{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T10:26:20Z","timestamp":1788603980675,"version":"build-2803163510"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2001,8,1]],"date-time":"2001-08-01T00:00:00Z","timestamp":996624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH) produce cystic and nodular disease, respectively, in the lungs of patients with tuberous sclerosis. The objective of this study was to prospectively characterize the prevalence, clinical presentation, and genetic basis of lung disease in TSC. We performed genotyping and computerized tomographic (CT) scanning of the chest on 23 asymptomatic women with tuberous sclerosis complex (TSC). Cystic pulmonary parenchymal changes consistent with LAM were found in nine patients (39%). These patients tended to be older than cyst-negative patients (31.9 \u00b1 7.6 yr versus 24.8 \u00b1 11.6 yr, p = 0.09). There was no correlation between presence of cysts and tobacco use, age at menarche, history of pregnancy, or estrogen-containing medications. Three of the cyst-positive patients had a prior history of pneumothorax. Pulmonary function studies revealed evidence of gas trapping but normal spirometric indices in the cyst-positive group. All nine cyst-positive patients had angiomyolipomas (AML), which were larger (p &amp;lt; 0.05) and more frequently required intervention (p = 0.08) than cyst-negative patients (8 of 14 with AMLs, p &amp;lt; 0.05). Ten patients (43%) had pulmonary parenchymal nodules. Pulmonary nodules were more common in women with cysts (78% versus 21%, p &amp;lt; 0.05), and 52% of all patients had either cystic or nodular changes. TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease. Correlation of the mutational and radiographic data revealed one pair of sisters who were discordant for cystic disease, two mother\u2013 daughter pairs who were discordant for nodular disease, and no clear association between cyst development and a specific mutational type. This prospective analysis demonstrates that cystic and nodular pulmonary changes consistent with LAM and MMPH are common in women with TSC.<\/jats:p>","DOI":"10.1164\/ajrccm.164.4.2011025","type":"journal-article","created":{"date-parts":[[2013,4,4]],"date-time":"2013-04-04T14:49:35Z","timestamp":1365086975000},"page":"661-668","source":"Crossref","is-referenced-by-count":229,"title":["Mutational and Radiographic Analysis of Pulmonary Disease Consistent with Lymphangioleiomyomatosis and Micronodular Pneumocyte Hyperplasia in Women with Tuberous Sclerosis"],"prefix":"10.1093","volume":"164","author":[{"given":"DAVID NEAL","family":"FRANZ","sequence":"first","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ALAN","family":"BRODY","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CRISTOPHER","family":"MEYER","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JENNIFER","family":"LEONARD","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GAIL","family":"CHUCK","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SANDRA","family":"DABORA","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GOPALAN","family":"SETHURAMAN","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"THOMAS V.","family":"COLBY","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DAVID J.","family":"KWIATKOWSKI","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"FRANCIS X.","family":"Mc\u2009CORMACK","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Neurology, Radiology, and Medicine, Division of Pulmonary and Critical Care Medicine, and the Center for Biostatistical Services, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona; and Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, Massachussetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2001,8,15]]},"reference":[{"key":"2026032708014800300_B1","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1378\/chest.114.6.1689","article-title":"Lymphangioleiomyomatosis: a review.","volume":"114","author":"Sullivan","year":"1998","journal-title":"Chest"},{"key":"2026032708014800300_B2","first-page":"115","article-title":"Pulmonary tuberous sclerosis. Report of three patients and a review of the literature.","volume":"40","author":"Dwyer","year":"1971","journal-title":"Q J Med"},{"key":"2026032708014800300_B3","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1164\/ajrccm.162.2.9911006","article-title":"Pulmonary lymphangioleiomyomatosis in a man.","volume":"162","author":"Aubry","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032708014800300_B4","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/00005792-199909000-00004","article-title":"Pulmonary lymphangioleiomyomatosis: a study of 69 patients.","volume":"78","author":"Urban","year":"1999","journal-title":"Medicine (Baltimore)"},{"key":"2026032708014800300_B5","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1136\/thx.54.3.254","article-title":"Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms.","volume":"54","author":"Johnson","year":"1999","journal-title":"Thorax"},{"key":"2026032708014800300_B6"},{"key":"2026032708014800300_B7","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1164\/ajrccm.151.2.7842216","article-title":"Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors.","volume":"151","author":"Kitaichi","year":"1995","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032708014800300_B8","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1056\/NEJM199011013231807","article-title":"Lymphangioleiomyomatosis: clinical course in 32 patients.","volume":"323","author":"Taylor","year":"1990","journal-title":"N Engl J Med"},{"key":"2026032708014800300_B9","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1378\/chest.91.5.782","article-title":"Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens.","volume":"91","author":"Shen","year":"1987","journal-title":"Chest"},{"key":"2026032708014800300_B10","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/0003-4975(93)90135-5","article-title":"Pulmonary lymphangiomyomatosis causing bilateral pneumothorax during pregnancy.","volume":"55","author":"Warren","year":"1993","journal-title":"Ann Thorac Surg"},{"key":"2026032708014800300_B11","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1136\/thx.49.9.910","article-title":"Relation of pulmonary lymphangio-leiomyomatosis to use of the oral contraceptive pill and