Tuberous Sclerosis


  • Incidence: occurs in 1 in 5-10k live births

Cases Diagnosed in Adulthood

  • Case Series of Tuberous Sclerosis Cases with Delayed Presentation into Adulthood (2011) [MEDLINE]: 45 reported cases
    • Female Cases Diagnosed in Adulthood Had Minimal Morbidity During Childhood
      • 30 Cases: these cases met clinical criteria for tuberous sclerosis in childhood (remaining undiagnosed for a median of 21.5 yrs)
      • 15 Cases: these cases were >18 y/o before meeting the clinical criteria for tuberous sclerosis
    • Clinical Presentations in Case Series
      • Lymphangioleiomyomatosis Symptoms: 21 cases
      • Renal Angiomyolipoma: 19 cases
      • Seizures: 10 cases
    • Patients Diagnosed in Adulthood Had Similar Incidence of Pneumothorax, Dyspnea, Hemoptysis, Nephrectomy, and Death
    • Proposed Physiology: these cases probably have sporadic mutations of the TSC genes (without a positive family history)


Normal Function

TSC Genes

  • TSC1: encodes for hamartin protein (which is widely expressed in normal tissues)
    • Dysfuctional/absent hamartin results in a loss of functional tuberin-hamartin complex -> loss of inhibition on the cell cycle
  • TSC2: encodes for tuberin protein
    • Dysfuctional/absent tuberin results in a loss of functional tuberin-hamartin complex -> loss of inhibition on the cell cycle

Mechanistic Target of Rapamycin (mTOR)

  • mTOR Pathway Regulates Protein Expression (in Response to Nutrition), Cell Cycle Progression, and the Response to Hypoxia: hamartin-tuberin complex plays a role in mTOR signaling

Tuberous Sclerosis is Due to an Autosomal Dominant Mutation in TSC1 or TSC2 Tumor Suppressor Genes

  • Familial TSC Mutation: accounts for 20% of cases
    • Relative Prevalence of Mutations: the prevalence of TSC1 and TSC2 mutations are roughly equal in familial cases
  • De Novo Sporadic TSC Mutation (in Egg/Sperm Prior to Fertilization): accounts for 80% of cases
    • Relative Prevalence of Mutations: TSC2 mutations are 4x as common as TSC1 mutations in de novo cases
    • Once a mutation occurs, the patient’s offspring may inherit tuberous sclerosis, appearing as a familial trait in future generations

Tuberous Sclerosis Results in the Development of Hamartomatous Tumors in Brain/Kidney/Retina/Skin/Heart/Liver/Lung

  • Tuberous Sclerosis is Highly Variable in its Expression
    • Variability in Age of Onset
    • Variability in Severity of Disease
    • Variability in Symptoms Which Result from a Specific Genotype


Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

  • Anemia (see Anemia, [[Anemia]]): iron deficiency may occur if bleeding is severe or recurrent
  • Leukocytosis (see Leukocytosis, [[Leukocytosis]])

Erythrocyte Sedimentation Rate (ESR) (see Erythrocyte Sedimentation Rate, [[Erythrocyte Sedimentation Rate]])

  • Elevated

Serum Vascular Endothelial Growth Factor-D (VEGF-D)

  • VEGF-D is a Lymphangiogenic Growth Factor: may be helpful as a screening test for both tuberous sclerosis-associated lung disease and in lymphangioleiomyomatosis (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])
    • Serum VEGF-D is elevated in women with tuberous sclerosis-associated lung disease, as compared to women with tuberous sclerosis without lung disease (level of >900 pg/ml is a cut-off with 100% specificity in this setting)
    • Serum VEGF-D is correlated with disease severity and treatment response in lymphangioleiomyomatosis [MEDLINE]

Urinalysis (see Urinalysis, [[Urinalysis]])

  • Usually Normal

DNA Testing for TSC1 and TSC2 Mutations

  • Available: however, negative genetic testing does not rule out TS, because no mutation is identified in 15% of patients who fulfill the diagnostic criteria for TS

