Introduction The neurocutaneous syndromes or phakomatoses are a heterogeneous group of congenital disorders primarily involving structures derived from the embryological neuroectoderm. All of the syndromes involve the central nervous system (CNS). Peripheral nerves, skin and other organ systems may also be involved. Bourneville's disease or Tuberous sclerosis is the most common neurocutaneous syndrome after neurofibromatosis. Dermatologic manifestations may be the only clues the family physician has to the diagnosis of the disorder, which is also marked by childhood seizures and mental retardation. Characteristic signs of tuberous sclerosis vary widely in severity and can include hypopigmented "ash-leaf spots," fibrous plaques on the forehead, angiofibromas on the face (adenoma sebaceum), a shagreen patch on the lower back and fibromas of the nails. Computed tomographic scanning or magnetic resonance imaging reveal subependymal nodules or cortical "tubers" in the brain. Associated cardiac, retinal, renal and pulmonary pathology can increase morbidity and mortality. Genetic counseling is helpful but has limited use because of the variation in genetic expression and the frequency of new gene mutations that cause this disorder
Neuropathology The weight of the brain may be normal or moderately reduced. The pattern of convolutions over the cerebral hemispheres is usually normal, but may be altered by the presence of the tubers or sclerotic patches which give the disease its name. These lesions vary in size, seldom exceeding 20mm in diameter. Large, bizarre giant cells may be found in the lesions and sometimes also in the cortex of white matter. Calcification, varying in size from microscopic to massive brain stones, is often present in the tubers. Small subependymal tumor-like nodules are often seen projecting from the walls of the lateral ventricles into their cavities in a manner suggestive of candle guttering. They are also occasionally found in cerebellum or brainstem. They consist of collections of large round or oval cells mingled with fibrillary glial tissue and sometimes show calcification. Giant cell astrocytomas in Tuberous Sclerosis often obstruct the exit of the third ventricle, and present with vomiting, headaches, visual loss, ataxia or behavioral change, and occasionally with worsening of fit control. The retinal phacoma involves mainly the nerve cell layer of the retina.
Presentation A. Neurological (i) Infantile Spasms - A common presentation between 4 -7 months of age, the child having either appeared developmentally normal previously or shown some evidence of delay. Onset of spasms is usually associated with a loss of social responsiveness and marked slowing in subsequent development. (ii) Retinal Phakomas - A raised, mushroom like lesion present either near the optic disc, sometimes overlying it, or more peripherally. Usually symptom less. (iii) Raised Intracranial Pressure - Blockage of one foramen of monro or of the aqueduct of Sylvius by a strategically placed nodule may cause obstruction to the flow of CSF and thus cause obstruction. Rarely these long-standing benign nodules may also undergo malignant transformation. (iv) Psychiatric - More than half of the cases show psychotic (hyperkinetic and aggressive) behavior. Autistic features are also present in most the children with infantile spasms.
B. Cutaneous (i) Adenoma sebaceum - A papular, acneform rash over the butterfly area of the face. This is rarely detectable under the age of 2 years. They are microscopically an overgrowth of sebaceous glands, connective tissue and small blood vessels. (ii) Amelanotic navei - Pale leaf shaped lesions in which pigmentation is absent so that they contrast with the normal surrounding darker skin. In fair colored children they need to be seen with woods lamp before they can be considered absent. Histologically the navei contain melanocytes but despite this little or no melanin is produced, suggesting a metabolic block. (iii) Shagreen Patch - A raised, irregular, rough area of skin usually over the lumbar region. (iv) Periungual Fibroma - A fleshy outgrowth on a finger or toe made up of a mixture of fibrous and angiomatous tissue. (v) Macrodactyly, Cafe au late patches and vascular naevi may also be rarely seen.
