A75-15 Pulmonary Involvement (lymphangioleiomyomatosis) In Tuberous Sclerosis Complex (TSC): Analysis Of TSC Alliance Natural History Database

Background

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder frequently associated with lymphangioleiomyomatosis (LAM), a progressive cystic lung disease. The 2022 Updated International TSC Consensus guidelines recommend clinical assessment for LAM and chest CT in all females, and symptomatic males, 18 years or older. We aimed to evaluate pulmonary screening practices along with demographic, genetic and clinical characteristics of those with TSC-LAM in a large national TSC cohort.

Methods

We conducted a retrospective observational study using the TSC Alliance Natural History Database. Demographic, genetic, and clinical data were extracted. Screening rates for LAM were assessed, and clinical, genetic, and pulmonary characteristics of patients diagnosed with LAM were analyzed.

Results

Among 2,636 patients with TSC (1,301 females, 49%), molecular testing was performed in 1,591 (60%), identifying TSC1 mutations in 349 (21.9%) and TSC2 mutations in 978 (61.5%). Screening for LAM was reported by 312 patients (11.8%; 42 (13.5%) males), of whom 116 were diagnosed with LAM; 111 (95.7%) were female. Mean age at cohort characterization was 48 years (range 21-80, SD 12.9), and mean age at LAM diagnosis (available in 82 patients) was 33 years (range 14-69, SD 12.5). Among LAM patients, molecular testing was performed in 74 (64%), TSC1 mutations were present in 8 (6.9%), TSC2 in 47 (40.5%), and dual mutations in 2. Common clinical manifestations included renal angiomyolipomas (104, 89.7%), facial angiofibromas (90, 77.6%), epilepsy (70, 60.3%), and subependymal giant cell astrocytoma (27, 23.3%). Pulmonary function data were limited (mean FEV₁ 84.9% predicted, n = 43; mean DLCO 77.6% predicted, n = 27). Serum VEGF-D available in 10 patients, range 331-9,523 pg/mL). Chest CT was performed in 87 patients (75%) and biopsy in 4 (3%). Patient-reported respiratory complications included pneumothorax (14, 12.1%), chylothorax (3, 2.6%), and oxygen requirement (4, 3.4%). Treatments included mTOR inhibitors in 32 (27.6%) and lung transplantation in 1 patient.

Conclusion

Evaluation for LAM in patients with TSC appears to be underutilized in the U.S. LAM mainly affects women, is linked to TSC2 mutations, and is associated with high rates of renal and dermatologic manifestations. Although guidelines focus on females, LAM can occur in males, highlighting the need for awareness in all TSC patients. Limited lung function and biomarker data reveal gaps in evaluation, with some patients developing severe disease requiring oxygen or lung transplantation. These findings support standardized, genotype-informed surveillance for early detection and targeted care in TSC-related LAM.

This abstract is funded by: None