Arnold P. Gold
Marc C. Patterson
Tuberous sclerosis complex (TSC) was first described by von Recklinghausen in 1863. In 1880, Bourneville coined the term sclérose tubéreuse for the potato-like lesions in the brain. In 1890, Pringle described the facial nevi, or adenoma sebaceum. Vogt later emphasized the classic triad of seizures, mental retardation, and adenoma sebaceum. TSC is called Pringle disease when there are only dermatologic findings, Bourneville disease when the nervous system is affected, and West syndrome when skin lesions are associated with infantile spasms, hypsarrhythmia, and mental retardation. TSC (MIM 191100) is a progressive genetic disorder characterized by the development in early life of hamartomas, malformations, and congenital tumors of the CNS, skin, and viscera.
GENETICS AND INCIDENCE
Tuberous sclerosis is inherited as an autosomal dominant trait, with a high incidence of sporadic cases and protean clinical expression. These features are attributed to modifier genes, for which the homozygous condition results in a phenotypically normal individual despite the presence of the gene for tuberous sclerosis; when heterozygous, the modifier gene results in a mildly affected patient. The defective gene has been mapped to chromosome 9q34 (TSC1) in some families and to chromosome 16p13.3 (TSC2) in others. TSC1 or TSC2 is mutated in 75% to 85% of TSC patients; no mutation is found in 15%. Hamartin is the gene product for TSC1, and tuberin is the gene product for TSC2. Children with TSC2 mutations tend to have more serious neurologic manifestations when compared with those with TSC1. Both are involved in the regulation of cell growth and are considered tumor suppressor genes. Hamartin and tuberin form a complex that functions as a negative regulator of the insulin receptor/phosphoinositide 3-kinase/S6 kinase pathway, which suppresses tumorigenesis. Understanding this pathway may lead to targeted drug therapies.
Incidence figures are considered minimal because milder varieties are often unrecognized. Autopsy data gave an incidence of 1 in 6,000 people; clinical surveys gave a prevalence between 1 in 10,000 and 1 in 170,000. Although all races are affected, the disease is thought to be uncommon in blacks, and there may be a greater frequency in males. Pulmonary lymphangiomyomatosis, progressive and often fatal, is present only in young women.
PATHOLOGY AND PATHOGENESIS
The pathologic changes are widespread and include lesions in the nervous system, skin, bones, retina, kidney, lungs, and other viscera. Tuberous sclerosis is a migrational disorder. Multiple small nodules often line the ventricles.
TSC is characterized by the presence of hamartias and hamartomas. Hamartias (from the Greek for “tragic flaw”) are malformations in which cells native to a tissue show abnormal architecture and morphology. These lesions do not grow disproportionately for the tissue or organ in which they are found. Hamartomas have the same characteristics, but grow excessively for their site of origin. This old concept is valuable in recognizing the proliferative potential of lesions found in TSC. Thus, cortical tubers are hamartias and do not grow excessively, whereas angiomyolipomas are hamartomas that grow disproportionately and may produce symptoms as a consequence.
The brain is usually normal in size, but variable numbers of hard nodules occur on the surface of the cortex. These nodules are smooth, round, or polygonal and project slightly above the surface of the neighboring cortex. They are white, firm to the touch, and of various sizes. Some involve only a small portion of one convolution; others encompass the convolutions of one whole lobe or a major portion of a hemisphere. In addition, there may be developmental anomalies of the cortical convolutions in the form of pachygyria or microgyria. On sectioning of the hemispheres, sclerotic nodules may be found in the subcortical gray matter, the white matter, and the basal ganglia. The lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity (candle gutterings; Fig. 109.1). Sclerotic nodules are less frequently found in the cerebellum. The brain stem and spinal cord are rarely involved.
Histologically, the nodules are characterized by a cluster of atypical glial cells in the center and giant cells in the periphery. Calcifications are relatively frequent. Other features include heterotopia, vascular hyperplasia (sometimes with actual angiomatous malformations), disturbances in the cortical architecture, and, occasionally, development of subependymal giant cell astrocytomas. Intracranial giant aneurysm and arterial ectasia are uncommon findings.
The skin lesions are multiform and include the characteristic facial nevi (adenoma sebaceum) and patches or plaques of skin fibrosis, typically localized to the frontal area. The facial lesions are not adenomas of the sebaceous glands, but rather, small hamartomas arising from nerve elements of the skin combined with hyperplasia of connective tissue and blood vessels (Fig. 109.2). In late childhood, lesions similar to those on the face are found around or underneath the fingernails and toenails (ungual fibroma). Circumscribed areas of hypomelanosis or depigmented nevi are common in tuberous sclerosis and are often found in infants. Although these depigmented nevi are less specific than the adenoma sebaceum, they are important in raising suspicion for the diagnosis in infants with seizures. Histologically, the skin appears normal except for the loss of melanin, but ultrastructural studies show that melanosomes are small and have reduced content of melanin.
