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

Inheritance

NF2 is inherited in an autosomal dominant manner with almost complete penetrance by the age of 60 years.

Natural History and Prognosis

The mean age of first symptoms in the U.K. study32 was 22.6 years (range, 2–52 years) and the median age of diagnosis was 27.6 years (range, 5–66 years). Ten percent of patients presented before the age of 10 years, and nearly all patients eventually developed symptoms related to the vestibular schwannomas, typically progressing to bilateral deafness. The mean age of death in the Evans study was 36.25 years; the mean duration of survival from diagnosis was 15 years.

Treatment

Therapy for vestibular schwannoma and other tumors remains primarily surgical.41,67,82 Close neurological monitoring is mandatory for determining the timing of surgical intervention. Advances in hearing augmentation, such as auditory cochlear implants, may improve the quality of life for many patients. In addition, brainstem implants are now being developed for individuals with no cochlear nerve function.

TUBEROUS SCLEROSIS COMPLEX

History

In 1880, Bourneville described a case of a 15-year-old girl who had had seizures since childhood.8 At autopsy, multiple sclerotic nodules were observed in the cerebral cortex, with similar tumors of the kidney and diffuse hamartomata of other tissues. He recognized the presence of skin lesions in his original case. Although tuberous sclerosis complex (TSC) has become the name used, the eponym Bourneville’s disease is still recognized. It was not until 1908 that Vogt established the classic triad of epilepsy, mental retardation, and adenoma sebaceum of TSC.109

Incidence

The incidence of TSC is estimated at approximately 1 in 10,000 births.57,84

Etiology

TSC is a relatively common neurocutaneous syndrome caused by mutation in either of two genes, TSC1 or TSC2. The TSC1 gene is located at 9q34 and TSC2 is at 16p13.3.88 The TSC1 and TSC2 genes encode novel proteins that have been termed hamartin and tuberin for which the cellular roles are largely unknown. Molecular genetic analysis of constitutional mutation in affected individuals and of somatic mutations in TSCassociated hamartomas has elucidated a tumor suppressor mechanism that underlies the phenotypic manifestations in many organs. It is now estimated that TSC1 and TSC2 each account for about 50% of the cases of TSC. TSC2 mutations are associated with more severe disease compared to TSC1 mutations.25

Ophthalmologic Features

Ocular lesions are shown in Table 6-5. The eye is involved in at least half of TSC patients. Glial hamartomas of the retina are present in 53% of patients.80 Two types of retinal hamartoma have been recognized: (1) a more translucent, soft-appearing, relatively flat lesion usually located in the peripheral fundus and

(2) an elevated, nodular, calcific mulberry lesion. The mulberry lesions are typically located in the posterior pole adjacent to the optic nerve but may be found anywhere in the fundus. An intermediate type may be encountered.80 Most of these lesions remain static. Rarely, vitreous seeding may be associated with vitreous inflammation and hemorrhage. The retinal tumors are generally sparsely vascularized or nonvascularized.89 Visual loss is an exception but may be caused by foveal involvement or continuing growth of nodular lesions. The appearance and has been compared with tapioca grains, fish eggs, or mulberries.

Retinitis pigmentosa has been associated with optic disc hamartomas; however, it is uncertain if any of these patients actually had TSC. Localized hypopigmented lesions of the fundus with ash leaf configurations have been described in TSC. Sectoral pigmentation of the iris has also been reported, along

TABLE 6-5. Ocular Manifestations of Tuberous Sclerosis.

1.Orbital General

Proptosis

Fibrous dysplasia of orbit Lids

Adenoma sebaceum (angiofibroma) Poliosis (hypopigmented lashes) Nevus flammeus

2.Extraocular

Small pedunculated whitish-gray tumors on palpebral conjunctiva Subconjunctival nodules

3.Intraocular Anterior segment

Corneal opacities Lens opacities Cataract

Depigmented sectors of iris Hypopigmented iris spots Coloboma of iris Coloboma of lens Megalocornea (single case)

Posterior embryotoxin (single case) Media

Vitreous often cloudy

Vitreous hemorrhage (from hamartoma) Choroid

Diffuse angiomatosis Coloboma of choroid

Punched-out chorioretinal defects Retina

Retinal mushroom-like tumor of grayish-white color

Yellow-white plagues with small hemorrhages and cystic changes in retina Neurofibrilloma

