Tuberous sclerosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

Tuberous sclerosis complex (TSC), is a rare autosomal dominant congenital disorder that affects multiple organ systems and is characterized by an abnormal growth of ectodermal and mesodermal cells that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin.

Tuberous Sclerosis was described as a specific disease in the 19th century, being initially referred to adenoma sebaceum, epiloia, Pringle’s disease or Bourneville’s disease. In 1862, von Recklinghausen reported a tumor of the heart found in a newborn during autopsy, and by that he is credited to be the first that described the microscopic appearance of tuberous sclerosis. Bourneville in 1880, a French neurologist, described the case of a girl who presented at the age of 3 with facial eruption and died at 15 years of age due to epilepsy, which complicated with pneumonia and inanition. He found brain and kidney tumors on the autopsy which were correctly believed to be the cause of her seizures and mental retardation.

There is no established system for the classification of tuberous sclerosis.

Patients with tuberous sclerosis have loss-of-function germline mutations in both alleles of the following tumor suppressor genes: TSC1 or TSC2. One third of the mutations is inherited, two thirds are de novo mutations. The mutations causes the loss of one allele, but as long as the second one remains intact, the cell won’t present any metabolic change. When there is a second TSC1 or TSC2 mutation, which typically occurs in multiple cells over a person’s lifetime, then the disease starts to manifest (fitting the “two-hit” tumor-suppressor gene model, with the germline mutation inactivating one gene and then a somatic event inactivating the remaining other one). TSC1 codes for a protein called hamartin, and TSC2 codes for a protein called tuberin. They belong to a protein complex that inhibits the mammalian target of rapamycin (mTOR) complex 1, which regulates cell growth.

Loss of function mutation of the genes TSC1 and TSC2 which are responsible for the production of hamartin and tuberin. These proteins regulate the cell cycle. Damage to this pathway leads to a very variable presentation of benign tumors in multiple systems.

TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson’s “two hit” hypothesis. That is, a second random mutation must occur before a tumor can develop.

Tuberous sclerosis must be differentiated from other diseases that cause myxoma or other benign tumors and/or seizures, such as Sturge-Weber, hypomelanosis of Ito, Birt-Hogg-Dube syndrome, multiple endocrine neoplasia and various seizures disorders.

Tuberous sclerosis complex affects about 1 in 6,000 people, occurring in all races and ethnic groups, and in both genders. Prior to the invention of CT scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower and the disease associated with those people diagnosed clinically with learning disability, seizures, and facial angiofibroma. Whilst still regarded as a rare disease, TSC is common when compared to many other genetic diseases, with at least 1 million individuals worldwide.

There are no established environmental risk factors for tuberous sclerosis. One third of the cases are familial, so family history can be a risk factor for the disease.

As it is a rare disease, screening is not recommended.

Symptoms develop in almost all patients with TSC and include ungual fibromas, facial angiofibromas (may demand treatment and may worsen with UV exposure), shagreen patches (oval-shaped lesions, generally skin-colored but can be sometimes pigmented, may be crinkled or smooth), focal hypopigmented macules (ash-leaf spots), dental enamel pits (present in 100% of the patients), oral fibromas, retinal astrocytic hamartomas (tumors of the retinal nerve), retinal achromic patches (light or dark spots on the eye).

TSC leads to the formation of renal angiomyolipomas (present in 60-80% of the TSC patients), which are commonly multiple and bilateral. Angiomyolipomas larger than 4 cm are at risk for potentially catastrophic hemorrhage either spontaneously or with minimal trauma. Patients may also develop epithelial cysts, polycystic kidney disease and renal-cell carcinomas.

Lymphangiomyomatosis is a proliferation of smooth-muscle cells that may result in cystic changes in the lungs. Diagnosed mostly during early adulthood, may cause pneumothorax. Multifocal micronodular pneumocyte hyperplasia can occur in both men and women and are mostly asymptomatic.

TSC may cause epilepsy, which is the most common neurological presentation occurring in 70-80% of patients and may complicate with infantile spasms, a severe form of epileptic syndrome. Neuropsychiatric disorders are present in two-thirds of the patients and anxiety is one of the most common presentations. Autism is one possible manifestation and is especially associated with cerebral cortical tubers.

Rhabdomyomas may be present, being intramural or intracavitary in its distribution along the myocardium. May be detected in utero on fetuses and is associated with cardiac failure. Often disappear spontaneously in later life.

