Lymphangioleiomyomatosis Association with Underlying Genotype in Patients with Tuberous Sclerosis Complex.

Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease caused by mutations in the tuberous sclerosis complex (TSC) genes and . To examine the association between TSC mutation subtypes and the prevalence of LAM in women with TSC. Adult women seen at the Cincinnati Children's Hospital Medical Center's TSC clinic were stratified into the following three groups: those with mutation, those with mutation, and those with no mutation identified (NMI). Individual TSC manifestations were ascertained by blinded review of chest computed tomographic scans (LAM, multifocal micronodular pneumocyte hyperplasia, and sclerotic bone lesions) and chart review (all other manifestations). The association between mutation status and TSC manifestations was assessed by the Wilcoxon rank-sum test. Our cohort consisted of 55 TSC women, including 30/55 (55%) with , 12/55 (22%) with , and 13/55 (23%) with NMI. Twenty-three women (42%) had characteristic cysts consistent with LAM, of whom 16 had mutations and seven had NMI. The prevalence of LAM was higher in women with mutations compared with women with mutations (16/29 [55%] vs. 0/12;  = 0.003). Similarly, renal angiomyolipomas were more common in women with mutations compared with women with mutations (29/30 [97%] vs. 6/12 [50%];  = 0.01). There was no association between TSC mutation subtype and the presence of multifocal micronodular pneumocyte hyperplasia, sclerotic bone lesions, and skin or brain involvement. Serum VEGF-D (vascular endothelial growth factor-D) concentrations (median [95% confidence interval]) tended to be higher in patients harboring mutations compared with patients with mutations (725 pg/ml [612-1,317] vs. 331 pg/ml [284-406];  = 0.03) and in patients with LAM compared with patients without LAM (725 pg/ml [563-1,609] vs. 429 pg/ml [357-773];  = 0.02). LAM and angiomyolipomas are more common in women with TSC harboring mutations compared with women with mutations. Serum VEGF-D is a useful biomarker to suggest the presence of LAM in women with TSC.