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Pulmonary involvement in tuberous sclerosis complex

Talmadge E King, Jr, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editors
Helen Hollingsworth, MD
Geraldine Finlay, MD


Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin (image 1A-B) [1-3]. The estimated prevalence is approximately 9 per 100,000 live births. The classic clinical triad consists of mental retardation, seizures, and facial adenoma sebaceum. The features are variable, however, and some affected individuals can have normal intelligence (table 1).

TSC is transmitted as an autosomal dominant trait, but only about one-third of cases are familial. Two different genetic loci have been identified: one on chromosome 9 (TSC1) and one on chromosome 16p (TSC2), which is immediately adjacent to the gene for the most common form of autosomal dominant polycystic kidney disease (PKD1) [4-6]. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Genetics'.)

Nonfamilial cases represent either spontaneous mutations or mosaicism, in which only some cells in the affected parent express the mutant gene. Mosaicism should be suspected if mild abnormalities are detected by careful evaluation of the parents or when apparently unaffected parents have a second child with TSC [7].

The pulmonary manifestations of TSC, also known as pulmonary lymphangioleiomyomatosis (LAM), will be reviewed here. The genetics, clinical features, and natural history of TSC and the diagnosis and management of sporadic pulmonary LAM are discussed separately. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis" and "Renal manifestations of tuberous sclerosis complex" and "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis" and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis".)


A number of studies have found a female predominance among patients with TSC who have lung involvement [8-12]. In studies looking at computed tomographic (CT) evidence of cystic lung disease among patients with known TSC, the proportion of women with lung involvement ranges from 30 to 50 percent, although the proportion may approach 80 percent with advancing age [11-15]. The proportion of men with lung involvement is approximately 10 percent [14,16]. However, a retrospective review of CT scans of the chest and abdomen from 29 men with TSC encountered during a 13-year period showed cystic lung disease (defined as ≥4 cysts) in 11 (38 percent) [13]. The variability is likely due to the small size of the study populations. In one series, cystic lung disease was more common among women with the TSC2 mutation than TSC1 [12]. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Genetics'.)


