A French physician more than 100 years ago first identified a disorder-once known as epiloia or Bourneville’s disease. Today it’s known as Tuberous sclerosis also called tuberous sclerosis complex (TSC). TSC is a rare, multi-system genetic disease
that causes benign tumors to grow in the brain and on other vital organs such as kidneys, heart, eyes, lungs , and the skin. It commonly affects the central nervous system and results in a combination of symptoms including seizures, developmental delay, behavioral problems, skin abnormalities, and kidney disease.
I will look at the following:
1. Clinical manifestations
3. Genetics of TSC
4. Signs and symptoms
5. Psychopharmacology in children with TS
The manifestation of TSC is a disease that affects multiple organs such as skin, kidneys, brain, heart, eyes, lungs, teeth as well as other organ systems. However in most individuals the disease affects only some of the organs. TSC may present at birth, but signs of the disorder may take some time to develop. At least two children born each year will have TSC. Current estimates place TSC affected births at one in 6,000, nearly 1 million people worldwide and, approximately 50,000 in the Untied States. As a result, TSC is frequently unrecognized and misdiagnosed for years. The severity of TSC can range from mild skin abnormalities to, in severe cases, mental retardation and renal failure. Many TSC manifestations also develop later in life. Most individuals who are mildly affected lead active and productive lives. TSC is a life long disease and individuals should receive continuous follow-up care.
In most cases the first clue to recognizing TSC is the presence of seizures or delayed development. In other cases the first sign might be white patched on the skin. Careful clinical exam in combination with CT or MRI of the brain may show tubers in the brain, and an ultra sound of the heart, liver, kidney scan show tumors there In July 1998 the Tuberous Sclerosis Alliance, convened a consensus conference of international experts to review the literature and the status of knowledge and research about TSC. One of the consensus panels developed a revised scheme for the TSC diagnostic criteria based on new clinical and molecular genetic studies. The new diagnostic criteria eliminated any single finding as specifically distinctive or characteristic of the disorder. Cortical tubers were believed to be pathognomonic of TSC. Evidence now suggests that radio graphic brain imaging and histologic studies are unable to distinguish these tubers from isolated cortical dysplasia. Subependymal giant cell astrocytomas and subependymal nodules can be distinguished from cortical tubers and from each other. The two subependymal lesions have a histologic and radiographic appearance that differs from the cortical tuber, whereas the giant cell astrocytomas is the only on that tends to enlarge. An important tool in diagnosing is its dermatologic manifestation, which comprises four major and one minor feature of TSC. Hypomelanotic macules are considered a new grouping, whereas the histologically similar forehead plaque, facial angiofibroma, and renal or other retinal hamartomas, are considered to major features used in diagnosis. Liver, spleen, rectal, or other lesions preferably
Histologically confirmed hamartomatous lesions constitute minor features.
TSC is caused by defects, or mutations, on two genes-TSC1 and TSC2. Only one gene needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. Scientists believe these proteins act as tumor growth suppressors, agents that regulate cell proliferation.
Some individuals may inherit the disorder from a parent; most cases occur as spontaneous mutations. In other cases, TSC is an autosomal dominates disorder. Which means only one parent needs to have the gene, and each child has a 50% chance of developing the disorder. Some individuals acquire TSC through gonadal mosaicism. Approximately 33%, or 1/3, of the people with TSC inherits it from a parent who has it.
Signs of discovery vary depending on which system and which organs are involved. Kidney problems such as cysts and
angioyolipomas occur in an estimated 40 to 80 percent of individuals with TSC, usually occurring between ages 20 and 30. Three types of tumors are associated with TSC: cortical tubers, generally form on the surface of the brain, but may also appear in deep areas of the brain; subependymal nodules, which form in the walls of the ventricles the fluid filled cavities of the brain; giant-cell astrocytomas, a type of tumor that can grow and block the flow of fluids within the brain. Cardiac rhabdomyomas are tumors found in the heart of infants and young children. Phakomas are benign tumors found in the eyes, appearing as white patches on the retina.
A wide variety of skin abnormalities can occur such as: hypomelanic macules, which are white or lighter patches of skin appearing anywhere; facial angiofibromas also called adenoma sebaceum, which appear on the face and consist of blood vessels and fibrous tissue; forehead plaques, which are common; shagreen patches, usually found on the lower back or the neck; ungula or subungual fibromas that grow around the toenails and fingernails.
It’s known that children with TS are a higher risk for several different behavioral problems. The most sever is probably autistic disorder, which usually starts by 36 months and often succeeds early onset seizures. In the preschool years another problem that arises is attention-deficit/hyperactivity disorder (ADHD). During adolescence depression, anxiety appears as they try to deal with new demands of maturing and continuing difficulties of chronic medical problems. If medications are given to treat behavioral problems, parents need to be aware of the effects they will have in a child who may have cardiac rhabdomyomas, renal angiomyoplomas or polycystic kidneys, cortical tubers, subependymal nodules. The child with rhabdomyomy may have disturbance in the cardiac rhyme including increased heart rate, complete heart block, junctional ectopic beats, and Wolf-Parkinson-White syndrome. With seizures certain drugs can lower the threshold leading to new seizures; breakthrough of seizures in a child who had controlled; or an increased number of seizures in a child with chronic epilepsy. Renal damage from medication is not likely in most drugs used for behavior. Topiramate has caused renal stones in 1-2% of patients. Lithium and carbamazepine can cause a change in the ability of the kidney to concentrate urine. As in other medical problems it is always best to reach what you are taking before taking it.
There is no cure TSC, although there are a number of treatments for the symptoms. Because TSC is a life long condition, individuals need to regularly monitor by a doctor the best treatments possible. I think children probably suffer the most having to grow up with chronic medical condition with other kids always making fun of you has to really tough on them. However these types of kids are very loving and don’t take much for granted not much of a pay off, but a good one. With the right medication and treatment plans people with TSC might be able to live comfortably. Research is being done to understand the disorder by learning more the TSC1 and the TSC2 genes and the function of the proteins –tuberin and hamartin produced by these genes. Scientists hope knowledge gained from their current research will improve the genetic test for TSC and lead to new avenues of treatment, methods of prevention, and ultimately a cure.
• http://www.rare disease.org
• Tuberous Sclerosis Alliance fact sheet
• Hyman MH, Whittemore VH. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000 May;57(5):662-5. Review. No abstract available. PubMed citation
• Lewis JC, Thomas HV, Murphy KC, Sampson JR. Genotype and psychological phenotype in tuberous sclerosis. J Med Genet. 2004 Mar;41(3):203-7. No abstract available. PubMed citation
• Maria BL, Deidrick KM, Roach ES, Gutmann DH. Tuberous sclerosis complex: pathogenesis, diagnosis, strategies, therapies, and future research directions. J Child Neurol. 2004 Sep;19(9):632-42. No abstract available. PubMed citation
• Narayanan V. Tuberous sclerosis complex: genetics to pathogenesis. Pediatr Neurol. 2003 Nov;29(5):404-9. Review. PubMed citation
• Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004 Sep;19(9):643-9. Review. PubMed citation
• Rose VM. Neurocutaneous syndromes. Mo Med. 2004 Mar-Apr;101(2):112-6. Review. PubMed citation