Epidemiology
- 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)
Physiology
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
Diagnosis
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]])
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]])
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
- 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
Other
- 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
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
Bronchodilators
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]])
Prognosis
- 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
References
- 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]