Diagnostic Criteria for Tuberous Sclerosis Complex

General Diagnostic Criteria

  • Identification of Either a TSC1 or TSC2 Pathogenic Mutation in DNA from Normal Tissue is Sufficient to Make the Diagnosis: pathogenic mutation is defined as one which inactivates TSC1 or TSC2 protein function (nonsense mutation), prevents protein synthesis (large deletion), or is a missense mutation whose effect on protein function has been established by functional assessment
    • 10-25% of patients with tuberous sclerosis have no identifiable mutation by genetic testing: therefore, a normal result does not exclude the diagnosis of tuberous sclerosis
  • Definite Tuberous Sclerosis Complex: 2 major criteria or 1 major + at least 2 minor criteria
    • However, the combination of LAM and angiomyolipomas without other features does not meet criteria for a definite diagnosis
  • Possible Tuberous Sclerosis Complex: either 1 major clinical feature or at least 2 minor criteria

Major Clinical Criteria

  • Angiofibromas: at least 3
  • Cardiac Rhabdomyoma
  • Cortical Dysplasias (Including Tubers and Cerebral White Matter Radial Migration Lines)
  • Fibrous Cephalic Plaque
  • Hypomelanotic Macules: at least 3, at least 5 mm diameter:
  • Multiple Retinal Hamartomas
  • Pulmonary Lymphangioleiomyomatosis (LAM)
  • Renal Angiomyolipomas: at least 2
  • Shagreen Patches (Connective Tissue Nevi)
  • Subependymal Giant Cell Astrocytomas
  • Subependymal Nodules
  • Ungual Fibromas: at least 2

Minor Clinical Criteria

  • “Confetti” Skin Lesions: 1 to 2 mm hypomelanotic macules
  • Dental Enamel Pits: at least 3
  • Intraoral Fibromas: at least 2
  • Multiple Renal Cysts
  • Non-Renal Hamartomas
  • Retinal Achromic Patch

Clinical Manifestations

Cardiovascular Manifestations

  • Aortic Aneurysm (see Thoracic Aortic Aneurysm, [[Thoracic Aortic Aneurysm]] and Abdominal Aortic Aneurysm, [[Abdominal Aortic Aneurysm]]): occasionally associated with tuberous sclerosis
  • Aortic Coarctation (see Aortic Coarctation, [[Aortic Coarctation]])
  • Cardiac Rhabdomyoma(s) (see Cardiac Mass, [[Cardiac Mass]])
    • Epidemiology: characteristic cardiac feature of tuberous sclerosis
    • Physiology: benign tumor (with no evidence of malignant transformation)
    • Clinical: multifocal > unifocal

Dermatologic Manifestations

  • General Comments: 81-95% of cases have at least one of the characteristic skin lesions
    • Lesions tend to increase in size/number through puberty, then remain stable over time
  • Brown Fibrous Plaque on Forehead: most easily recognized skin finding in affected neonates
  • Dermal Angiofibromas (Adenoma Sebaceum, Fibroadenomas)
    • Appearance: usually on the malar region of the face
  • Hypopigmented (Hypomelanotic) Macules (Ash-Leaf Spots)
    • Onset: usually appear earlier than facial angiofibromas or ungual fibromas
    • Appearance: typically ellipitical
  • Longitudinal Leukonychia: less common
    • Appearance: white streaks extending from nail matrix to the end of nail
  • Longitudinal Nail Grooves: may also be seen
  • Ungual (Periungual/Subungual) Fibromas
    • Onset: may develop during adolescence/adulthood
    • Appearance: more common on toenails than fingernails
  • Shagreen Patches (Connective Tissue Nevi)
    • Appearance: most commonly on the lower trunk
  • Splinter Hemorrhages (see Splinter Hemorrhages, [[Splinter Hemorrhages]]): less common
  • Subungual Red Comets: less common
    • Appearance: red longitudinal streaks with a larger distal head and a narrowed proximal tail

Hematologic/Oncologic Manifestations

Increased Risk of Malignancy

  • General Comments: risk of malignancy is higher with TSC2 mutations, as compared to TSC1 mutations
  • Brain Tumors
    • Subependymal Giant Cell Tumor with Malignant Transformation
  • Kidney
    • Renal Cell Carcinoma (see Renal Cancer, [[Renal Cancer]])
    • Renal Angiomyolipoma with Malignant Transformation
  • Soft Tissue