TSC can be first diagnosed at any stage of life and it is diagnosed if a set of diagnostic criteria are met. If a case meets the clinical diagnostic criteria, then it is performed a genetic molecular testing which is seem mostly as corroborative. The latest diagnostic criteria was developed by the 2012 International Tuberous Sclerosis Complex Consensus Conference.

The most common symptoms of tuberous sclerosis are due to the growth of the already disclosed benign tumors. Tumors in the CSN may cause epilepsy, autism and children may also present with cognitive disabilities. Tumors in the kidneys may compromise renal function and metastasize to the lungs, which in most cases is asymptomatic.

Skin lesions are present and they are usually remarkable for dental enamel pits (present in 100% of the patients), hypomelanotic macules, shagreen patches, and forehead plaques.

There are no typical diagnostic laboratory findings associated with tuberous sclerosis. Patients may present with elevated BUN or creatinine if their renal angiomyolipomas compromise renal function or if they also present with autosomal dominant polycystic kidney disease.

There are no ECG findings associated with tuberous sclerosis.

There are no typical x-ray findings associated with tuberous sclerosis, but patients may present with pneumothorax and/or chylous pleural effusions due if they develop lymphangioleiomyomatosis.

Echocardiography/ultrasound may be helpful raising the suspicion of tuberous sclerosis. Echocardiographs can detect cardiac rhabdomyomas, present in more than 80% of the children with TSC. Ultrasound can detect hepatic angiomyolipomas, renal angiomyolipomas (present in 55-75% of patients) and renal cysts (present in 18-55% of the patients).

CT scan may be helpful in the diagnosis of tuberous sclerosis. It can diagnose cortical or subependymal tubers and white matter abnormalities, subependymal hamartomas, subependymal giant cell astrocytomas, renal angiomyolipomas, renal cysts, renal cell carcinoma (associated with tuberous sclerosis), retroperitoneal lymphangiomyomatosis, gastrointestinal polyps, pancreatic neuroendocrine tumors, lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia and cardiac rhabdomyomas.

MRI may be helpful in the diagnosis of tuberous sclerosis as it can find the same abnormalities found on CT scan which are described above, some of them with much more detail, but it is especially useful for evaluating white matter changes seen in the disease.

There are no other imaging findings associated with tuberous sclerosis.

Genetic testing may be helpful in the diagnosis of tuberous sclerosis but some patients may not have detectable genetic mutations on the test and still have the disease. It is considered to be a corroborative test.

Treatment with mTOR inhibitors may be indicated for subependymal giant cell astrocytomas, asymptomatic angiomyolipomas or lymphangioleiomyomatosis. Depending on the size, location and symptoms, surgery can be required to treat subependymal giant cell astrocytomas, and, should angiomyolipomas bleed, the best treatment is embolisation. Epilepsy should be managed with vigabatrin and adrenocorticotropic hormone.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

Tuberous sclerosis is a disease first described in the 19th century. The brain changes were hypothesized to be the cause of the epilepsy and mental retardation only in 1880.

• Tuberous Sclerosis was described as a specific disease in the 19th century, being initially referred to adenoma sebaceum, epiloia, Pringle’s disease or Bourneville’s disease.
• Rayer, a French dermatologist, was the one to first describe the disease and the fibrovascular papules that characterize it, making illustrations of it.
• In 1850 the first written report of tuberous sclerosis appeared in “Vitiligoidea”, published by Addison and Gull. It was not recognized as a distinct disease but was classified as “vitiligoidea tuberosa”.
• In 1862, von Recklinghausen reported a tumor of the heart found in a newborn during autopsy, and by that he is credited to be the first that described the microscopic appearance of tuberous sclerosis.
• Bourneville in 1880, a French neurologist, described the case of a girl who presented at the age of 3 with facial eruption and died at 15 years of age due to epilepsy, which complicated with pneumonia and inanition. He found brain and kidney tumors on the autopsy which were correctly believed to be the cause of her seizures and mental retardation.
• In 1911, E. B. Sherlock, superintendent of Belmont Asylum of Idiots, London, coined the word “epiloia” that indicated a clinical triad of epilepsy, low intelligence and adenoma sebaceum.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

There is no established system for the classification of tuberous sclerosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

Hamartin and tuberin, which are encoded by TSC1 and TSC2 genes respectively, function as a complex which is involved in the control of cell growth and cell division. Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors.

