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Overview

Tuberous sclerosis is a rare multi system genetic disorder that leads to growth of tumors in various areas such as brain,skin,heart,lungs and kidneys. It commonly involves the CNS and causes various symptoms such as seizures,hypotonia,intellectual disability,developmental delay and behavioral disorders. Other associated symptoms of TS depend on the involvement of the organ system.

Causes

TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes 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 growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Inheritance

Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual.

In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or a more severe form of the disorder.

In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent's reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved. In cases of gonadal mosaicism, genetic testing of a blood sample might not reveal the potential for passing the disease to offspring.

Clinical Features

• Infantile spams
• Seizures
• Intellectual Disability
• Developmental Delay
• Behavioural Disorder
  • Higher incidence of autism
• Lesions in the brain
  • Tubers in the convolutions of the white matter.
  • Sub Ependymal Giant Cell Astrocytoma
  • Sub Ependymal Nodules
• Rhabdomyosarcoma
• Skin Lesion
  • Ash Leaf spots
  • Shagreen Patches
  • Facial sebaceous adenomas
  • Forehead plaques
• Hamartomas in nail beds
• Renal
  • Cysts
  • Angiomyolipomas
• Lungs
  • Lymphangioleiomyomatosis (LAM)
  • Multinodular multifocal pneumocyte hyperplasia (MMPH)

Diagnosis

Diagnosing TSC is based upon clinical criteria. The first clue may be the presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

Diagnosis of the disorder is based on a careful clinical exam in combination with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain—which may show tubers in the brain, and an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. Doctors should carefully examine the skin for the wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions. A small hand-help lamp that uses black light, otherwise known as ultraviolet light, may show hypomelanotic macules which are sometimes hard to see on infants and individuals with pale or fair skin. A doctor experienced in the diagnosis of TSC should evaluate a potential patient.

In infants, TSC may be suspected if the child has cardiac rhabdomyomas at birth or seizures (especially the kind called infantile spasms) in the first six months of life. With a careful examination of the skin and brain, it may be possible to diagnose TSC in a very young infant. However, many children are not diagnosed until later in life when their seizures begin and other symptoms such as facial angiofibromas appear. McCune Albright Syndrome occurs due to mutation in the GNAS gene which leads to constant G- protein activation which leads to overproduction of pituitary hormones.
Thus in addition to precocious puberty ( GnRH independent increase in LH and FSH), MAS can cause an increasein n TSH and GH and ACTH leading to Cushing syndrome..