Tertiary Features

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Hvpomelanotic macules

"Confetti" skin lesions

Renal cysts (radiographical evidenec)

Randomly distributed enamel pits in deciduous or permanent teeth Hamartomatous rectal polyps (histological confirmation) Bone cysts (radiographical evidence)

Pulmonary lymphangiomyomatosis ( radiographical evidence )

Cerebral white matter ' migration tracts" or heterotopias (radiographical evidence) Gingival fibromas

Hamartoma of other organs (histological confirmation) Infantile spasms DEFINITE TSC

One primary feature, two secondary features, or one secondary plus two tertiary features PROBABLE TSC

Either one secondary plus one tertiary feature or three tertiary features SUSPECT TSC

Either one secondary feature or two tertiary features

From Roach ES, Smith M, Hottenlocher P, et al: Report of the diagnostie enteria eommitte'e of the National Tuberous Selerosis Assoeiation. J Child Neurol 1992,7:221.

changes of the skin, nervous system, and other organ systems.

Ihe clinical expression of the disease is dependent on which organs are affected and the extent of their involvement. Seizures, either partial or generalized, are the most common symptom of the disease, and infantile spasms are particularly frequent during the first several years of life. Ihe early onset and severity of the seizure disorder are correlated with the degree of mental abnormality. Mental function is notably variable, however, and about a third of patients have normal intelligence. Some patients develop normally during their early years only to experience a deterioration in mental function in the latter part of the first decade.

Ihe most common skin lesion is the hypopigmented macule, which is found in about 90 percent of patients 41 ( ...Fig 32-6 ). According to Fitzpatrick, the most frequent

Figure 32-6 A typical ash leaf-shaped area of hypopigmentatioarrows) found in most patients with tuberous sclerosis.

shape is the polygonal or "thumb-print" lesion, followed by the "ash leaf" spot, and finally by a "confetti-like" structure, characterized by myriads of tiny white macules.[42] Adenoma sebaceum, which is an angiofibromatous lesion, had been generally considered the most common skin change in tuberous sclerosis, but the lesions occur in only 50 percent of patients ( . Fig 32.-Z ). The lesions appear in patches or in a butterfly distribution about the nose, cheeks, and chin. They are rarely apparent at birth, are usually first observed between the ages of 1 and 4 years, and tend to enlarge over time. Other skin changes include the "shagreen" patch (a "leathery" plaque), which is usually found over the lumbosacral or gluteal region, cafe au lait spots, fibromas, and angiomas. Subungual or periungual fibromas (Koenen's tumors) are found in about 20 percent of patients and affect the toes more commonly than the fingers. Ihese lesions are usually first noted during adolescence. Gingival fibromas also can occur as well as pitting of the dental enamel.

Retinal tumors, which seldom affect vision, can occur and are thought to be astrocytic hamartomas. They are nodular or mulberry-like in configuration and may be solitary or multiple; they tend to calcify. Other associated ocular findings include gray-yellow glial patches, and iridic hypomelanotic spots, cataracts, and colobomas of the iris, lens, and choroid. Renal tumors occur in about half of patients with ISC and are primarily renal cysts or renal angiomyolipomas. Ihese tumors can occur separately or in combination, and they are typically multiple, involving both kidneys. Although they can be symptomatic because of renal enlargement, they are usually indolent. Angiomyolipomas are also thought to be benign, yet they may result in hemorrhage and can cause serious morbidity or mortality. Early onset and severe hypertension can occur in patients with numerous renal cysts, and it has been suggested that patients with ISC have an increased risk of renal cell carcinoma. Cardiac rhabdomyomas are present in about half of patients and can be solitary, multiple, or infiltrative, diffusely affecting the myocardium. Newer techniques of echocardiography have facilitated early recognition of this tumor.

Ihe lungs can also be affected in patients with ISC; they demonstrate multicystic lesions that have been shown to be similar pathologically to lymphangiomyomatosis.[43] Pulmonary abnormalities occur almost entirely in females, presenting as dyspnea, spontaneous pneumothorax, and pulmonary hypertension. Endocrine abnormalities have also been reported.

Differential Diagnosis. Ihe clinical features of ISC just described are characteristic, and although other neurocutaneous syndromes may have some similar features, it is rarely difficult to make the correct diagnosis. Infants who show developmental delay and intracranial calcifications and seizures should be evaluated for the possible presence of intrauterine infections such as toxoplasmosis and cytomegalovirus, among others.

Evaluation. Visualization of these hypomelanotic macules is enhanced by using a Wood light because melanin absorbs light of that frequency (360 nm), and areas deficient in melanin are visually accentuated. Imaging studies of affected patients can be effectively used to assist in diagnosis. Intracranial calcifications, commonly found in the region of the foramen of Monro or the periventricular region, are present in about 60 percent of skull radiographs in these patients. CI may demonstrate cerebral hamartomas, subependymal nodules, ventriculomegaly, and areas of demyelination. Ihe calcified subependymal nodule (the tuber) is the most reliable finding on CI head scans, but periventricular calcifications can also be observed in patients with toxoplasmosis, cytomegalic inclusion disease, and Fahr's syndrome.[44] MRI demonstrates with greater specificity not only the uncalcified subependymal nodules but also the distortion of the normal cerebral cytoarchitecture. y

Other characteristic radiographic abnormalities include

Figure 32-7 Adenoma sebaceum are angiofibromatosus lesions found about the nose, the nasolabial folds, or chin, and are present in about 50 percent of patients with tuberous sclerosis.

cystic changes of the phalanges and metacarpals, sclerotic areas in the long bones, and areas of increased or decreased bone density in the skull. Renal changes can be demonstrated by CI, MRI, or renal angiography, and the presence of a cardiac tumor is readily demonstrated by echocardiography. Patients with rare pulmonary involvement show a fine reticular infiltrate or multicystic changes on chest radiographs. Electroencephalography and examination of the cerebrospinal fluid are of little help in establishing the diagnosis.