Neurocystoma Retinal glioneuroma

Glial hamartoma of the retina in 53% of patients Pigmentary changes in the retina

Ash leaf patches

Atypical retinitis proliferans Retinal telangiectasia Retinal angioma

Exophytic retinal astrocytoma Optic nerve

Optic atrophy Papilledema Pseudopapilledema Disc drusen

Glial hamartoma of the optic nerve (ON) anterior to the lamina cribosa (giant drusen)

4.Other

Secondary glaucoma

Glaucoma

Nystagmus

Strabismus

Phthisis bulbi

Progressive external ophthalmoplegia (single case)

with subtler hypopigmented iris spots. Poliosis of the eyelashes is common, present in 18% in one series. The ocular lesions of TSC do not normally interfere with visual function unless a large tumor is situated in the macula. Visual loss, however, may result from intracranial tumors disrupting the visual pathways. Tubers may directly compress the anterior visual pathways or disturb the geniculocalcarine radiations. Tumors in the posterior fossa can produce hydrocephalus with subsequent optic atrophy. Astrocytic hamartomas do not involve the orbital or intracranial portion of the optic nerve or chiasm, in contrast to gliomas in NF1. Orbital tumors are rare, and the incidence of glaucoma is not increased compared to normals. The ocular adnexa may be involved with angiofibromata, forming small salmon-colored nodules in the lid and under the conjunctiva. Lens colobomas with uveal colobomas of the iris have been reported. Isolated cases of progressive external ophthalmoplegia, megalocorneal, and posterior embryotoxin have been described in TSC patients.

Clinical Assessment

Diagnostic criteria for tuberous sclerosis are listed in Table 6-6.94 Because of the variability of disease expression, it is recommended that parents and siblings and first-degree relatives of probands have a clinical evaluation; this should include dermatological examination (including ultraviolet lamp examination in a dark room), examination of the teeth for dental pits, and indirect ophthalmoscopy with dilated pupils to search for retinal astrocystomas. Cranial neuroimaging, cardiac and renal ultrasound, and skeletal surveys should also be done. Examination of the parents and siblings of apparently isolated cases, including ophthalmologic examination, is indicated. Cranial MRI of the patient and parents should be performed. MRI is the neuroimaging modality of choice. Cortical tubers are best imaged with T2 weighting whereas subependymal nodules are better demonstrated with T1 weighting. The cerebellum is involved in less than 15% of patients, and the spinal cord is rarely affected. Giant cell astrocytoma of the brain occurs in 2% of the patients.

The tubers of TSC occur predominantly at the gray–white matter interface; they are characterized by loss of normal cortical cytoarchitecture and the presence of abnormal neurons and glial cells. The subependymal nodules usually line the third ventricle and there are composed of densely segregated and uni-

TABLE 6-6. Diagnostic Criteria for Tuberous Sclerosis.

Major features

1.Facial angiofibromas or forehead plaques

2.Nontraumatic ungual or periungual fibromas

3.More than three hypomelanotic macules

4.Shagreen patch (connective tissue nevus)

5.Multiple retinal hamartomas

6.Cortical tuber

7.Subependymal nodule

8.Subependymal giant cell astrocytoma

9.Cardiac rhabdomyoma

10.Lymphangioleiomyomatosis

11.Renal angiomyolipoma

Minor features

1.Multiple randomly distributed pits in dental enamel

2.Hamartomatous rectal polyps

3.Bone cysts

4.Cerebral white matter “migration tracts”

5.Gingival fibromas

6.Nonrenal hamartoma

7.Retinal achromic patch

8.“Confetti” skin depigmentation

9.Multiple renal cysts

From Ref. 94, with permission.

formally appearing large, irregular cells. The nodules may grow to a size of 3 cm or more, appropriately termed by some subependymal giant cell astrocytoma. Also, some of the lesions may require histological confirmation of the diseases or radiologic confirmation. Next to central nervous system (CNS) hamartomas, renal involvement is the second most common source of morbidity. Regular monitoring for hypertension and renal ultrasounds, performed as frequently as yearly, have been recommended as surveillance measures.94 Renal function should be monitored in those patients with structural renal abnormalities.

