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  Disease summary:

  
  
  
  
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    Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by benign growths called hamartomas that can occur anywhere throughout the body. Hypopigmented macules, facial angiofibromas, shagreen patches, ungual fibromas, and dental pitting are characteristic of the disease. Central nervous system involvement is associated with highest morbidity and clinically manifests as epilepsy, learning disabilities or cognitive impairment, autism and other behavioral disorders, psychiatric disorders, and sleep abnormalities. The hallmarks of cerebral involvement are cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Angiomyolipomas (AMLs) of the kidney, lymphangioleiomyomatosis (LAM) of the lung, and rhabdomyomas of the heart also cause significant morbidity.

  
  
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  Hereditary basis:

  
  
  
  
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    TSC is an autosomal dominant genetic disorder with near 100% penetrance, but clinical severity is highly variable. It is genetically heterogeneous, with mutations in one of two genes (TSC1 or TSC2) causing the disorder. About one-third of cases are familial, the remainder is sporadic. Genetic mosaicism, including germline mosaicism, also exists. Genetic testing is available for affected individuals. Mutation in either gene (TSC1, TSC2) is detected in 85% of cases.

  
  
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  Differential diagnosis:

  
  
  
  
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    The combination of multiple features of TSC is rarely mistaken for other disorders. However, individual features may overlap with those of other syndromes. Hypopigmented macules (ash leaf macules) can occur from many different etiologies; vitiligo, piebaldism, hypomelanosis of Ito, and incontinentia pigmenti are among the differential diagnosis. Renal AMLs and pulmonary LAM can occur sporadically but certainly occur in high association with TSC. Cortical migration defects can occur as an isolated, idiopathic finding unrelated to TSC. Other neurocutaneous disorders, such as neurofibromatosis 1 or 2, have distinct skin manifestations and tumor types which should not be mistaken for TSC.

  
  
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  Management:

  
  
  
  
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    Treatment with the mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus results in significant shrinking of SEGAs and renal AMLs, and can be an alternative to surgery in some cases. Benefit in lung disease (LAM) has also been demonstrated. Additional studies are ongoing to determine their efficacy for epilepsy and neurocognition in TSC.

Diagnostic Criteria*

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  Clinically definite tuberous sclerosis: two major or one major + two minor features

  
  
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  Clinically probable tuberous sclerosis: one major + one minor feature

  
  
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  Clinically possible tuberous sclerosis: one major or two minor features

*Genetic confirmation of known disease-causing mutation in either TSC1 or TSC2 gene is also considered sufficient for confirmed diagnosis of TSC. However, failure to identify a disease-causing mutation in TSC1 or TSC2does not exclude the diagnosis if clinical criteria are met.

Clinical Characteristics

Any organ system can be affected in patients with tuberous sclerosis, with central nervous system, skin, kidney, lung, and heart being most common. Many of the features are age dependent.

Central Nervous System

Cortical and subcortical tubers are essentially migration defects occurring in utero and are the hallmark of tuberous sclerosis. SENs are also characteristic and in 15% to 20% of affected individuals can exhibit spontaneous growth in childhood or early adulthood. While benign, these SEGAs can impede central spinal fluid flow through the foramen of Monro, leading to hydrocephalus. Seizures occur in more than 90% of patients, often presenting during infancy as infantile spasms. In adulthood, partial motor and complex partial seizures that often generalize are typical and can be difficult to manage with conventional anticonvulsant therapies. Learning difficulties and cognitive impairment are present in the majority of patients, although many can have normal IQ. Obsessive-compulsive behaviors, anxiety, mood disorders, aggressive behaviors, autism, and sleep disorders also frequently are associated with tuberous sclerosis.

Skin

Hypopigmented macules are present at birth but may be more noticeable as patients get older. Likewise connective tissue nevus (shagreen patch) may not be visible initially. Facial angiofibromas (adenoma sebaceum) usually appear by mid- or late-childhood and can continue to grow or accumulate during adulthood. Ungual fibromas can affect hands or feet and are most likely to appear during adolescence or as early adults. Dental pitting is nearly universally present in all adults with TSC.

Kidney

AMLs are discrete lesions containing fat, smooth muscle, and abnormal blood vessels and may appear as small lesions scattered throughout the kidneys or as larger, isolated lesions. Significant risk of hemorrhage (Wunderlich syndrome) is associated with AMLs greater than 4 to 6 cm in diameter. Lesions are also associated with renal hypertension and renal insufficiency or failure. Renal cysts, including polycystic kidney disease, can be associated with TSC, especially if a large deletion of 16p is present such that both TSC2 and PKD1 gene loci are affected. Renal cell carcinoma can occur, but is very rare.

Lung

A rare but potentially fatal progressively destructive pulmonary disease known as LAM can affect up to 40% of female patients of childbearing age with TSC. It is rare for pediatric female or adult male patients to develop LAM, but cases do occur. Clinically, patients can present with progressive dyspnea on exertion, chylothorax, and pneumothorax.

Heart

Rhabdomyomas, benign growths arising from the cardiac chambers, may be diagnosed prenatally by fetal magnetic resonance imaging (MRI) or ultrasound. The majority will regress spontaneously within the first or second year of life, but it is not unusual for some to persist throughout adulthood. Disruption of conduction pathways may also result, leading to arrhythmias or other abnormalities noted on electrocardiography.

Other Organs

Extrarenal and pulmonary hamartomas can occur in any organ, including the eye, liver, uterus, and thyroid. Bone cysts, gingival and dermal fibromas also occur.

Counseling