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.

BackgroundTreacher Collins syndrome (TCS) is an autosomal dominant craniofacial disorder caused by frameshift deletions or duplications in the TCOF1 gene. These mutations cause premature termination codons, which are predicted to lead to mRNA degradation by nonsense mediated mRNA decay (NMD). Haploinsufficiency of the gene product (treacle) during embryonic development is the proposed molecular mechanism underlying TCS. However, it is still unknown if TCOF1 expression levels are decreased in post-embryonic human cells.MethodsWe have estimated TCOF1 transcript levels through real time PCR in mRNA obtained from leucocytes and mesenchymal cells of TCS patients (n = 23) and controls (n = 18). Mutational screening and analysis of NMD were performed by direct sequencing of gDNA and cDNA, respectively.ResultsAll the 23 patients had typical clinical features of the syndrome and pathogenic mutations were detected in 19 of them. We demonstrated that the expression level of TCOF1 is 18-31% lower in patients than in controls (p < 0.05), even if we exclude the patients in whom we did not detect the pathogenic mutation. We also observed that the mutant allele is usually less abundant than the wild type one in mesenchymal cells.ConclusionsThis is the first study to report decreased expression levels of TCOF1 in TCS adult human cells, but it is still unknown if this finding is associated to any phenotype in adulthood. In addition, as we demonstrated that alleles harboring the pathogenic mutations have lower expression, we herein corroborate the current hypothesis of NMD of the mutant transcript as the explanation for diminished levels of TCOF1 expression. Further, considering that TCOF1 deficiency in adult cells could be associated to pathologic clinical findings, it will be important to verify if TCS patients have an impairment in adult stem cell properties, as this can reduce the efficiency of plastic surgery results during rehabilitation of these patients.