Tuberous sclerosis complex (TSC), an autosomal dominant disorder, is characterized by hamartomas in many organs, especially the brain, eyes, skin, kidneys, and heart. The incidence is 1 in 10,000 births. Two thirds of cases are sporadic and thought to represent new mutations. Germline mosaicism is uncommon, but explains how parents who apparently do not have the disease can have multiple children with tuberous sclerosis. Mutations affecting either of the presumed tumor suppressor genes, TSC1 or TSC2, cause tuberous sclerosis. The TSC1 and TSC2 genes encode distinct proteins, hamartin and tuberin, which are widely expressed in the brain and result in constitutive activation of the protein kinase mTOR (mammalian target of rapamycin), leading to the formation of numerous benign tumors (hamartomas).
TSC is an extremely heterogeneous disease with variable expression and a wide clinical spectrum varying from normal intelligence without seizures to severe mental retardation with refractory seizures, often within the same family. Tuberous sclerosis is one of the most common causes of infantile spasms. These children often develop intractable epilepsy, mental retardation, autism, and hyperactivity. Patients may have retinal lesions (retinal hamartomas, white depigmented patches) and brain lesions (cortical tubers, subependymal nodules, hydrocephalus). Tubers in the cerebral cortex are areas of dysplasia that, in combination with other microscopic areas of abnormal development, are responsible for the symptoms of mental retardation and epilepsy. Subependymal nodules are hamartomas that may mutate into a growth phase and become subependymal giant cell astrocytomas causing obstruction of cerebrospinal fluid outflow and resultant hydrocephalus.
Extracerebral manifestations include typical skin findings of hypomelanotic macules (ash leaf spots) which are easiest to visualize under a Wood ultraviolet lamp and are apparent in infancy. Facial angiofibromas (adenoma sebaceum) appear as small red nodules over the nose and cheeks that are sometimes confused with acne. Shagreen patches are elevated, rough plaques of skin with a predilection for the lumbar and gluteal regions that develop in late childhood or early adolescence. Cardiac rhabdomyomas are largest during prenatal life and infancy and are rarely symptomatic. Occasionally, they may cause arrhythmias or cardiac outflow obstruction. Renal angiomyolipomas may undergo malignant transformation and are the most common cause of death in adults with TSC. Interstitial pulmonary disease also affects adults with TSC (pulmonary lymphangioleiomyomatosis).
Sturge-Weber syndrome is sporadic (not inherited) and characterized by abnormal blood vessels (angiomas) of the leptomeninges overlying the cerebral cortex in association with an ipsilateral facial port-wine stain involving the ophthalmic division of the trigeminal nerve (forehead and upper eyelid) and, often, glaucoma. The port-wine stain, also known as nevus flammeus, is due to an ectasia of superficial venules and may have a much more extensive and even bilateral distribution. Not all children with a facial port-wine stain have Sturge-Weber syndrome.