FREM2 encodes an extracellular matrix protein that plays critical roles in epithelial integrity and organ development. The protein is required for maintenance of skin epithelium and renal epithelia, functioning in epidermal adhesion and cell-matrix interactions 1. FREM2 is essential for eye development, particularly eyelid formation and anterior segment morphogenesis 23. The protein forms a self-stabilizing complex with FREM1 and FRAS1 in the extracellular matrix 4. FREM2 also regulates organ size through modulation of elastic fiber organization, ROCK signaling, and cell polarity in mesothelial cells, particularly affecting lung growth 5. Loss-of-function mutations in FREM2 cause Fraser syndrome 2 and isolated cryptophthalmos, characterized by eyelid malformation and ocular dysplasia 3. FREM2 deficiency is also associated with congenital diaphragmatic hernia development through effects on mesothelial fold progression 4. Additionally, FREM2 expression is elevated in glioblastoma and appears to play a role in malignant brain tumor progression, with pathway activation serving as a potential biomarker 67. The gene is also regulated by ACTH in fetal adrenal development 8.