The retinal lesions are small congenital tumors (phakomas) composed of glia, ganglion cells, or fibroblasts. Glioma of the optic nerve has been reported.
Other lesions include cardiac rhabdomyoma; renal angiomyolipoma, renal cysts, and, rarely, renal carcinoma; cystic disease of the lungs and pulmonary lymphangioleiomyomatosis; hepatic angiomas and hamartomas; skeletal abnormalities with localized areas of osteosclerosis in the calvarium, spine, pelvis, and limbs; cystic defects involving the phalanges; and periosteal new bone formation confined to the metacarpals and metatarsals.
SYMPTOMS AND SIGNS
The cardinal features of tuberous sclerosis are skin lesions, convulsive seizures, and mental retardation. The disease is characterized by variability and expressivity of the clinical manifestations and is often age related: the symptomatic neonate with cardiac rhabdomyoma and heart failure; the infant with hypomelanotic macules and infantile spasms; preschool and school-age children with adenoma sebaceum, developmental delay, learning disability or retardation, and seizures; and adults with migrational dermatologic lesions, subungual fibromas, seizures, and often retardation.
CUTANEOUS FINDINGS
Depigmented or hypomelanotic macules are the earliest skin lesion (Fig. 109.3). They are present at birth, persist through life, and may be found only with a Wood lamp examination. The diagnosis is suggested if there are three or more macules measuring 1 cm or more in length. Numerous small macules sometimes resemble confetti or depigmented freckles. Most macules are leaf shaped, resembling the leaf of the European mountain ash tree and sometimes following a dermatomal distribution. Facial adenoma sebaceum (facial angiofibroma) is never present at birth but is clinically evident in more than 90% of affected children by age 4. At first, the facial lesion is the size of a pinhead and red because of the angiomatous component. It is distributed symmetrically on the nose and cheeks in a butterfly distribution. The lesions may involve the forehead and chin but rarely involve the upper lip. They gradually increase in size and become yellowish and glistening. Shagreen patches, connective tissue hamartomas, are also characteristic. Rarely present in infancy, the patches become evident after age 10. Usually found in the lumbosacral region, shagreen patches are yellowish-brown elevated plaques that have the texture of pigskin (from which the name originated in French). Other skin lesions include café au lait spots, small fibromas that may be tiny and resemble coarse gooseflesh, and ungual fibromas that appear after puberty.
Neurologic Findings
Seizures and mental retardation indicate a diffuse encephalopathy. Infantile myoclonic spasms with or without hypsarrhythmia are the characteristic seizures in young infants and, when associated with hypopigmented macules, are diagnostic of tuberous sclerosis. The older child or adult has generalized tonic-clonic or partial complex seizures. There is a close relationship between the onset of seizures at a young age and mental retardation. Mental retardation rarely occurs without clinical seizures, but intellect may be normal, despite seizures. Other than delayed acquisition of developmental milestones, intellectual impairment, or nonspecific language or coordinative deficiencies, the formal neurologic examination is typically nonfocal. TSC is a major cause of autism which is related to cortical and subcortical dysfunction.
Hamartomas of the retina or optic nerve are observed in about 50% of patients. Two types of re tinal lesions are seen on fundoscopy: first, the easily recognized calcified hamartoma near or at the disc with an elevated multinodular lesion that resembles mulberries, grains of tapioca, or salmon eggs (Fig. 109.4), and second, the less distinct, relatively flat, smooth-surfaced, white or salmon-colored, circular or oval lesion located peripherally in the retina (Fig. 109.5). Nonretinal lesions may range from the specific depigmented lesion of the iris (Fig. 109.6) to nonspecific, nonparalytic strabismus; optic atrophy; visual-field defects; or cataracts.
Visceral and Skeletal Findings
Renal lesions include hamartomas (angiomyolipomas) and hamartias (renal cysts). Typically, both are multiple, bilateral, and usually innocuous and silent. Renal angiomyolipomas grow and occasionally bleed, but most can be followed with annual CT scans. Renal cell carcinoma is a rare complication in the older child or adult. In one series, there was a 50% incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. Often asymptomatic, this cardiac tumor may be symptomatic at any age and in infancy can result in death.