• Patients with tuberous sclerosis have loss-of-function germline mutations in one of the alleles of the following tumor suppressor genes: TSC1 or TSC2.
• One third of the mutations is inherited, two thirds are de novo mutations. The mutations causes the loss of one allele, but as long as the second one remains intact, the cell won’t present any metabolic change.
• When there is a second TSC1 or TSC2 mutation, which typically occurs in multiple cells over a person’s lifetime, then the disease starts to manifest (fitting the “two-hit” tumor-suppressor gene model, with the germline mutation inactivating one gene and then a somatic event inactivating the remaining other one).
• TSC1 codes for a protein called hamartin, and TSC2 codes for a protein called tuberin.
• Tuberin and Hamartin belong to a protein complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 via RAS homologue enriched in brain (RHEB) which regulates cell growth.
• In a normal patient, RHEB activates mTORC1 when bound to GTP, but in TSC there is a hyperactivation of RHEB and consequently of mTORC1. mTOR regulates cellular proliferation, autophagy, growth and protein and lipid synthesis and it enhances protein translation when activated, reprograming the cell metabolism, which increases cell proliferation but also may make it vulnerable to death in nutrient-restricted media.
• Besides the TSC–RHEB–mTORC1 pathway, there is evidence of alternate pathways also having a role in the disease that are mTORC1 independent, but they are currently under investigation.^[1][2]

Tuberous Sclerosis is caused by a loss of function mutation of the genes TSC1 and TSC2 which are responsible for the production of hamartin and tuberin.

Loss of function mutation of the genes TSC1 and TSC2 which are responsible for the production of hamartin and tuberin. These proteins regulate the cell cycle. Damage to this pathway leads to a very variable presentation of benign tumors in multiple systems. TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson’s “two hit” hypothesis. That is, a second random mutation must occur before a tumor can develop.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

Tuberous sclerosis must be differentiated from other diseases that cause myxoma or other benign tumors and/or seizures, such as:

• Sturge-Weber;
• Hypomelanosis of Ito;
• Birt-Hogg-Dube syndrome;
• Multiple endocrine neoplasia;
• Seizures disorders.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

• Tuberous sclerosis complex affects about 16 in 100,000 individuals.^[1]
• The disease was underdiagnosed before the invention of imaging methods like CT scans and ultrasound.
• TSC is considered a rare disease, but it is comparably common in comparison to other genetic diseases, affecting more than 1 million patients worldwide.^[2]

• The total population prevalence figures have steadily increased. 1:150,000 in 1956, to 1:100,000 in 1968, to 1:70,000 in 1971, to 1:34,200 in 1984, to 1:12,500 in 1998.
• The incidence of rhabdomyomas in the newborn may be as high as 90% and in adults as low as 20%. These tumors grow during the second half of pregnancy and regress after birth. Many will disappear entirely. Alternatively, the tumor size remains constant as the heart grows, which has much the same effect.

• Tuberous sclerosis occurs in all races and ethnic groups, and in both genders.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

There are no established environmental risk factors for tuberous sclerosis. One third of the cases are familial, so family history can be a risk factor for the disease.

There are no established environmental risk factors for tuberous sclerosis. One third of the cases are familial, so family history can be a risk factor for the disease.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

There is insufficient evidence to recommend routine screening for tuberous sclerosis.

There is insufficient evidence to recommend routine screening for tuberous sclerosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

Tuberous sclerosis is a disease that presents with a wide spectrum of clinical manifestations. With appropriate medical care, most individuals can expect normal life expectancy.

• Those individuals with mild symptoms generally do well and live long productive lives, while individuals with the more severe form may have serious disabilities.
• However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

• Common complications of tuberous sclerosis include:
  • Blindness (due to retinal astrocytic hamartomas);^[1]
  • Internal bleeding (due to ruptured angiomyolipomas);
  • Renal-cell carcinomas;^[2][3]
  • Chronic kidney disease;^[4]
  • Lymphangiomyomatosis;
  • Multifocal micronodular pneumocyte hyperplasia;^[2]
  • Epilepsy, including its more severe form: infantile spasms;
  • Obstructive hydrocephalus due to subependymal giant cell astrocytomas;
  • Anxiety;
  • Autism;^[2]
  • Heart failure due to intracavitary cardiac rhabdomyomas.^[5]

• The prognosis for individuals with TSC depends on the severity of symptoms, which range from mild skin abnormalities to varying degrees of learning disabilities and epilepsy to severe mental retardation, uncontrollable seizures, and kidney failure.