Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006

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 neurofibromas and café au lait spots.59 Thus, Lisch nodules are specific for NF1 but their absence in children does not exclude the diagnosis. Lisch nodules have been described unilaterally in segmental 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 secondary 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 hemangiomas, 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 Conjunctival 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 sphenoid 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

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

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 diagnosis. 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 strabismus. Chiasmal invasion and expansion may lead to hydrocephalus or, in 39% of patients, precocious puberty.43,78

FIGURE 6-1. Numerous iris hamartomas on a lightly colored iris in a teenage boy.

FIGURE 6-4. Optic glioma: gross pathology.

Clinical Assessment

Diagnostic criteria for NF1 developed by NIH Consensus Conferences are listed in Table 6-3.78 The focus of the clinical assessment 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 preschool children. The possibility of hypertension from renal artery stenosis or pheochromocytoma demands annual measurement 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

TABLE 6-3. Diagnostic Criteria for Neurofibromatosis Type 1.

Diagnosis requires at least two of the following:

1.More than five café au lait macules

Diameter: 5 mm or larger in prepubescent children, 15 mm or larger in adults

2.More than two neurofibromas (any type) or one plexiform neurofibroma

3.Axillary or inguinal freckling

4.Optic pathway glioma

5.More than two Lisch nodules (see text)

6.Osseous lesions (including sphenoid dysplasia or thinning of long bone cortex) pseudoarthrosis

7.Affected first-degree relative

From Ref. 79, with permission.

diagnosis is usually straightforward, attempts at DNA testing are rarely required.

Systemic Associations

The principal cutaneous lesions are café au lait spots and neurofibromas (diffuse and plexiform); both lesions are found in 95% of patients. Café au lait spots are flat pigmented lesions, often with poorly defined, irregular borders; they are usually present on the trunk but may occur anywhere on the body. Neurofibromas are benign growths of Schawann cells, axons, fibroblasts, and perineural and epithelial cells. Multiple cutaneous neurofibromas develop in 90% of patients. Malignant peripheral nerve sheath tumors can occur in all types of neurofibromas. The overall risk is about 5%. Early diagnosis is hampered by frequent occurrence within preexisting large tumors, making new growth or change difficult to detect.52

Axillary and inguinal freckling is the presence of small café au lait spots in these areas.24 Mild mental retardation and/or learning difficulties appear to affect about 30% to 40%.86

Recent studies show that the learning deficits caused by mutations that inactivate NF1 in mice and humans are caused by disruption of neurofibromin function in the adult brain, a finding with important implications for the development of a treatment for the learning disabilities with NF1.23,116

Other clinical features of NF1 include seizures, headaches, abdominal pain (caused by intestinal neurofibromas), vasculopathy, and possibly reduced platelet function. Some patients with NF1 have a phenotype overlapping Noonan’s syndrome.83

Watson syndrome, a disease characterized by café au lait patches, mental retardation, and pulmonary stenosis, is thought to be allelic to NF1.58

Inheritance

NF1 is transmitted in an autosomal dominant fashion. Approximately 50% of cases are sporadic. There is no known racial, sexual, or ethnic predilection. Near-complete penetrance with variable phenotypic expression within and between families is typical.

Natural History

The majority of affected individuals have a benign course. Neurofibromas rarely develop in children younger than 6 years of age. Neurofibromas may increase in size and number during puberty, pregnancy, and the later decades. The complications of NF1 must be continuously sought and followed throughout the life of the patient.

Treatment

Specific treatments are available for some of the manifestations of NF1.47 Tumors causing functional impairment or which are cosmetically objectionable may be treated with judicious surgical excision or debulking. A sympathetic plastic surgeon or ophthalmic plastic surgeon can benefit patient quality of life greatly. Obvious café au lait spots can be treated by dermabrasion. Neurofibromas causing pruritis can be treatment with ketotifen.93 Optic gliomas in NF1 are treated conservatively, as their growth characteristics are typically most consistent with harmatomas rather than a true malignancy. Figure 6-4 shows an old specimen of optic nerve glioma treated surgically. Currently, aggressive and complicated cases are treated with radiation chemotherapy and surgical excision.64