Ihe tubers can be located anywhere in the cerebral hemisphere but are commonly found in the cortical gyri. Smaller nodules can be located in the region of the sulcus terminalis or the basal ganglia, protruding into the ventricle. Those tubers situated in the region of the foramen of Monro or the aqueduct of Sylvius may become large enough to obstruct the normal flow of cerebrospinal fluid, resulting in hydrocephalus. Ihe tuber is characterized pathologically by a decreased number of neurons with large, bizarre, and sometimes vacuolated "monster" neurons. A proliferation of fibrillary astrocytes, areas of demyelination, and abnormalities of cortical cytoarchitectonics are seen. Some vessel walls may show hyaline degeneration. Ihe subependymal nodules are fibrocellular with round or oval cells and whorls of fibrillary glial tissue. Calcium and amyloid deposits may be present within the tuber or the subependymal nodule; cerebellar calcification rarely occurs.

Management. Convulsive disorders are treated by the administration of standard anticonvulsant medications; control, however, cannot be ensured. Ihe individual ISC patient with recurrent partial seizures may experience some improvement with the excision of carefully identified epileptogenic foci. No specific treatment is available for the angiofibromatous lesions of adenoma sebaceum. They may be surgically removed if subject to repeated irritation or trauma, as is true, for example, of lesions obstructing the nares. Patients with ISC must not only receive careful medical management but should also be evaluated and followed by social workers and psychologists. Genetic counseling for the family is mandatory.

VON HIPPEL-LINDAU DISEASE

Von Hippel-Lindau disease, which is inherited as an autosomal dominant trait, is characterized by hemangioblastomas of the retina and cerebellum. Von Hippel thought the retinal lesion was a hemangioblastoma, but he labeled it angiomatosis retinae.[46] Lindau first recognized the association between the retinal and cerebellar hemangioblastomas; moreover, he was aware that patients could have other lesions, including spinal cord angiomas and cystic tumors of the pancreas, liver, and epididymis.^ Linkage analysis has localized the gene defect to chromosome 3p25-26. y , y Additional findings include cysts of the pancreas, liver, and spleen as well as renal tumors. Compared with other neurocutaneous disorders, skin lesions are not associated with the disease. y

The retinal hemangioblastoma is one of the earliest manifestations of the disease, and although it is reported to occur in childhood, it is usually found during or after the third decade. Aneurysmal dilation of the peripheral retinal vessels appears to be the earliest characteristic feature of the lesion, but, later, tortuous vessels marked by an afferent arteriole and venule leading to a raised retinal lesion appear. Some retinal lesions are small and easily overlooked. The retinal abnormalities have been divided into three stages: first, a pinkish red vascular lesion found in the midperipheral retina with visible "feeder" vessels and variable exudate; second, a pale gray lesion in which the feeder vessels can be observed on fluorescein retinal angiography; and third, retinal vascular lesions that are similar to diabetic microaneurysms but have no retinal vascular connections. These peripheral retinal lesions may not result in any visual impairment; however, if the lesion involves the macula or optic disc, progressive visual loss can occur.

The diagnosis of a cerebellar hemangioblastoma is usually made during the third or fourth decade, but there are reports of its occurrence before puberty. The presenting signs and symptoms are those of cerebellar dysfunction and increased intracranial pressure. These tumors may also involve the medulla and spinal cord, and about 80 percent of patients have an associated syringomyelia. Supratentorial hemangioblastomas, while uncommon, have been reported in the region of the pituitary gland and the third ventricle as well as the cerebral hemispheres.

Associated renal lesions are found in von Hippel-Lindau disease and include benign cysts, angiomas, and hypernephromas, which are common and are a significant cause of morbidity and mortality in the disease. Benign cysts may also be found in the pancreas, adrenal gland, and epididymis; they are usually asymptomatic. There is an increased frequency of pheochromocytomas in patients with von Hippel-Lindau disease. y Retinal hemangioblastomas are recognized by careful ophthalmoscopy, and fluorescein angiography can show the vascular characteristics of the lesion. CT and MRI demonstrate the lesions of the cerebellum and spinal cord. The intra-abdominal lesions are shown by abdominal CT and ultrasonography.

Some retinal lesions are recognized because of visual impairment and retinal detachment. y Obliteration of these lesions has been accomplished with cryocoagulation or photocoagulation. Cerebellar hemangioblastomas are removed surgically in about 90 percent of patients, who have a risk of recurrence of about 15 percent. Small renal tumors should be judiciously removed because the presence of multiple tumors is a possibility. In patients with cystic renal disease, nephrectomy should be considered, followed by dialysis.

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