HYAL2 (hyaluronidase 2) is a lysosomal glycosylphosphatidylinositol-anchored cell-surface protein that catalyzes hyaluronan degradation 1. It functions as the initial enzyme in a two-step hyaluronan catabolism pathway, cleaving high-molecular-mass hyaluronan into ~20 kDa fragments that are subsequently processed by HYAL1 and exoglycosidases in lysosomes 1. HYAL2 exhibits low hyaluronidase activity at acidic pH (below pH 4) and can maintain activity in near-neutral conditions when bound to its cell-surface receptor CD44, enabling hyaluronan degradation within the extracellular matrix microenvironment 2. Beyond hyaluronan metabolism, HYAL2 serves as the cell-surface receptor for jaagsiekte sheep retrovirus and ovine nasal adenocarcinoma virus 3, and participates in tumor metastatic colonization through extracellular matrix remodeling 4. Biallelic HYAL2 variants cause Muggenthaler-Chowdhury-Chioza syndrome, characterized by syndromic cleft lip/palate, congenital heart disease, craniofacial dysmorphism, myopia, and developmental delays 5. Pathogenic missense variants impair protein folding and stability, resulting in absent or reduced cell-surface HYAL2 expression 5. HYAL2 deficiency disrupts extracellular matrix homeostasis during critical developmental processes, particularly craniofacial and cardiac morphogenesis 6.