Glaucoma in NF1 typically requires surgical intervention. Hypertension in NF1 can be caused by renal artery stenosis and pheochromocytomas and are treated with medication or surgery.51 Orthopedic problems can be severe in NF1. Cervical kyphoscoliosis and tibial bowing are the two most common orthopedic problems. Spinal MRI is recommended to locate focal lesions in patients with kyphoscoliosis. Early treatment consists

Etiology

Cytogenetic study of meningiomas showing frequent loss of chromosome 22 provided the clue to the chromosome localization of NF2. The location of the NF2 gene was subsequently confirmed by linkage analysis.32,96 Further studies identified flanking markers but showed no suggestion of locus heterogeneity.77 The identification of a number of germline deletions in NF2 patients facilitated the cloning of the disease gene. The identified mutations include deletion of the entire gene or defective genes, which yields a truncated protein.95 The gene product is called merlin or schwannomin, and is also a tumor supressor.

Ophthalmologic Features

The ocular signs in NF2 are extremely important because of the vision-threatening processes that may occur in affected children, who eventually become deaf. Posterior subcapsular cataracts (PSC) and posterior cortical cataracts occur in as many as 81% of patients.87 These lesions caused significant visual disturbance in 2 of 47 patients with NF2. Retinal hamartomas (including combined pigment epithelium and retinal hamartomas, congenital hypertrophy of retinal pigment epithelium syndrome, and astrocytic hamartomas), epiretinal membranes, and optic disc meningiomas may lead to vision loss.9 Additionally, intracranial tumors may cause papilledema with secondary optic atrophy. Cranial neuropathies can present with ocular motility disturbances.

Clinical Assessment

Clinical examinations continue to be important in the diagnosis of NF2. The diagnostic criteria for NF2 are listed in Table 6- 3. Audiological testing may detect early sensorineural hearing loss, but contrast-enhanced MRI is required to identify or exclude small vestibular schwannomas.10 Previously, at-risk individuals required biannual screening until 10 to 16 years of age and then yearly until 50 years of age. Molecular testing has altered traditional methods of clinical assessment. Molecular testing using linked genetic markers or direct mutational analysis can determine which at-risk individuals do not carry the disease mutation, freeing those patients from repeated clinical testing. Molecular testing permits earlier disease identification, allowing improved treatment.

A careful clinical examination with special attention to a dermatological evaluation, neurological symptomatology and ophthalmologic changes is mandatory. Initial radiographic evaluation of a patient known or suspected to have NF2 should include a cranial MRI scan with and without gadolinium enhancement.30 Small intracanalicular tumors may not be seen on standard 5-mm slice thickness through the posterior fossa. Optimal evaluation includes 3-mm cuts overlapping by 1.5 mm on both axial and coronal postcontrast enhancement views through the internal auditory canals. CT scan may visualize large vestibular schwannomas and meningiomas. Audiological evaluation may show brainstem auditory evoked responds (BAER). Spinal MRI may be helpful in defining asymptomatic tumors. Genetic testing may be done on the basis of linkage when there is more than one affected individual. Because no mutation can be detected in at least one-third of individuals with typical NF2, mutational analysis is not useful for confirming a suspected diagnosis in a proband.

Systemic Associations

The hallmark of NF2 is the presence of bilateral vestibular schwannomas that occur in 85% of patients (Fig. 6-5).31 In addition to the diagnostic criteria given in Table 6-4, if an individual with an affected first-degree relative has either a unilateral eighth nerve mass or any two of the following, then NF2 may be diagnosed: neurofibroma, hemangioma, glioma, schwannoma, or posterior subcapsular cataract or lens capacity at a young age.32,79 Spinal tumors are a frequent manifestation of NF2.74 There are often multiple tumors of variable types. Patients with NF2 tend to develop tumors of the neural coverings or linings such a meningiomas, optic nerve sheath meningiomas, schwannomas, and ependymonas.18 Cutaneous and subcutaneous neurofibromas are found in NF2 but not nearly as frequently or severely as in NF1. Definitive genetic studies are useful in understanding patients with overlapping features of NF1 and NF2. Hearing loss in NF2 typically begins in the teens or twenties. However, it may present as early as the first or as late as the seventh decade. Schwannomas of the CNS are the most common type of tumor in NF2. In addition to the vestibular schwannomas already covered, other cranial nerves, especially the fifth, ninth, and tenth, frequently are involved. Spinal root and intramedullary schwannomas are also seen. Peripheral