Pulmonary hamartomas consisting of multifocal alveolar hyperplasia associated with cystic lymphangioleiomyomatosis occur in fewer than 1% of patients. These become symptomatic (often with a spontaneous pneumothorax) in women in the third or fourth decade and are progressive, often leading to death. Hamartomatous hemangiomas of the spleen and racemose angiomas of the liver are rare and usually asymptomatic. Sclerotic lesions of the calvarium and cystic lesions of the metacarpals and phalanges are asymptomatic. Enamel pitting of the deciduous teeth may aid in diagnosis.
Unless renal lesions are present, routine laboratory studies are normal. Renal angiomyolipomas are usually asymptomatic and rarely cause gross hematuria, but they may show albuminuria and microscopic hematuria. Sonography (Fig. 109.7), angiography, and CT are often diagnostic. Multiple or diffuse renal cysts may be associated with albuminuria or azotemia and hypertension. Intravenous pyelography is diagnostic.
Chest radiographs may reveal pulmonary lesions or rhabdomyoma with cardiomegaly. ECG findings are variable, but the echocardiogram is diagnostic.
Skull radiographs usually reveal small calcifications within the substance of the cerebrum (Fig. 109.8). The CSF is normal, except when a large intracerebral tumor is present. The EEG is often abnormal, especially in patients with clinical seizures. Abnormalities include slow-wave activity and epileptiform discharges such as hypsarrhythmia, focal or multifocal spike or sharp-wave discharges, and generalized spike-and-wave discharges. CT is diagnostic when calcified subependymal nodules encroach on the lateral ventricle (often in the region of the foramen of Monro); there may also be calcified cortical or cerebellar nodules (Fig. 109.9). A few nodules appear isodense on CT and are better visualized on MRI. Fluidattenuated inversion recovery (FLAIR) provides more accurate delineation of cortical and subcortical tubers. Calcified periventricular and cortical lesions have been visualized shortly after birth. The number of cortical tubers often correlates with the severity of cortical dysfunction. There is enough variation in clinical outcome that prognosis cannot be based on cortical tuber count alone. PET often reveals hypometabolic regions that are not noted on MRI, indicating a more extensive disturbance of cerebral function.
Diagnostic Criteria (2 majors or one major plus one minor criteria)
DIAGNOSIS
Clinical diagnosis is possible at most ages. In infancy, three or more characteristic depigmented cutaneous lesions suggest the diagnosis, and this is reinforced in the presence of infantile myoclonic spasms. In the older child or adult, the diagnosis is made by the triad of tuberous sclerosis: facial adenoma sebaceum, epilepsy, and mental retardation. Retinal or visceral lesions may be diagnostic. The disease, however, is noted for the protean manifestations, and the family history may be invaluable in establishing the diagnosis, which is often reinforced by CT or MRI lesions. Internatal diagnosis of TSC by fetal ultrasound and MRI is suggested by the presence of a cardiac rhabdomyoma and cortical tubers. Prenatal diagnosis is available for both TSC1 and TSC2.
The differential diagnosis includes other neurocutaneous syndromes that are differentiated by their characteristic skin lesions. Multisystem involvement may complicate the diagnosis of tuberous sclerosis. The National Tuberous Sclerosis Association has developed a classification of diagnostic criteria (Table 109.1), and the Tuberous Sclerosis Complex Consensus Conference (Table 109.2) provided an additional classification.
COURSE AND PROGNOSIS
Mild or solely cutaneous involvement often follows a static course, whereas patients with the full-blown syndrome have a progressive course with increasing seizures and dementia. The child with infantile myoclonic spasms is at great risk of later intellectual deficit. Brain tumor, status epilepticus, renal insufficiency, cardiac failure, or progressive pulmonary impairment can lead to death.
TREATMENT
There is no specific treatment. The cutaneous lesions do not compromise function, but cosmetic surgery may be indicated for facial adenoma sebaceum or large shagreen patches. Infantile myoclonic spasms respond to corticosteroid or corticotropin therapy; currently, vigabatrin is the drug of choice. Focal and generalized seizures are treated with anticonvulsants. Patients with unilateral seizures and minimal developmental delay may experience long-term seizure control following surgical resection of epileptogenic tubers. Oral rapamycin has been shown to cause regression of astrocytomas associated with TSC and may eventually be an alternative to operative therapy. Progressive cystic renal disease often responds to surgical decompression, but with renal failure, dialysis or renal transplantation may be necessary. Intramural cardiac rhabdomyoma and complicating congestive heart failure are managed medically with cardiotonics, diuretics, and salt restriction. Whole obstructive intracavity tumors and congestive heart failure require surgical extirpation of the tumor. Progressive pulmonary involvement is an indication for respiratory therapy, but response is poor and most patients die a few years after the onset of this complication.
