Defining genetic and physiopathological bases of orbital hypertelorism: about a systematic literature review.

Orbital hypertelorism is observed in a wide spectrum of congenital disorders, such as in case of frontonasoethmoidal tumors or encephaloceles, craniofrontonasal dysplasia, craniofacial clefts, syndromic craniosynostosis, Rasopathies and various malformative and multisystemic congenital syndromes. Yet its underlying pathophysiological mechanisms remain incompletely understood. Our systematic literature review aimed to delineate and classify the different conditions associated with true orbital hypertelorism based on both genetic bases and physiopathological mechanisms of orbital hypertelorism. Anomalies at different developmental stages can result in hypertelorism. Early embryonic defects - such as neurulation abnormalities, impaired fusion of frontonasal and maxillary prominences or nasal capsule hypoplasia - result in primary orbital widening. Perinatal disturbances of cranial suture fusion or skull base development, particularly of the sphenoid bone and cranial base synchondroses, contribute to hypertelorism in syndromic craniosynostoses and some RASopathies. Advances in molecular genetics have identified numerous genes implicated in these processes. However, establishing genotype-phenotype correlations remain challenging due to variable clinical expressivity and remaining confusion between true orbital hypertelorism and telecanthus or depressed nasal bridge. Better understanding of developmental, genetics and physiopathological mechanisms leading to orbital hypertelorism, is essential to improve diagnostic rate, genetic counseling and, to optimize therapeutic strategies including multidisciplinary management and surgical planning.