Systemic Associations

TSC can involve almost any organ, with propensity for the CNS, eyes, skin, heart, and kidney. Symptoms of TSC generally appear in the first 3 years of life. Infants usually present with seizures or infantile spasms, which carry a worse prognosis.

The CNS is involved in most cases of TSC. Seizures occur in 80% to 90%, and autism, other behavioral abnormalities, and mental retardation in more than 50%.98 Adenoma sebaceum

(angiofibromas) of the skin of the face occur in 83% of cases as small, flesh-colored papules of the malar area of the face; these are the only cutaneous sign in about one-third of patients. Adenoma sebaceum are in fact not tumors of the sebaceous glands but rather angiofibromas, histologically similar lesions that may be present in the subungual and periungual areas. Periungual fibromas are seen in the late teens in 20% of tuberous sclerosis patients and are pathognomonic.82 Approximately twothirds of patients have ash leaf spots, which are hypopigmented melanotic macules; these appear as oval lesions, usually present on the trunk, and may be detected using the Woods lamp. These hypopigmented lesions are usually present at birth and thus are often the earliest neurocutaneous sign of TSC. Unlike the other neurocutaneous disorders, approximately one-fourth of patients have shagreen patches, which are fibrous yellow elevated plaques, usually located in the lumbar region.

Following CNS hamartomas, renal involvement is the second most important source of morbidity. Renal cysts predominate in children and may cause failure and hypertension if large. Multiple vascular angiomyolipomas of the kidneys are usually asymptomatic but can be fatal if hemorrhage occurs. They are detectable by ultrasonography. Multiple cardiac rhabdomyomas in infancy are often asymptomatic but maybe responsible for embolism, cardiac arrythmia, or heart failure.

Inheritance

TSC is transmitted as an autosomal dominant trait with very high and possibly complete penetrance. Some 60% to 70% of cases are sporadic and appear to represent new mutations.

Natural History

Morbidity and mortality in TSC is dictated by the presence or absence of the various features, their severity, and their location. Hamartomas usually become evident in early childhood and may increase at adolescence. Facial nodular lesions are present in 50% of children by 5 years, whereas ash leaf spots or white macules are present at birth or in early infancy in almost all. Six percent of patients develop brain tumors such as periventricular nodules. However, malignant transformation of the periventricular nodules is rare. Seizures, which tend to develop in early childhood, may initially be myoclonic and later grand mal in

type; control may be difficult. An EEG abnormality is found in 87% of patients, in an hypsarrhythmic pattern.99 The seizures and mental defect seem to be related to the extent of the hamartomatous change in the brain. For those with mental deficiency, 100% have seizures, 88% by 5 years of age; in contrast, of those without serious mental deficiency, 69% have seizures, 44% by 5 years of age. Mental deterioration is unusual, except with intractable seizures.

The commonest cause of death is renal disease (renal failure, renal cell carcinoma), and this risk increases with age.50 The next most frequent cause of death is subependymal giant cell astrocytoma. These tumors occur most frequently in the teens. Lymphangiomyomatosis of the lung is a more frequent cause of death in patients older than 40 years. Patients with severe mental handicap often die of status epilepticus and bronchopneumonia. Cardiovascular deaths usually occur in early childhood from cardiac rhabdomyomas and ruptured thoracic aortic aneurysms.

Treatment

Poor intellectual function is associated with early onset and intractability of seizures, and particularly with infantile spasms. Urgent control of generalized seizures in an infant or young child with TSC is a priority. Vigabatrin is widely used in Europe and has proven to be the most effective drug for treatment of infantile spasms in TSC. It has been recommended that treatment be continued for at least 3 years in patients who become seizure free. Vigabatrin has been associated with visual field defects, and visual fields should be monitored where possible. Carbamazepin is frequently used in the treatment of focal seizures in older children and adults, but may precipitate the recurrence of infantile spasms in very young patients.

