Our aim in this review is to discuss currently known mechanisms associated with three important syndromes of the first and second pharyngeal arches: Treacher Collins syndrome (TCS), Oculo-auriculo-vertebral syndrome (AOVS) and Auriculo-Condylar syndrome (ACS) or question mark ear syndrome. TCS and ACS are autosomal dominant diseases, with nearly complete penetrance and wide spectrum of clinical variability. The phenotype of the latter has several overlapping features with OAVS, but OAVS may exist in both sporadic and autosomal dominant forms. Mutations in the TCOF1 gene are predicted to cause premature termination codons, leading to haploinsuficiency of the protein treacle and causing TCS. Low amount of treacle leads ultimately to a reduction in the number of cranial neural crest cells migrating to the first and second pharyngeal arches. Other than TCS, the genes associated with ACS and OAVS are still unknown. The first locus for ACS was mapped by our group to 1p21-23 but there is genetic heretogeneity. Genetic heterogeneity is also present in OAVS. Based on the molecular analysis of balanced translocation in an OAVS patient, it has been suggested that abnormal expression of BAPX1 possibly due to epigenetic disregulation might be involved with the etiology of OAVS. Involvement of environmental events has also been linked to the causation of OAVS. Identification of factors leading to these disorders are important for a comprehensive delineation of the molecular pathways underlying the craniofacial development from the first and the second pharyngeal arches, for genetic counseling and to open alternative strategies for patient treatment.
2009 Wiley-Liss, Inc.