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WIREs Dev Biol
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Rare syndromes of the head and face: mandibulofacial and acrofacial dysostoses

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Craniofacial anomalies account for approximately one‐third of all congenital birth defects reflecting the complexity of head and facial development. Craniofacial development is dependent upon a multipotent, migratory population of neural crest cells, which generate most of the bone and cartilage of the head and face. In this review, we discuss advances in our understanding of the pathogenesis of a specific array of craniofacial anomalies, termed facial dysostoses, which can be subdivided into mandibulofacial dysostosis, which present with craniofacial defects only, and acrofacial dysostosis, which encompasses both craniofacial and limb anomalies. In particular, we focus on Treacher Collins syndrome, Acrofacial Dysostosis‐Cincinnati Type as well as Nager and Miller syndromes, and animal models that provide new insights into the molecular and cellular basis of these congenital syndromes. We emphasize the etiologic and pathogenetic similarities between these birth defects, specifically their unique deficiencies in global processes including ribosome biogenesis, DNA damage repair, and pre‐mRNA splicing, all of which affect neural crest cell development and result in similar tissue‐specific defects. WIREs Dev Biol 2017, 6:e263. doi: 10.1002/wdev.263 This article is categorized under: Signaling Pathways > Cell Fate Signaling Birth Defects > Craniofacial and Nervous System Anomalies
Neural crest cells and craniofacial development. (a–c) Mef2c‐F10N‐Lacz whole‐mount expression marking migrating neural crest cells as they migrate away from the dorsal neural tube to colonize the frontonasal prominence (FNP) and pharyngeal arches 1 and 2 (PA1,PA2). (d–f) NCC derivatives. (d) TUJ1 whole‐mount immunostaining for NCC and placode‐derived neurons. (e) Alizarin red and alcian blue staining for bone and cartilage, respectively. Frontal bone derived from the FNP, and maxilla and mandible derived from PA1. (f) Schematic of the NCC‐derived craniofacial bones of a healthy human adult. Frontal bone derived from the FNP, and maxilla and mandible derived from PA1.
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Ribosome biogenesis. (a) Wild‐type cell. 1, normal ribosome biogenesis; 2, normal MDM2 inhibition of p53; and 3, normal protein synthesis, cell growth and cell proliferation. (b) Tcof1+/−, polr1c−/−, polr1d−/− cell. 1, nucleolar stress and decreased ribosome biogenesis; 2, ribosomal proteins bound to MDM2 causing a conformational change leading to enhanced p53 expression; and 3, decreased protein synthesis, cell cycle arrest and apoptosis.
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Mandibulofacial dysostosis. (a) Schematic of the pharyngeal arches of a healthy human embryo. (b) Maxilla and mandible bone structures derived from neural crest cells that colonize the first pharyngeal arch. (c) Schematic of the pharyngeal arches of a human embryo with mandibulofacial dysostosis which arises as a consequence of hypoplastic first and second pharyngeal arches. (d) Hypoplastic maxilla and mandible bone structures observed in mandibulofacial dysostoses.
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Signaling Pathways > Cell Fate Signaling
Birth Defects > Craniofacial and Nervous System Anomalies