Tuberous sclerosis history and symptoms

Symptoms develop in almost all patients with TSC and include:^[1]

• 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);
• Hocal 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).^[1]

• Renal angiomyolipomas (present in 60-80% of the TSC patients), benign tumors composed of abnormal vessels, smooth-muscle cells and fat cells which may cause hematuria. These tumors can be detectable in early childhood by MRI, CT or ultrasound. Although benign, in TSC they are commonly multiple and bilateral. Angiomyolipomas larger than 4 cm are at risk for potentially catastrophic hemorrhage either spontaneously or with minimal trauma;
• Epithelial cysts;
• Polycystic kidney disease (as 2-3% of the patients carries a deletion that affects both TSC2 gene and one of the genes that lead to autosomal dominant polycystic kidney disease);
• Renal-cell carcinomas that may be diagnosed at a younger age (mean 28 years);^[1][2]
• Patients ≥18 years may have higher rates of chronic kidney disease, hematuria, kidney failure, embolization (EMB), and partial and complete nephrectomy compared to patients <18 years.^[3]

• Lymphangiomyomatosis affects mostly women and is a proliferation of smooth-muscle cells that may result in cystic changes in the lungs. Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in TSC-related lymphangioleiomyomatosis is monoclonal metastasis from a coexisting renal angiomyolipoma. Cases of TSC-related lymphangioleiomyomatosis recurring following lung transplant have been reported.^[4] Diagnosed mostly during early adulthood, may cause pneumothorax.

• Multifocal micronodular pneumocyte hyperplasia can occur in both men and women and are mostly asymptomatic.^[1][2]

These manifestations are one of the major causes of morbidity in patients with TSC.

• 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. If epilepsy presents with an early onset t is associated with cognitive disabilities, which are also very prevalent in such patients. In 2020 a paper showed that epilepsy remission by appropriate treatment in early life can possibly prevent autism and intellectual disability.^[5]
• 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. It consists of neurologic tissue that grows in a different pattern, losing the normal six-layered cortical structure, with dysmorphic neurons, large astrocytes and giant cells.
• Subependymal nodules;
• Subependymal giant cell astrocytomas, which may cause obstructive hydrocephalus. Risk of such benign tumors decreases after age of 20.^[2][1]

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.^[1] 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several.^[6]

• 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.