Neurologic Manifestations

  • Autism/Behavioral Problems (Hyperactivity/Self-Injurious Behavior): common in tuberous sclerosis
  • Cognitive Deficits/Mental Retardation
    • Epidemiology: cognitive deficits occur in 44-65% of cases
    • Physiology: the degree of cerebral dysfunction (cognitive dysfunction, seizures) is only roughly correlated with the burden of glioneural hamartomas
  • Hamartomas: in central nervous system (may calcify)
    • Cortical Glioneuronal Hamartomas (Cortical Tubers)
    • Subependymal Nodules: considered a type of hamartoma
  • Seizures (see Seizures, [[Seizures]])
    • Epidemiology
      • Seizures are the most frequent presenting symptom of tuberous sclerosis
      • Seizures are the most significant cause of morbidity in tuberous sclerosis
    • Physiology: the degree of cerebral dysfunction (cognitive dysfunction, seizures) is only roughly correlated with the burden of glioneural hamartomas
    • Clinical: seizures begin during the first year of life in 60% of cases (but risk of new seizures persists into adult life)
  • Subependymal Giant Cell Tumors (Subependymal Giant Cell Astrocytomas): in central nervous system
    • Characteristic Tumor in Tuberous Sclerosis
  • White Matter Heterotopia: in central nervous system

Ophthalmic Manifestations

  • Retinal Hamartomas
  • Chorioretinal Depigmentation
  • Eyelid Angiofibromas
  • Non-Paralytic Strabismus
  • Colobomas
  • Sector Iris Depigmentation
  • Refractory Errors: myopia, hyperopia, astigmatism

Pulmonary Manifestations

General Comments

  • Onset of Pulmonary Involvement: usually in the 4th decade of life (30’s), rarely before age 20

Chyloptysis (see Chyloptysis, [[Chyloptysis]])

  • Epidemiology: occurs in 6% of patients with tuberous sclerosis-associated lung disease

Chylothorax (see Pleural Effusion-Chylothorax, [[Pleural Effusion-Chylothorax]])

  • Clinical: may be unilateral or bilateral

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])

  • Physiology: absence of pulmonary capillaritis
  • Clinical: usually mild
    • Hemoptysis: occurs in 20% of patients with tuberous sclerosis-associated lung disease

Interstitial Lung Disease (ILD) (see Interstitial Lung Disease, [[Interstitial Lung Disease]])

  • Epidemiology: higher incidence of pulmonary manifestations in females with tuberous sclerosis, as compared to males
  • Diagnosis
    • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]]): the degree of PFT abnormalities correlates with the severity of HRCT abnormalities
      • Obstruction with Decreased DLCO and Preserved Lung Volumes
    • Chest X-Ray (CXR) (see Chest X-Ray, [[Chest X-Ray]]): same as lymphangioleiomyomatosis (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])
    • High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]]): same as lymphangioleiomyomatosis (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])
      • Recommended: baseline HRCT at age 18 with subsequent HRCT’s q5-10 yrs
      • Diffuse Thin-Walled Cysts: usually <1 cm in diameter (may be as large as 3 cm in some cases), usually round/ovoid (may be polygonal in advanced disease), and more numerous/larger in females
      • Centrilobular Micronodules: may occur due to multifocal nodular pneumocyte hyperplasia
      • Septal Thickening: may occur due to lymphatic obstruction
    • Open Lung Biopsy: pathologically similar to lymphangioleiomyomatosis (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])
      • Open lung biopsy is rarely required in tuberous sclerosis-associated lung disease, due to characteristic HRCT findings in the setting of other tuberous sclerosis-associated clinical findings
      • Pathology may additionally demonstrate clear cell tumor of the lung or multifocal nodular pneumocyte hyperplasia
  • Clinical: similar to lymphangioleiomyomatosis (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])
    • May Worsen During Pregnancy (see Pregnancy, [[Pregnancy]])
    • Cystic Lung Disease May Be More Common with TSC2 Mutations Than with TSC1 Mutations

Pneumothorax (see Pneumothorax, [[Pneumothorax]])

  • Epidemiology: pneumothorax occurs in 33% of patients with tuberous sclerosis-associated lung disease
  • Clinical: similar to lymphangioleiomyomatosis (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])

Small Airways Disease (see Obstructive Lung Disease, [[Obstructive Lung Disease]])

  • Clinical: wheezing occurs in 60% of patients with tuberous sclerosis-associated lung disease

