Tuberous Sclerosis Complex – Causes, Symptoms, Diagnosis, Treatment and Ongoing care



  • Tuberous sclerosis complex (TSC) is a genetic neurocutaneous syndrome (phakomatosis). Many organ systems are affected, with the formation of multiple hamartomas.
  • Manifestations may be subtle but can include lesions of the central nervous system, skin, retina, heart, lung, viscera, kidney, bone, teeth, liver, and nails.
  • System(s) affected: Cardiovascular; Musculoskeletal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
  • Synonym(s): Bourneville disease

Pregnancy Considerations

Prenatal diagnosis by mutational analysis is possible when a molecular cause is known.



  • 1/5,000–1/10,000 live births
  • Predominant age: Clinical expression is variable; usually diagnosed during the 1st decade of life.
  • Predominant gender: Male = Female, but autism is more common in males.

Risk Factors

  • Family history
  • Expressivity is variable, even within a family.
  • If neither parent of an affected child meets criteria for TSC, then the recurrence risk is 1–2% per child due to the possibility of parental germ-line mosaicism.


  • Autosomal dominant with complete penetrance and variable expressivity
  • OMIM 191100
  • 2/3 of cases result from new mutations.
  • 2 chromosomal loci have been mapped: Tuberous sclerosis complex 1 (TSC1, 9q34) and tuberous sclerosis complex 2 (TSC2, 16p13.3)
  • Somatic mosaicism occurs in 2–10% of de novo tuberous sclerosis (TS).
  • Clinical phenotype of TSC1 mutations generally is milder than that of TSC2 mutations, but genotype–phenotype correlation is not established.

General Prevention

Genetic counseling


Mutations in either of two genes TSC1 and TSC2 that code for the tumor growth-suppressor proteins hamartin and tuberin, respectively:

  • The hamartin–tuberin complex is involved in cell proliferation and differentiation.
  • Mutations may result in decreased production of these proteins and excessive cell proliferation, resulting in tuber formation.


Some hamartomas in patients with TS show loss of heterozygosity in the chromosomal region 9q34 or 16p13.3.

  • This implies that the patient has inherited a mutation or a deletion in one copy of the gene, but the patient develops a lesion only when there is a somatic mutation in the other copy.
  • This 2-hit mechanism appears to apply to cardiac rhabdomyomas, renal angiomyolipomas, and subependymal giant cell tumors, but not to cerebral tubers.

Commonly Associated Conditions

  • Mental retardation (60–70%), usually associated with history of seizures
  • Seizures (80%); 25% of patients with infantile spasms have TS
  • Autism (10–20%)
  • Cardiac arrhythmias
  • Renal insufficiency


  • Physical examination and imaging are most useful, although molecular diagnostics may be useful when clinical criteria are not met or for family members of affected patients.
  • Diagnostic criteria for TS (1) (approximate percentage of patients affected):
    • Major criteria:
      • Facial angiofibromas (80%) or forehead plaques
      • Shagreen patch (connective tissue nevus)
      • 3 or more hypomelanotic macules (50%)
      • Nontraumatic ungula or periungual fibromas (20%)
      • Lymphangioleiomyomatosis (<10%, also known as lymphangiomyomatosis), predominantly in premenopausal women
      • Renal angiomyolipoma
      • Cardiac rhabdomyoma (50%, mostly in newborns)
      • Multiple retinal nodular hamartomas (50–80%)
      • Cortical tuber
      • Subependymal nodules
      • Subependymal giant cell astrocytoma
    • Minor criteria:
      • Confetti skin lesions (multiple 1- to 2-mm hypomelanotic macules)
      • Gingival fibromas
      • Multiple randomly distributed pits in dental enamel
      • Hamartomatous rectal polyps
      • Multiple renal cysts (50–80%)
      • Nonrenal hamartomas (liver hamartoma in 10%)
      • Bone cysts
      • Retinal achromic patch
      • Cerebral white matter radial migration lines
  • Definite TS: 2 major criteria or 1 major criterion and 2 minor criteria
  • Probable TS: 1 major criterion and 1 minor criterion
  • Possible TS: 1 major criterion or 2 minor criteria
  • 95% of patients with TSC may have a seizure disorder.
  • Although epilepsy and mental retardation are more common in TS, they are not included among diagnostic criteria because they are common in the general population (2).
  • Hypomelanotic macules often can be seen in newborns, especially with Wood lamp examination.
  • When a new diagnosis is made in a child with no family history of TSC, careful evaluation of the parents should include:
    • A comprehensive dermatologic examination (in room light and with a Wood lamp)
    • Ophthalmologic examination
    • Cranial CT scan or MRI
    • Renal ultrasound


  • Family history of TSC stigmata; about 1/3 of patients with TSC have a positive family history.
  • Assess for seizures and developmental delay in children.
  • Patients with TSC are at increased risk of brain tumors and may present with symptoms of obstructive hydrocephalus, including headaches, vomiting, and neurologic deficits (including loss of vision). Children with obstructive hydrocephalus may present with nonspecific symptoms, including fatigue, decreased appetite, depression, and increased frequency of seizures.

