Lymphangioleiomyomatosis Association with Underlying Genotype in Patients with Tuberous Sclerosis Complex

RATIONALE Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease caused by mutations in the Tuberous Sclerosis Complex (TSC) genes - TSC1 and TSC2. OBJECTIVE Examine the association between TSC mutation subtypes and the prevalence of LAM in women with TSC. METHODS Adult women seen at the Cincinnati Children's Hospital Medical Center's TSC clinic were stratified into three groups: those with TSC1 mutation, those with TSC2 mutation, and those with no mutation identified (NMI). Individual TSC manifestations were ascertained by blinded review of chest CT scans (LAM, multifocal micronodular pneumocyte hyperplasia (MMPH) 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. RESULTS Our cohort consisted of 55 TSC women: TSC2: 30/55 (55%), TSC1: 12/55 (22%), and NMI: 13/55 (23%). 23 women (42%) had characteristic cysts consistent with LAM, of whom 16 had TSC2 mutations and 7 were NMI. The prevalence of LAM was higher in women with TSC2 mutations compared to women with TSC1 mutations (16/29, 55% vs. 0/12, p=0.003). Similarly, renal angiomyolipomas (AMLs) were more common in women with TSC2 mutations compared to women with TSC1 mutations (29/30, 97% vs. 6/12, 50%, p=0.01). There was no association between TSC mutation subtype and the presence of MMPH, sclerotic bone lesions, skin or brain involvement. Serum vascular endothelial growth factor-D (VEGF-D) levels (median (95% confidence interval) were higher in patients harboring TSC2 mutations compared to patients with TSC1 mutations [725pg/ml (612 - 1,317) vs. 331pg/ml (284 - 406), p=0.03], and in patients with LAM compared to patients without LAM [725pg/ml (563 - 1,609) vs. 429pg/ml (357 - 773), p=0.02]. CONCLUSIONS LAM and AMLs are more common in TSC women with TSC2 mutations compared to women with TSC1 mutations. Serum VEGF-D is a useful biomarker to suggest the presence of LAM in women with TSC.