Renal Manifestations

Renal Benign Mesenchymal Neoplasms with Perivascular Epithelioid Cell Differentiation (PEComas)

  • Extrapulmonary Lymphangioleiomyomatosis: renal sinus, perirenal
  • Glomerular Microhamartomas
  • Renal Angiomyolipoma (Classic or Epithelioid): most common renal manifestation of tuberous sclerosis
    • Clinical
      • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): due to replacement and/or compression of the renal parenchyma
      • Flank Pain (see Flank Pain, [[Flank Pain]])
      • Hematuria (see Hematuria, [[Hematuria]]): risk of hemorrhage increases with size
      • Renin-Dependent Hypertension (see Hypertension, [[Hypertension]]): may occur
      • Renal Mass (see Renal Mass, [[Renal Mass]]): often with areas of fat attenuation on CT

Renal Cysts

  • Glomerulocystic Kidney Disease
  • Simple Renal Cyst (see Renal Cysts, [[Renal Cysts]]): occur less commonly
  • TSC2/PKD1 Contiguous Gene Syndrome


  • Focal Segmental Glomerulosclerosis
  • Horseshoe Kidney
  • Lymphangioma: occurs less commonly
  • Renal Artery Stenosis (see Renal Artery Stenosis, [[Renal Artery Stenosis]]): occasionally associated with tuberous sclerosis
  • Renal Cell Carcinoma (see Renal Cancer, [[Renal Cancer]]): occurs less commonly
  • Renal Interstitial Disease
  • Renal Oncocytoma


Treatment of Tuberous Sclerosis-Associated Lung Disease

  • Treatment Regimen is Currently Undefined: usually similar to treatment for lymphangioleiomyomatosis (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])

General Measures

  • Avoidance of Estrogen Therapy (Oral Contraceptive/Hormone Replacement Therapy) (see Estrogen, [[Estrogen]]): estrogen therapy is believed to accelerate the progression of pulmonary LAM and should be avoided
  • Oxygen (see Oxygen, [[Oxygen]]): per standard criteria
  • Pulmonary Rehabilitation (see Pulmonary Rehabilitation, [[Pulmonary Rehabilitation]])
  • Smoking Cessation (see Tobacco, [[Tobacco]]): if applicable
  • Vaccination


Medroxyprogesterone Acetate (Provera, Depo-Provera) (see Medroxyprogesterone Acetate, [[Medroxyprogesterone Acetate]])

  • Pharmacology: progestin
  • Indications: although progesterone (oral/intramuscular) is not generally recommended for the treatment of tuberous sclerosis-associated lung disease, it may be useful in some patients who are not candidates for mTOR inhibitors
  • Administration: IM (monthly x 12 mo) or PO
  • Adverse Effects (with Long-Term Progesterone Administration)
    • Increased Risk of Meningioma (see Meningioma, [[Meningioma]])
    • Increased Risk of Thromboembolic Disease (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
    • Menstrual Abnormalities

Mechanistic Target of Rapamycin (mTOR) Inhibitors (see Mechanistic Target of Rapamycin Inhibitors, [[Mechanistic Target of Rapamycin Inhibitors]]) (mTOR Inhibitors)

  • General Comments: mTOR inhibitors act similarly to the normally functioning hamartin-tuberin complex (note that this complex is dysfunctional in tuberous sclerosis)
  • Sirolimus (Rapamune, Rapamycin) (see Sirolimus, [[Sirolimus]])
    • FDA-Approved for Moderate-Severe Tuberous Sclerosis-Associated Lung Disease
    • Clinical Benefit: improves lung function [MEDLINE]

Treatments with No Demonstrated Clinical Benefit

  • Corticosteroids (see Corticosteroids, [[Corticosteroids]]): not beneficial
  • Interferon Alfa-2b (see Interferon Alfa-2b, [[Interferon Alfa-2b]]): while beneficial for LAM, does not have clinical benefit in tuberous sclerosis-associated lung disease
  • Tamoxifen (see Tamoxifen, [[Tamoxifen]]): anti-estrogenic therapy is not beneficial
  • Oophorectomy: not beneficial

Lung Transplant (see Lung Transplant, [[Lung Transplant]])

  • May Be Required in Some Cases

Treatment of Chylothorax (see Pleural Effusion-Chylothorax, [[Pleural Effusion-Chylothorax]])