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Literature review current through: Mar 2017. | This topic last updated: Dec 01, 2016.
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  1. Stillwell TJ, Gomez MR, Kelalis PP. Renal lesions in tuberous sclerosis. J Urol 1987; 138:477.
  2. von Ranke FM, Zanetti G, e Silva JL, et al. Tuberous Sclerosis Complex: State-of-the-Art Review with a Focus on Pulmonary Involvement. Lung 2015; 193:619.
  3. Henske EP, Jóźwiak S, Kingswood JC, et al. Tuberous sclerosis complex. Nat Rev Dis Primers 2016; 2:16035.
  4. Brook-Carter PT, Peral B, Ward CJ, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome. Nat Genet 1994; 8:328.
  5. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277:805.
  6. European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75:1305.
  7. Kwiatkowska J, Wigowska-Sowinska J, Napierala D, et al. Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. N Engl J Med 1999; 340:703.
  8. Lamb RF, Roy C, Diefenbach TJ, et al. The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2000; 2:281.
  9. Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000; 75:591.
  10. Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 2001; 164:661.
  11. Moss J, Avila NA, Barnes PM, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001; 164:669.
  12. Muzykewicz DA, Sharma A, Muse V, et al. TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J Med Genet 2009; 46:465.
  13. Ryu JH, Sykes AM, Lee AS, Burger CD. Cystic lung disease is not uncommon in men with tuberous sclerosis complex. Respir Med 2012; 106:1586.
  14. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49:243.
  15. Cudzilo CJ, Szczesniak RD, Brody AS, et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 2013; 144:578.
  16. Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, et al. Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. Clin Radiol 2011; 66:625.
  17. Hancock E, Tomkins S, Sampson J, Osborne J. Lymphangioleiomyomatosis and tuberous sclerosis. Respir Med 2002; 96:7.
  18. Stefansson K. Tuberous sclerosis. Mayo Clin Proc 1991; 66:868.
  19. Maragliano S, Di Miceli G, Librizzi D, Muscolino G. Tuberous sclerosis with pulmonary involvement. A rare cause of bilateral pneumothorax. A case report. Chir Ital 2003; 55:465.
  20. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006; 173:105.
  21. Valensi QJ. Pulmonary lymphangiomyoma, a probable forme frust of tuberous sclerosis. A case report and survey of the literature. Am Rev Respir Dis 1973; 108:1411.
  22. Yamamoto K, Anzai F, Kusajima K, et al. Acute respiratory failure with gross hemoptysis in a patient with lymphangioleiomyomatosis as part of tuberous sclerosis complex. Intern Med 2004; 43:755.
  23. Ryu JH, Doerr CH, Fisher SD, et al. Chylothorax in lymphangioleiomyomatosis. Chest 2003; 123:623.
  24. Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med 2008; 358:199.
  25. Young LR, Vandyke R, Gulleman PM, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138:674.
  26. McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med 2016; 194:748.
  27. Young L, Lee HS, Inoue Y, et al. 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; 1:445.
  28. Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010; 35:14.
  29. Lenoir S, Grenier P, Brauner MW, et al. Pulmonary lymphangiomyomatosis and tuberous sclerosis: comparison of radiographic and thin-section CT findings. Radiology 1990; 175:329.
  30. Seaman DM, Meyer CA, Gilman MD, McCormack FX. Diffuse cystic lung disease at high-resolution CT. AJR Am J Roentgenol 2011; 196:1305.
  31. Kobashi Y, Sugiu T, Mouri K, et al. Clinicopathological analysis of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis in Japan. Respirology 2008; 13:1076.
  32. Meraj R, Wikenheiser-Brokamp KA, Young LR, et al. Utility of transbronchial biopsy in the diagnosis of lymphangioleiomyomatosis. Front Med 2012; 6:395.
  33. Harari S, Torre O, Cassandro R, et al. Bronchoscopic diagnosis of Langerhans cell histiocytosis and lymphangioleiomyomatosis. Respir Med 2012; 106:1286.
  34. Ye L, Jin M, Bai C. Clinical analysis of patients with pulmonary lymphangioleiomyomatosis (PLAM) in mainland China. Respir Med 2010; 104:1521.
  35. Muir TE, Leslie KO, Popper H, et al. Micronodular pneumocyte hyperplasia. Am J Surg Pathol 1998; 22:465.
  36. Popper HH, Juettner-Smolle FM, Pongratz MG. Micronodular hyperplasia of type II pneumocytes--a new lung lesion associated with tuberous sclerosis. Histopathology 1991; 18:347.
  37. Maruyama H, Ohbayashi C, Hino O, et al. Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2. Pathol Int 2001; 51:585.
  38. Hayashi T, Kumasaka T, Mitani K, et al. Loss of heterozygosity on tuberous sclerosis complex genes in multifocal micronodular pneumocyte hyperplasia. Mod Pathol 2010; 23:1251.
  39. Tobino K, Hirai T, Johkoh T, et al. Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol 2012; 81:1340.
  40. Mitchell AL, Parisi MA, Sybert VP. Effects of pregnancy on the renal and pulmonary manifestations in women with tuberous sclerosis complex. Genet Med 2003; 5:154.
  41. Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49:255.
  42. Johnson SR. The ERS guidelines for LAM: trying a rationale approach to a rare disease. Respir Med 2010; 104 Suppl 1:S33.
  43. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364:1595.
  44. Luna CM, Gené R, Jolly EC, et al. Pulmonary lymphangiomyomatosis associated with tuberous sclerosis. Treatment with tamoxifen and tetracycline-pleurodesis. Chest 1985; 88:473.
  45. Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999; 160:628.
  46. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, et al. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest 2004; 126:1867.
  47. de la Fuente J, Páramo C, Román F, et al. Lymphangioleiomyomatosis: unsuccessful treatment with luteinizing-hormone-releasing hormone analogues. Eur J Med 1993; 2:377.
  48. Rossi GA, Balbi B, Oddera S, et al. Response to treatment with an analog of the luteinizing-hormone-releasing hormone in a patient with pulmonary lymphangioleiomyomatosis. Am Rev Respir Dis 1991; 143:174.
  49. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991; 66:792.