Medically uncontrollable seizures call for neurosurgical assessment. However, only a small minority of patients will be found to have sufficiently focal epileptogenic foci to be good candidates for epilepsy surgery. Giant cell astrocystomas are histologically benign, but locally invasive, tumors that develop in approximately 6% of patients, usually in childhood and early adult life. They are often located near the foramen of Munro, leading to hydrocephalus. Recognition of raised intracranial pressure is frequently delayed in patients with intellectual disability. Therefore, some authors have suggested regular neuroradiologic surveillance. Developmental and behavioral problems

are a major concern for the families of many patients with TSC. Early recognition facilitates appropriate referral to educational, psychological, and social agencies. Deterioration in development or behavior should prompt assessment to exclude underlining medical problems including brain tumor, subclinical epilepsy, pain from renal disease, and side effects of antiepileptic medications.

Vascular facial angiofibromas can be effectively treated using a dye laser or VerPulse laser. Argon laser treatment appears to carry a high risk of causing hypopigmentation. Skin-resur- facing lasers, such as the ultrapulse CO2 or erbium/YAG, are required for more fibrotic lesions. Regular monitoring for hypertension and yearly renal ultrasounds are recommended as surveillance measures. Renal function should be monitored in those patients with structural renal abnormalities. Large (greater than 3.5 cm) angiomyolipomas are more likely to hemorrhage than smaller lesions, but absolute criteria for intervention in the asystemic patient have not been agreed upon.

Those patients with polycystic kidney disease caused by contiguous deletion of the TSC2 and PKD1 gene are at high risk of renal failure. Respiratory symptoms, particularly in the postpubertal female patient, should prompt investigation for lymphangioleiomomatosis by computerized tomography of the chest and pulmonary function testing. Echocardiography for the detection of cardiac rhabdomyomas may prove helpful diagnostically in the infant with suspected TSC. Routine follow-up is not required in the asymptomatic patient, and surgical resection of cardiac rhabdomyomas is very rarely indicated. The possibility of arrhythmia masquerading as a seizure disorder should be considered in patients with unexplained loss of consciousness.

VON HIPPEL–LINDAU DISEASE

Historical Perspective

von Hippel–Lindau’s eponymous name originates from the contributions made by Eugene von Hippel (1904)110 and Arvid Lindau (1926).61 von Hippel studied the retinal lesions, concluded that they were hemangioblastomas and coined the term “angiomatosis retinae.” Lindau, in a study of cerebellar cysts, concluded that most were associated with an angioblastic tumors of the CNS, retina, and kidneys.

Incidence

The incidence of von Hippel–Lindau (VHL) disease is 1 in approximately 40,000 to 53,000 of the general population.68

Etiology

VHL is a classic heritable tumor suppressor gene syndrome predisposing affected individuals to hemangioblastomas of the retina and CNS, renal cell carcinomas, pheochromocytomas, and renal, pancreatic, and epididymis cysts.62 The gene for VHL disease was identified in 1993, 5 years after its localization to chromosome 3p25–3p26. The cloned coding sequence of VHL gene is represented in three exons with a predicted open reading frame of 213 amino acids. Molecular genetic studies of germ line mutations in VHL kindred have detected mutations in 70% to 75% of affected patients. Approximately 20% of patients have germ line deletions. Intragenic mutations can be detected in a further 50% of patients, almost half of which are missense mutations. Amino acid substitutions at codon 167 occur in up to 10% of patients and are associated with a high risk of pheochromocytoma and renal cell carcinoma. Kindreds with a missense mutation at codon 98 appear to have a high incidence of pheochromocytoma and a low incidence of renal cell carcinoma. In patients with germ line deletions, insertions, or nonsense mutations, the risk of pheochromocytoma is low (however, most VHL patients with pheochromocytoma have missense mutations). The VHL protein may be a nuclear protein, possibly with some capability of moving between the nucleus and cytosol. It may function by forming specific multiprotein complexes in the cytosol. Furthermore, it may act as a controller of the cellular transcription factor, elongin, which activates transcription elongation.62

Ophthalmic Features

Retinal hemangioblastomas (retinal angiomas or hemangiomas) (Fig. 6-6) are the most common presenting findings in patients with VHL disease.44 The consequences of these lesions occur throughout the eye (Table 6-7). The mean age of diagnosis of retinal hemangioblastomas is VHL disease is 25 years.71 Between 25% and 80% of patients with retinal hemangioblastomas will have VHL disease.70 All patients with a retinal hemangioblastoma