fertility in the UK: a national case control study.","volume":"49","author":"Wahedna","year":"1994","journal-title":"Thorax"},{"key":"2026032708014800300_B12","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1378\/chest.115.4.1041","article-title":"Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis.","volume":"115","author":"Chu","year":"1999","journal-title":"Chest"},{"key":"2026032708014800300_B13","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1136\/thx.54.7.618","article-title":"Pulmonary lymphangioleiomyomatosis in Korea.","volume":"54","author":"Oh","year":"1999","journal-title":"Thorax"},{"key":"2026032708014800300_B14"},{"key":"2026032708014800300_B15","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.","volume":"277","author":"van Slegtenhorst","year":"1997","journal-title":"Science"},{"key":"2026032708014800300_B16","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-Z","article-title":"Identification and characterization of the tuberous sclerosis gene on chromosome 16: The European Chromosome 16 Tuberous Sclerosis Consortium.","volume":"75","author":"Consortium","year":"1993","journal-title":"Cell"},{"key":"2026032708014800300_B17","doi-asserted-by":"crossref","first-page":"16409","DOI":"10.1074\/jbc.270.27.16409","article-title":"Identification of tuberin, the tuberous sclerosis-2 product: tuberin possesses specific Rap1GAP activity.","volume":"270","author":"Wienecke","year":"1995","journal-title":"J Biol Chem"},{"key":"2026032708014800300_B18","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/35010550","article-title":"The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho [see comments].","volume":"2","author":"Lamb","year":"2000","journal-title":"Nat Cell Biol"},{"key":"2026032708014800300_B19","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1086\/302381","article-title":"Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous 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relatives.","volume":"44","author":"Slingerland","year":"1989","journal-title":"Thorax"},{"key":"2026032708014800300_B26"},{"key":"2026032708014800300_B27","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/j.1365-2559.1991.tb00856.x","article-title":"Micronodular hyperplasia of type II pneumocytes\u2014a new lung lesion associated with tuberous sclerosis.","volume":"18","author":"Popper","year":"1991","journal-title":"Histopathology"},{"key":"2026032708014800300_B28","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1046\/j.1365-2559.1997.4600811.x","article-title":"Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis.","volume":"30","author":"Lantuejoul","year":"1997","journal-title":"Histopathology"},{"key":"2026032708014800300_B29","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1097\/00000478-199804000-00012","article-title":"Micronodular pneumocyte hyperplasia.","volume":"22","author":"Muir","year":"1998","journal-title":"Am J Surg Pathol"},{"key":"2026032708014800300_B30","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1177\/088307389801301206","article-title":"Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria.","volume":"13","author":"Roach","year":"1998","journal-title":"J Child Neurol"},{"key":"2026032708014800300_B31"},{"key":"2026032708014800300_B32","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1086\/316951","article-title":"Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.","volume":"68","author":"Dabora","year":"2001","journal-title":"Am J Hum Genet"},{"key":"2026032708014800300_B33","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/jnci\/91.10.882","article-title":"Prevalence of mutations in the BRCA1 gene among Chinese patients with breast cancer.","volume":"91","author":"Tang","year":"1999","journal-title":"J Natl Cancer Inst"},{"key":"2026032708014800300_B34","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s004390000348","article-title":"Molecular genetic advances in tuberous sclerosis [In Process Citation].","volume":"107","author":"Cheadle","year":"2000","journal-title":"Hum Genet"},{"key":"2026032708014800300_B35","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1074\/jbc.272.10.6097","article-title":"The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis.","volume":"272","author":"Xiao","year":"1997","journal-title":"J Biol Chem"},{"key":"2026032708014800300_B36","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1002\/(SICI)1098-1004(1998)12:6<408::AID-HUMU7>3.0.CO;2-P","article-title":"Exon scanning of the entire TSC2 gene for germline mutations in 40 unrelated patients with tuberous 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tuberous sclerosis and lymphangiomyomatosis.","volume":"163","author":"Strizheva","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032708014800300_B40","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1007\/s003300000504","article-title":"Functional significance of air trapping detected in moderate asthma [In Process Citation].","volume":"10","author":"Laurent","year":"2000","journal-title":"Eur Radiol"},{"key":"2026032708014800300_B41","doi-asserted-by":"crossref","first-page":"591","DOI":"10.4065\/75.6.591","article-title":"High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex.","volume":"75","author":"Costello","year":"2000","journal-title":"Mayo Clin Proc"},{"key":"2026032708014800300_B42","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/S0046-8177(97)90233-1","article-title":"Lymphangioleiomyomatosis: recurrence after single lung transplantations.","volume":"26","author":"Bittmann","year":"1997","journal-title":"Hum Pathol"},{"key":"2026032708014800300_B43","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1164\/ajrccm.151.6.7767554","article-title":"Lymphangioleiomyomatosis recurrence in the allograft after single lung transplantation.","volume":"151","author":"O'Brien","year":"1995","journal-title":"Am J Respir Crit Care"},{"key":"2026032708014800300_B44","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/S0046-8177(97)90061-7","article-title":"Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis.","volume":"28","author":"Hayashi","year":"1997","journal-title":"Hum Pathol"},{"key":"2026032708014800300_B45","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1148\/radiology.199.2.8668768","article-title":"Pulmonary 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