital glaucoma Secondary glaucoma Strabismus of life, and 50% to 75% of patients are asymptomatic at diag- nosis. Presenting symptoms depend on the location: Orbital tumors can cause proptosis, reduction in visual acuity, visual field defects, optic nerve dysfunction, relative afferent pupillary defect, optic disc edema (Fig. 6-2) or optic disc atrophy and stra- bismus. Chiasmal invasion and expansion may lead to hydro- cephalus or, in 39% of patients, precocious puberty.43,78 FIGURE 6-1. Numerous iris hamartomas on a lightly colored iris in a teenage boy. 296 handbook of pediatric eye and systemic disease FIGURE 6-2. Plexiform neuroma is the right upper lid giving an S-shaped configuration in a 5-year-old boy with neurofibromatosis 1 (NF1). FIGURE 6-3. Optic disc edema from optic nerve glioma. chapter 6: neurocutaneous syndromes 297 FIGURE 6-4. Optic glioma: gross pathology. Clinical Assessment Diagnostic criteria for NF1 developed by NIH Consensus Con- ferences are listed in Table 6-3.78 The focus of the clinical assess- ment depends on the age of the patient. In the first 2 years of life, the presence and consequences of plexiform neuromas, glaucoma, sphenoid wing dysplasia, and pseudoarthroses are sought. Psychological assessment becomes important in pre- school children. The possibility of hypertension from renal artery stenosis or pheochromocytoma demands annual meas- urement of blood pressure in all patients. Screening brain MRI scans in children with NF1 will detect optic nerve gliomas in 15%. In comparison to other conditions, the application of DNA testing in NF1 is relatively limited. The inability of present techniques to identify the numerous NF1 mutations limits their application. Even the most sensitive technique detects only 70% of mutations.86 However, because clinical 298 handbook of pediatric eye and systemic disease