Etiology and Pathogenesis of Hemifacial Microsomia

Hemifacial microsomia (HFM) is a common congenital malformation of the craniofacial region. There are 3 possible pathogenic models of HFM—vascular abnormality and hemorrhage in the craniofacial region, damage to Meckel’s cartilage, and the abnormal development of cranial neural crest cells—and the most plausible hypothesis is the vascular abnormality and hemorrhage model. These 3 models are interrelated, and none of them is completely concordant with all the variable manifestations of HFM. External environmental factors (e.g., thalidomide, triazene, retinoic acid, and vasoactive medications), maternal intrinsic factors (e.g., maternal diabetes), and genetic factors (e.g., the recently reported mutations in OTX2, PLCD3, and MYT1) may lead to HFM through ≥1 of these pathogenic processes. Whole genome sequencing to identify additional pathogenic variants, biological functional studies to understand the exact molecular mechanisms, and additional animal model and clinical studies with large stratified samples to elucidate the pathogenesis of HFM will be necessary. Small-molecule drugs, as well as CRISPR/CAS9-based genetic interventions, for the prevention and treatment of HFM may also be a future research hotspot.