The ocular surface consequences of lacrimal gland loss are life-stage dependent.

This study aimed to characterize the clinical manifestations of congenital isolated lacrimal gland aplasia (LGA) and to elucidate the life-stage-dependent effects of lacrimal gland (LG) loss on ocular surface homeostasis. Five MRI-confirmed congenital isolated LGA patients underwent comprehensive clinical evaluations, including tear volume, meibomian gland (MG) morphology, corneal sensitivity, and in vivo confocal microscopy. Tear proteomics was performed to identify molecular alterations. Neonatal (LGE-neo) and adult (LGE-adult) LG excision mouse models were established to study the pathogenesis of ocular surface impairments using transcriptomic, lipidomic, histological, and immunofluorescence analyses. Congenital isolated LGA patients exhibited severe dry eye with corneal epithelial defects, neurotrophic keratopathy (NK), and MG dysfunction (MGD), especially in bilateral cases. Tear proteomic profiling of LGA patients revealed activation of TNF/IL-17 inflammatory pathways alongside suppression of tear secretion-related signaling. LGE-neo mice substantially recapitulated patient phenotypes, demonstrating progressive tear loss, NK-like corneal nerve degeneration with reduced neurotrophic factors (NGF/BDNF) and activation of corneal senescence characterized by increased epithelial/stromal SA-β-gal activity and senescence-associated secretory phenotype (IL-6/TNFα) secretion. Conjunctival goblet cells exhibited early compensatory hyperplasia followed by mucin (MUC5AC/GALNT6) secretory suppression, while MG showed acinar dropout, ductal obstruction, and ceramide-dominated meibum lipid dysregulation. In contrast, LGE-adult mice showed minimal ocular surface alterations. Our experimental findings suggest that life stage may be a key influencer of disease severity following LG loss. Early-life LG loss impairs ocular surface integrity and is associated with features of chronic ocular surface neuroinflammation, mucin secretory deficiency, and MG lipid metabolic disorder.