C. Visceral (i) Renal - Kidneys are affected in Tuberous Sclerosis more than other viscera, with an estimate frequency of 80%, Polycystic kidney is common finding in tuberous sclerosis. (ii) Cardiac - Birth incidence for children presenting because of the effects of cardiac rhabdomyomas is 1/326,000 and a minimum of 80% have tuberous sclerosis. In a population of patients with tuberous sclerosis a minimum of 60% less than 18 years have cardiac rhabdomyomas. An echocardiogram and magnetic resonance image shows several tumors in the septum and in ventricular walls; histopathology study of the heart confirms the diagnosis. (iii) Pulmonary - Involvement of numerous small cysts is seen more often in males, and may cause pneumothorax.
Genetic Considerations Tuberous Sclerosis is inherited as an autosomal dominant trait, but most cases are considered to be examples of new mutations since neither parent shows any evidence of the disease. Studies have shown that the gene for tuberous sclerosis is on the distal long arm of chromosome 9. This has been named TSCI. An important locus on the proximal side of the polycystic kidney disease type I (PKDI) gene on chromosome 16 has been identified, and designated TSC2. TSC2 (on chromosome 16p13.3) encodes the protein tuberin and TSC1 (on 9q34) encodes hamartin. Tuberin has been immunolocalized to neurons and possibly astrocytes in normal brain and CD/TSC tubers, and is widely expressed in normal viscera; loss of heterozygosity and tissue culture studies suggests it functions as a growth suppressor. The TSC1 gene has been cloned within the last year and hamartin as yet has no well-defined cellular function, though its protein product may also function as a growth suppressor.
Diagnosis A. Clinical At the recent tuberous sclerosis complex consensus conference, the clinical diagnostic criteria for tuberous sclerosis complex were simplified and revised to reflect both new clinical information about tuberous sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for tuberous sclerosis complexes are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for tuberous sclerosis complex. Accordingly, the clinical and radiographic features of tuberous sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for tuberous sclerosis complex of each feature. A definitive diagnosis of tuberous sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with tuberous sclerosis complex, no extended family history, and no clinical features of tuberous sclerosis complex are more likely to have germline mosaicism for tuberous sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of tuberous sclerosis complex after a thorough diagnostic evaluation. B. EEG - The EEG typically shows the gross disturbance known as hypsarrhythmia. C. Imaging - Demonstration of calcified lesions in the subepenymal region or deeper in the brain substance will confirm the diagnosis in many cases with suggestive neurological and cutaneous features. Calcification may be rarely seen on X ray skulls of younger children, but may be detected earlier by the CT scan. Echocardiography will often demonstrate symptom less cardiac rhabdomyomas. Early detection of cardiac tumors is increasing, particularly rhabdomyomas. With fetal echocardiography, more patients should come to attention prenatally. B-color may be useful addition in assessing cardiac tumors, aiding detection and definition of intramural lesions.
Treatment Therapy with conventional anticonvulsant is often disappointing in its results, though nitrazepam, clonazepam or sodium valproate may prove helphul, and good results are reported with the newer drug, vigabatrin. ACTH or steroids - The response to ACTH or steroids is often gratifying, with cessation of attacks and improvement in EEG and development, but ultimate outcome tends to be bad in terms of intelligence level and later problems with epilepsy. Very short and low-dose adrenocorticotropic hormone (ACTH) therapy (i.e. 0.011 mg/kg per dose, 12 times in 20 days) controls the seizures, has been tried as adjuvant therapy. Vigabatrin - The cessation of spasms with vigabatrin has significant improvement of cognition and behavior in children with tuberous sclerosis. Controlling secondary generalization induced by infantile spasms seems to be a key factor for mental development. Infants with cryptogenic spasms have a good response to VGB monotherapy. Vigabatrin is being considered as first-line monotherapy for the treatment of infantile spasms in infants with either a confirmed diagnosis of tuberous sclerosis or those at high risk, i.e., those with a first-degree relative with tuberous sclerosis complex. Paradoxically, in those without tuberous sclerosis complex, vigabatrin might be less efficacious than suggested by studies including patients with tuberous sclerosis complex. When mental retardation is noticed before IS, and MRI is normal, there is no efficacy. In these cases, the best treatment seems to be prolonged corticosteroid therapy associated with vigabatrin. |