Treatment of Seizures (see Seizures, [[Seizures]])

  • Seizures Represent the Most Common and Difficult to Treat Aspect of Tuberous Sclerosis
  • Anti-Epileptic Agents: depend on the type of seizures

Treatment of Brain Tumors

  • Surgical Resection
    • Recommended for Acutely Symptomatic, Resectable Subependymal Giant Cell Tumors: especially single tumors
  • mTOR Inhibitors (see Mechanistic Target of Rapamycin Inhibitors, [[Mechanistic Target of Rapamycin Inhibitors]]) (mTOR Inhibitors): may be preferred as the initial therapy for symptomatic subependymal giant cell tumors, in some cases (particularly patients with multisystem disease and/or multifocal brain tumors that may not be amenable to resection)
    • Everolimus (see Everolimus, [[Everolimus]]): decreases size of subependymal giant cell tumors
      • Administration: target a serum trough level of 5-10 ng/mL

Treatment of Skin Lesions

  • Sunscreen/Protection from Ultraviolet Rays
    • UV ray-associated DNA damage may play a role in the development of facial angiofibromas
  • Topical mTOR Inhibitors (see Mechanistic Target of Rapamycin Inhibitors, [[Mechanistic Target of Rapamycin Inhibitors]]) (mTOR Inhibitors): may be useful for facial angiofibromas, ungual fibromas, and hypomelanotic macules
    • Sirolimus (Rapamune, Rapamycin) (see Sirolimus, [[Sirolimus]])

Treatment of Cardiac Rhabdomyoma

  • Resection: most regress spontaneously during infancy, resection is required only for symptomatic cases

Treatment of Renal Lesions

  • Resection
  • Selective Renal Artery Embolization
  • Complete/Radical Nephrectomy
  • Radiofrequency Ablation
  • mTOR Inhibitors (see Mechanistic Target of Rapamycin Inhibitors, [[Mechanistic Target of Rapamycin Inhibitors]]) (mTOR Inhibitors) [MEDLINE]
    • Sirolimus (Rapamune, Rapamycin) (see Sirolimus, [[Sirolimus]])


  • Survival: tuberous sclerosis carries a decreased survival rate, relative to the general population (however, disease severity is highly variable)
  • Causes of Death
    • Neurologic Disease: due to subependymal giant cell tumors, intractable seizures, severe mental retardation
    • Pulmonary Disease
    • Renal Disease: due to renal cell carcinoma, renal failure, hemorrhage into angiomyolipoma


  • Recognition of Tuberous Sclerosis in Adult Women: Delayed Presentation With Life-Threatening Consequences Ann Intern Med. 2011;154:806-813
  • Advances in the understanding of tuberous sclerosis. Arch Dis Child. 2000;83:140-2. [PMID: 10906022]
  • Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation. Ann Neurol. 2006;60:528-39. [PMID: 17120248]
  • Role of mutational analysis in diagnosis of tuberous sclerosis complex. Clin Genet. 2009;75:282-5. [PMID: 19250385]
  • Periungual fibroma (Koenen tumors) as isolated sign of tuberous sclerosis complex with tuberous sclerosis complex 1 germline mutation [Letter]. J Am Acad Dermatol. 2010;62:159-61. [PMID: 20082901]
  • Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358:140-51 [MEDLINE]
  • Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801-11 [MEDLINE]
  • Recognition of tuberous sclerosis in adult women: delayed presentation with life-threatening consequences. Ann Intern Med 2011;154:806-813 [MEDLINE]
  • Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med. 2011;154:797-805 [MEDLINE]
  • National Institutes of Health Rare Lung Diseases Consortium and the MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364:1595-606 [MEDLINE]
  • Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013 Aug;1(6):445-52 [MEDLINE]
  • Efficacy and safety of sirolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: a systematic review. J Urol. 2014 Nov;192(5):1424-30. doi: 10.1016/j.juro.2014.04.096. Epub 2014 May 9 [MEDLINE]
  • mTOR treatment in lymphangioleiomyomatosis. Expert Rev Respir Med. 2016 Feb 4. [Epub ahead of print] [MEDLINE]
  • Lung Transplantation for Lymphangioleiomyomatosis. PLoS One. 2016 Jan 15;11(1):e0146749. doi: 10.1371/journal.pone.0146749. eCollection 2016 [MEDLINE]