Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis

Lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyper plasia (MMPH) produce cystic and nodular disease, respectively, in the lung s of patients with tuberous sclerosis. The objective of this study was to p rospectively characterize the prevalence, clinical presentation, and geneti c basis of lung disease in TSC. We performed genotyping and computerized to mographic (CT) scanning of the chest on 23 asymptomatic women with tuberous sclerosis complex (TSC). Cystic pulmonary parenchymal changes consistent w ith LAM were found in nine patients (39%). These patients tended to be olde r than cyst-negative patients (31.9 +/- 7.6 yr versus 24.8 +/- 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. P ulmonary function studies revealed evidence of gas trapping but normal spir ometric indices in the cyst-positive group. All nine cyst-positive patients had angiomyolipomas (AML), which were larger (p < 0.05) and more frequentl y required intervention (p = 0.08) than cyst-negative patients (8 of 14 wit h AMLs p < 0.05). Ten patients (43%) had pulmonary parenchymal nodules. Pul monary nodules were more common in women with cysts (78% versus 21%, p < 0. 05), and 52% of all patients had either cystic or nodular changes. TSC2 mut ations 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-daughter pairs who were discordant for nodular disease, and no clear association be tween cyst development and a specific mutational type. This prospective ana lysis demonstrates that cystic and nodular pulmonary changes consistent wit h LAM and MMPH are common in women with TSC.