Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Tuberous Sclerosis Complex

Sometimes called Bourneville disease.

What is Tuberous Sclerosis Complex?

• Tuberous sclerosis complex is a rare genetic disease that impacts multiple body systems
• It causes non-cancerous tumors to appear in many areas of the body
• The prevalence of the disease is estimated to be 7 to 12 per 100,000
• It was first described in 1880 by Desire-Magloire Bourneville, a French neurologist
• The disease is diagnosed with genetic and clinical testing. There is no single sign that can diagnose tuberous sclerosis complex, so a combination of them must be considered together.
  • The disease can be diagnosed at any stage of life

How Do You Get It?

• Tuberous sclerosis complex is caused by genetic mutations affecting two genes: TSC1 and TSC2
  • TSC1 codes for the protein hamartin and TSC2 codes for tuberin
  • TSC2 mutations are responsible for the majority of cases and tends to inflict more severe symptoms
  • These proteins play a role as suppressors of tumor growth
• The disease is inherited in an autosomal dominant pattern
• However, about two thirds of cases appears sporadically
• In around 20 percent of cases, genetic tests can have difficulty finding the mutation

What Are The Symptoms?

• Tumors can appear in many different parts of the body, including the skin, heart, liver, lungs, eyes, and kidneys
• Brain
  • Three brain tumors are associated with tuberous sclerosis complex, including:
  • Cortical tubers
  • Subependymal nodules
  • Giant cell astrocytoma
• Neuropsychiatric problems are also common in the disorder, such as:
  • Sleep problems
  • Psychiatric disorders, such as autism, depression, anxiety, ADHD
  • Intellectual disability (typically found in TSC2 linked cases)
  • Behavioral problems
  • Developmental delays
  • Seizures
• Pancreas
  • Though rare, pancreatic neuroendocrine tumors have been reported with this disorder
• Kidneys
  • Kidney tumors are common in tuberous sclerosis complex. The most common type is angiomyolipoma, which often causes hematuria (blood in the urine)
  • Other problems, such as autosomal dominant polycystic kidney disease or renal cell carcinoma, are much less common
• Eyes
  • Astrocytic hamartomas are grey to yellowish retinal lesions that are visible upon ophthalmic examination.
  • Some nonretinal lesions can also appear, such as:
  • Papilledema
  • Coloboma
  • Angiofibromas
• Lungs
  • Tuberous sclerosis complex patients can develop lymphangioleiomyomatosis, in which cysts start replacing the lung parenchyma
• Skin
  • The vast majority of patients have some form of skin abnormality. In many instances, these manifestations are harmless, but some can cause disfigurement without treatment. Examples include:
    • Intraoral fibromas, which are found in the gums, tongue, or inner cheek.
    • Hypomelanic macules occur in 90 percent of patients. These lightened skin patches can appear almost anywhere on the body.
    • Dental enamel pits
    • Facial angiofibromas affect 75 percent of tuberous sclerosis patients. This facial rash consists of red spots in a butterfly pattern across the face.
    • Shagreen patches are areas of thickened, leathery skin that appear in around half of cases. They tend to appear more frequently as the patient gets older
    • Ungual fibromas are tumors that appear under the nail beds. They tend to affect women more than men, and the toes are more often affected than the fingers.
    • Fibrous cephalic plaques occur in 25 percent of cases. These mostly appear on the forehead, scalp, or face.
• Heart
  • Tumors called rhabdomyomas are common in tuberous sclerosis complex patients and appear on the heart muscle.
  • They tend to regress after age two. In most instances, they cause no problems, but can sometimes cause heart failure before birth or in the first year of life
  • These tumors may also play a role in heart arrhythmias, which appear later in life and are a common symptom

How Is It Treated?

• Prognosis for tuberous sclerosis complex is varied, but in most instances, life expectancy is not affected.
• As many different organ systems can be impacted by this disease, a multidisciplinary care team is essential
• As the different complications and symptoms of the disease can appear and vary throughout the lifespan, monitoring of changes is a critical aspect of management and treatment
  • This may include regular screenings, such as MRI, in order to detect new tumors or test for psychiatric disorders
• Everolimus, an mTOR inhibitor, is approved for the treatment of certain brain and kidney tumors
  • This treatment also appears to improve epilepsy symptoms in some patients
• Neurosurgery may also be employed to reduce seizures.
• Surgery may also be used for lung problems, including lung transplant
• Laser treatments have been used to address facial tumors, but risks scarring the face

Where Can I Learn More???

• Check out our cornerstone on this disease here.
• Learn more about this condition from the Tuberous Sclerosis Complex Alliance.