WOMEN WITH LYMPANGIOLEIOMYOMATOSIS: FROM RESPIRATORY FUNCTION TO SERUM BIOMARKERS ANALYSIS. PHENOTYPING OF A RARE DISEASE.

Lymphangioleiomyiomatosis (LAM) is a rare progressive cystic lung disease that affects almost exclusively women. LAM can occur sporadically, or can be associated with tuberous sclerosis complex (TSC); a rare disorder with multiorgan involvement effecting the brain, kidneys, heart, liver, skin and eyes and is associated with intellectual disability, epilepsy and autism spectrum disorders. Dr.Terraneo PhD project was developed with the aim to expand clinical knowledge about diagnosis and follow up as well as to analyze pathogenic aspect of the development of the disease. As a first step of the PhD project, the association between LAM and other features of TSC (e.g. demography, extrapulmonary manifestations, genetic mutations..) was investigated as well as the role of pulmonary function tests (PFTs) for LAM diagnosis. Our results demonstrate that age, but not PFTs, is independently associated with LAM development in patients with TSC. PFTs, even if indicated to assess impairment in lung function, result feasible in a limited number of patients due to cognitive impairment, and are not significantly useful for LAM diagnosis in women with TSC. Successively, the case of a patients with coexistence of three rare diseases (autoimmune hepatitis/primary biliary cirrhosis overlap syndrome, lymphangioleiomyomatosis/tuberous sclerosis complex (LAM-TSC), and sarcoidosis) was described. We speculated that the dysregulation of the pathway involving mTOR and MAPK and their interaction might play a role in the pathogenesis of diseases other than TSC, including sarcoidosis. In the last part of PhD project, the serum levels of VEGF-D, VEGF-C, MMP-2 and MMP-7 were assessed in a cohort of patients affected with S-LAM and TSC with and without LAM. Our results showed that VEGF-D, MMP-2 and MMP7 were higher in patients with LAM than in patients without. VEGF-D was confirmed as the biomarkers with the highest accuracy for LAM diagnosis. MMP-2 and MMP-7 could be a promising biomarker of LAM.