Treacher Collins syndrome: etiology, pathogenesis and prevention

Abstract

Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development that arises as the result of mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein known as Treacle. Individuals diagnosed with TCS frequently undergo multiple reconstructive surgeries, which are rarely fully corrective. Identifying potential avenues for rescue and/or repair of TCS depends on a profound appreciation of the etiology and pathogenesis of the syndrome. Recent research using animal models has not only determined the cellular basis of TCS but also, more importantly, unveiled a successful avenue for therapeutic intervention and prevention of the craniofacial anomalies observed in TCS.

Figure 1

Diagnostic algorithm summarizing the morphological and genetic identification of individuals with Treacher Collins syndrome and their subsequent management. By permission of Oxford University Press, Inc.

Figure 2

Clinical photographs and partial pedigree of a Somalian family. Individual I-2, who has an extensive family history of TCS, exhibits no apparent clinical features of mandibulofacial dysostosis. In contrast, all three children exhibit severe craniofacial anomalies consistent with TCS and furthermore share the same mutation (c.2259delA) as I-2. Adapted from chapter ‘Treacher Collins syndrome' by Dixon, Trainor and Dixon from ‘In born Errors of Development' edited by Epstein, Erickson and Wynshaw-Boris (2008). By permission of Oxford University Press, 2008.

Figure 3

Developmental basis of TCS craniofacial anomalies. Comparative skeletal stains of E18.5 wild-type embryos (a) revealed severe frontonasal hypoplasia in Tcof1^+/− littermates (b). Sox10 in situ hybridization of migrating neural crest cells in an E8.5 wild-type embryo (c) uncovered a severe reduction in the neural crest cell population in Tcof1^+/− embryos (d). Staining for apoptosis (TUNEL:green) showed low endogenous levels of cell death in E8.5 wild-type embryos (e) and massively elevated levels in Tcof1^+/− littermates (f). BrdU incorporation (red) into DAPI-stained nuclei (blue) of E9.0 embryos (g) highlighted a concomitant decrease in cell proliferation in Tcof1^+/− embryos (h). Immunostaining for the 28S ribosomal protein (red) in E8.5 embryos (i) uncovered deficient ribosome biogenesis in Tcof1^+/− littermates (j). Adapted from Dixon et al (2006).

Figure 4

Prevention of TCS through diminishment of p53 function. Activated capase3 immunostaining revealed low levels of cell death in E9.0 Tcof1^+/+ (a) embryos, elevated levels in Tcof1^+/− (b) and partially reduced levels in Tcof1^+/−; p53^+/− (c) littermates. Sox10 in situ hybridization labeled migrating neural crest cells in E9.5 Tcof1^+/+ (d) embryos highlighting the reduction in Tcof1^+/− (e) and restoration in Tcof1^+/−; p53^+/− (f) littermates. Bone (red) and cartilage (blue) staining showed normal cranioskeletal patterning in E18.5 Tcof1^+/+ (g) embryos, severe frontonasal hypoplasia and dysplasia in Tcof1^+/− (h) and complete rescue in Tcof1^+/−; p53^+/− (f) littermates. Bright field photograph of a 3-month-old Tcof1^+/+ mouse (j) and a rescued post-natal viable and fertile Tcof1^+/−; p53^+/− (k) littermate. Adapted from Jones et al (2008).