This leads to impaired regulation of cellular proliferation, survival, homeostasis, migration and other critical functions. The most typically affected organs include the brain, skin, kidney, heart and lung. The incidence of TSC is approximately 1 in 6,000 live births. Similar to other neurocutaneous disorders there is variable penetrance and expressivity. TSC1 mutations tend to have a less severe phenotype and are more likely to be familial. A major development in the treatment of this condition occurred in 2010s when the FDA approved mTOR inhibitors for the treatment of several manifestations of TSC. Epilepsy is among the most common manifestations of TSC and it occurs 80-90% of patients. It usually presents during the first few years of life and is medically refractory in two-thirds of patients. Approximately, one-third of patients have infantile spasms. There are several types of brain lesions that can be found in TSC including subependymal nodules (SENs), cortical tubers and subependymal giant cell astrocytomas (SEGAs). SENs and cortical tubers occur in approximately 80% and 90% of patients, respectively. SEGAs occur in 10-15% of patients and are a major potential cause of morbidity and potentially mortality. They tend to present during the first 20 years of life. TSC-Associated Neuropsychiatric Disorder (TAND) refers to the behavioral, intellectual and psychiatric manifestations of TSC including autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, depression and anxiety. Approximately 90% of patients will have at least 1 symptom of TAND.Lymphangioleiomyomatosis (LAM) occurs in the lung and may result in pneumothorax, cystic lung destruction and pleural effusions.
They are usually asymptomatic but they may become thickened overtime and may be associated with an increased risk for glaucoma.Seizures typically develop within the first two years of life and occur in 75-100% of patients. Onset of seizures occur in 95% by the age of 5 years. Status epilepticus occurs in approximately 50% of patients. Approximately 25% of patients develop drug-resistant epilepsy. In these cases, surgery may be pursued with the two main approaches being lesionectomy and hemispherectomy.Neurological impairment can accrue gradually over time and may occur in the context of stroke-like episodes which may be triggered by seizures or head injuries. Intellectual disability occurs in approximately one-half of patients. In addition, patients with Sturge-Weber syndrome have an increased prevalence of depression, endocrinological abnormalities, headaches with migraine-like features, ADHD and behavioral problems. Cortically mediated visual field defects and hemiparesis occur in approximately one-third and one-half of patients, respectively. Von Hippel–Lindau syndrome (hemangiomatosis)
Von Hippel-Lindau (VHL) disease is an autosomal dominant condition caused by mutations of the VHL gene. Approximately one-in-five cases are de novo rather than familial and it has nearly complete penetrance. VHL occurs in an estimated 1 in 36,000-45,000 live births. VHL normally functions as a tumor suppressor gene and thus when not functioning normally results in the development of benign and malignant tumors as well as cysts. Some of the most common manifestations include hemangioblastomas in the retina and central nervous system, clear cell renal cell carcinomas, pheochromocytomas, endolymphatic sac tumors and pancreatic neuroendocrine tumors.