Physical Exam

  • Dermatologic:
    • 96% percent of patients with TSC have characteristic skin lesions, which include (3)
      • Hypopigmented macules (ash-leaf spots, usually elliptical), not usually present before age 5 years
      • Angiofibromas (formerly, and incorrectly, adenoma sebaceum), typically involving the malar regions of the face (butterfly distribution), usually appear later than hypopigmented macules.
      • Shagreen patches, most commonly on the lower trunk
    • A brown fibrous plaque on the forehead may be the 1st recognized feature of TSC on physical examination of infants.
    • Periungual and ungual fibromas may appear in adolescence or adulthood.
  • Ophthalmologic:
    • Funduscopic evaluation:
      • Retinal hamartomas: Hamartoma may be a flat, translucent lesion (most common) or a multilobular mulberry lesion (with calcification), or may have features of both.
      • Retinal giant cell astrocytoma, secondary retinal detachment
      • Chorioretinal depigmentation (punched-out appearance)
      • Papilledema or visual loss: Suggestive of brain tumors
      • An abnormal red reflex should not be mistaken for retinoblastoma.
    • Angiofibromas of the eyelids, nonparalytic strabismus, colobomas, and sector iris depigmentation
    • Refractive errors not different from those of the general population
  • Dental: Multiple, randomly distributed pits in dental enamel
  • Neurologic: Focal deficits may indicate growth of brain tumors.

Diagnostic Tests & Interpretation


Molecular diagnostics:

  • Mutations can be detected in approximately 75% of patients who meet the diagnostic criteria for TS.
  • Mutations in the TSC2 gene are about 3 times as common as those of the TSC1 gene (4).
  • Identification of a mutation in TSC1 or TSC2 can confirm the diagnosis in a child whose clinical evaluation is suggestive but not diagnostic of TSC.
  • A negative result in molecular testing cannot rule out TS in a patient with a clinical diagnosis of TS.
  • Mutational analysis is useful for prenatal diagnosis and for evaluation of relatives of those with a known mutation.


Initial approach

  • Cranial MRI before age 2, with gadolinium enhancement.
  • Fetal cardiac rhabdomyomas may be seen by ultrasound or MRI in late gestation.
  • CT scan or ultrasound of kidneys
  • Pulmonary CT scan or chest imaging of the lungs, as indicated, in females beginning at age 18; pulmonary pathology is uncommon in males.

Diagnostic Procedures/Surgery

  • Ash-leaf spots more readily seen with a Wood lamp
  • Biopsy of questionable lesions
  • Clinical neuropsychological evaluation may reveal attentional deficits in children and adolescents with TSC, even when they have normal intellectual abilities and no seizures or disruptive behaviors (5)[B].

Pathological Findings

  • Lesions may be sparse at birth.
  • Facial angiofibromas, ungual fibromas, and renal angiomyolipomas may develop months or years after birth.
  • Brain lesions:
    • Cortical tubers (glioneural hamartomas): Histology shows disorganized neuronal and glial elements with astrocytosis. Epileptogenic nature is widely accepted, but controversial.
    • White matter heterotopia: Dysplastic and dysmyelinated white matter
    • Subependymal nodules: Hamartomas composed of atypical enlarged glial and neuronal cells may transform to giant cell astrocytomas (from which they are histologically indistinguishable except for size).
    • Subependymal giant cell astrocytomas
    • Giant cell astrocytomas are of mixed glioneuronal lineage.
    • Calcification of subependymal lesions may not occur until several months after birth.
    • Extensive anatomic abnormalities may be seen in gray and white matter, even in patients with normal intelligence.
  • Renal lesions (50–80%):
    • Angiomyolipomas, benign cysts, and lymphangiomas
    • Lesions may adversely affect renal function.
  • Pulmonary lesions:
    • 1% of patients with TSC may present with pulmonary lymphangioleiomyomatosis.
    • These patients are usually women of reproductive age.
  • Cardiac rhabdomyoma (50–70% of infants), usually asymptomatic.

