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
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]
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
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]])
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
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
β2 Agonists (see β2-Adrenergic Receptor Agonists): may be useful in patients with airflow obstruction (particularly those with bronchodilator responsiveness)
Muscarinic Antagonists (see Muscarinic Antagonists): may be useful in patients with airflow obstruction
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
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
Progesterone (see Progesterone, [[Progesterone]]): not beneficial
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
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]