Differential Diagnosis

  • Non-TSC polycystic kidney disease
  • Other causes of seizure disorders, mental retardation, autistic behavior
  • Traumatic ungual fibromata
  • Other phakomatoses: Neurofibromatosis, Sturge-Weber syndrome, von Hippel-Lindau syndrome.



  • Anticonvulsants for seizure control
  • No drugs are routinely used for TSC management, although the biochemical rationale for the potential use of rapamycin has been described in detail, with clinical trials suggesting that this agent may be useful to treat TSC (6).

Additional Treatment

Support's development and hosting

Issues for Referral

  • A multidisciplinary team should evaluate every new patient: Genetics, neurology, ophthalmology, nephrology, surgery, dermatology, neurosurgery, radiology, and plastic surgery.
  • Physical therapy, occupational therapy, and speech therapy; social workers for home care, vocational training support

Surgery/Other Procedures

Surgery may be necessary for hydrocephalus, increased intracranial pressure, rapidly growing subependymal giant cell tumors, malignant tumors, and seizure control.

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • Pediatric:
    • Annual physical examination, growth assessment, ophthalmologic examination
    • Annual developmental testing and review of school progress, neuropsychologic evaluation, and IQ testing if indicated
    • Echocardiography
      • Pediatric cardiologist should follow children with cardiac rhabdomyoma.
      • Cardiac rhabdomyomas typically develop in utero, regress spontaneously in early childhood, and involute completely by adulthood.
  • Electroencephalogram: For seizure management
  • Renal ultrasound: Every 1–3 years beginning in adolescence; abdominal MRI or CT scan for evaluation of large angioleiomyomas
  • Chest CT scan: For pulmonary dysfunction
  • Screening MRI without contrast (7): Every 1–3 years for children and adolescents, less frequently in adults; if a giant cell astrocytoma is identified, surgery is performed, if appropriate. Otherwise, repeat cranial MRI every 3–6 months.

Patient Education

Tuberous Sclerosis Alliance, 801 Roeder Road, Suite 750, Silver Spring, MD, 20910; (800) 225-6872; e-mail:;


Variable; shortened longevity in individuals with complications


  • In addition to benign tumors associated with TSC (e.g., angiofibromas, hamartomas, rhabdomyomas, and angiomyolipomas), there is an 18-fold increase in risk of malignancy, especially of the kidney, brain, and soft tissues.
  • Rhabdomyosarcoma, although rare, has increased incidence in TSC.
  • 1–2% of adults develop renal cell carcinoma, 25 years earlier than in general population.
  • CNS complications, including epilepsy, cognitive impairment, behavioral problems, hyperactivity, self-injurious behavior, and autism, occur in 85% of children and adolescents with TS.
  • Neuropsychological attention deficits may be greater than intellectual impairment.
  • Causes of death: Neurologic disease most common (subependymal giant cell tumors and status epilepticus), renal disease, pulmonary disease
  • Subependymal giant cell tumors are benign but may undergo malignant transformation or may grow rapidly or hemorrhage.


1. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998;13:624–8.

2. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004;19:643–9.

3. Webb DW, Clarke A, Fryer A, et al. The cutaneous features of tuberous sclerosis: a population study. Br J Dermatol. 1996;135:1–5.

4. Au KS, Williams AT, Roach ES, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007;9:88–100.

5. de Vries PJ, Gardiner J, Bolton PF, et al. Neuropsychological attention deficits in tuberous sclerosis complex (TSC). Am J Med Genet A. 2009;149A:387–95.

6. Orlova KA, Crino PB, et al. The tuberous sclerosis complex. Ann N Y Acad Sci. 2010;1184:87–105.

7. Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in tuberous sclerosis complex.Neurology. 2004;63:1457–61.

Additional Reading

See Also (Topic, Algorithm, Electronic Media Element)




759.5 Tuberous sclerosis


7199000 Tuberous sclerosis syndrome (disorder)

Clinical Pearls

Hypopigmented areas (e.g., ash-leaf spots), mainly on trunk and extremities, are often the 1st sign, present at birth or shortly after (50%). These are best seen with a Wood lamp.

About the author

Many tips are based on recent research, while others were known in ancient times. But they have all been proven to be effective. So keep this website close at hand and make the advice it offers a part of your daily life.