Prevention methods for Treacher Collins syndrome: A systematic review.

OBJECTIVES: Treacher Collins syndrome (TCS) is a severe congenital mandibulofacial dysostosis that occurs one in every 50,000 births. The main clinical treatment of this rare disorder is reconstruction surgery. However, the high invasion, low security and long period of surgical intervention make it essential to explore prevention methods to decrease morbidity. The authors' aim is to summarize the prevention methods based on known mechanisms of TCS. METHODS: A systematic review was conducted through an electronic search of PubMed, EMBASE and Web of Science databases through November 2019 using the following items: 'Treacher Collins syndrome OR TCS OR Franceschetti-Zwahlein-Klein syndrome OR Berry syndrome', 'gene therapy OR prevention'. Four causative gene names were also used. Articles which published in English language and explored the prevention methods for TCS were included and data concerning animal model, intervention, phenotype, conclusion were gathered. RESULTS: Sixty-five studies were reviewed in total, and seven articles were included in this systematic review. Four articles used prevention methods related to the inhibition of p53, and three related to preclusion of oxidative stress-induced DNA damage. CONCLUSIONS: This article provides a comprehensive review of the prevention methods for craniofacial abnormalities characteristic of TCS based on known pathogenesis in the current literatures. The craniofacial phenotype could be rescued through several treatment methods experimentally such as p53 inhibition and antioxidant administration.

Restoration of polr1c in Early Embryogenesis Rescues the Type 3 Treacher Collins Syndrome Facial Malformation Phenotype in Zebrafish.

Treacher Collins syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects. Recently, the authors' group unfolded the pathogenesis of polr1c Type 3 TCS by using the zebrafish model. Facial development depends on the neural crest cells, in which polr1c plays a role in regulating their expression. In this study, the authors aimed to identify the functional time window of polr1c in TCS by the use of photo-morpholino to restore the polr1c expression at different time points. Results suggested that the restoration of polr1c at 8 hours after fertilization could rescue the TCS facial malformation phenotype by correcting the neural crest cell expression, reducing the cell death, and normalizing the p53 mRNA expression level in the rescued morphants. However, such recovery could not be reproduced if the polr1c is restored after 30 hours after fertilization.

Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation.

Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Since the majority of the bones, cartilage and connective tissues that comprise the head and face are derived from a multipotent migratory progenitor cell population called the neural crest, craniofacial disorders are typically attributed to defects in neural crest cell development. Treacher Collins syndrome (TCS) is a disorder of craniofacial development and although TCS arises primarily through autosomal dominant mutations in TCOF1, no clear genotype-phenotype correlation has been documented. Here we show that Tcof1 haploinsufficiency results in oxidative stress-induced DNA damage and neuroepithelial cell death. Consistent with this discovery, maternal treatment with antioxidants minimizes cell death in the neuroepithelium and substantially ameliorates or prevents the pathogenesis of craniofacial anomalies in Tcof1(+/-) mice. Thus maternal antioxidant dietary supplementation may provide an avenue for protection against the pathogenesis of TCS and similar neurocristopathies.

Craniofacial birth defects: The role of neural crest cells in the etiology and pathogenesis of Treacher Collins syndrome and the potential for prevention.

Of all the babies born with birth defects, approximately one-third display anomalies of the head and face [Gorlin et al., 1990] including cleft lip, cleft palate, small or absent facial and skull bones and improperly formed nose, eyes, ears, and teeth. Craniofacial disorders are a primary cause of infant mortality and have serious lifetime functional, esthetic, and social consequences that are devastating to both children and parents alike. Comprehensive surgery, dental care, psychological counseling, and rehabilitation can help ameliorate-specific problems but at great cost over many years which dramatically affects national health care budgets. For example, the Center for Disease Control and Prevention estimates that the lifetime cost of treating the children born each year with cleft lip and/or cleft palate alone to be US$697 million. Treating craniofacial malformations, of which in excess of 700 distinct syndromes have been described, through comprehensive, well-coordinated and integrated strategies can provide satisfactory management of individual conditions, however, the results are often variable and rarely fully corrective. Therefore, better techniques for tissue repair and regeneration need to be developed and therapeutic avenues of prevention need to be explored in order to eliminate the devastating consequences of head and facial birth defects. To do this requires a thorough understanding of the normal events that control craniofacial development during embryogenesis. This review therefore focuses on recent advances in our understanding of the basic etiology and pathogenesis of a rare craniofacial disorder known as Treacher Collins syndrome and emerging prospects for prevention that may have broad application to congenital craniofacial birth defects.

Treacher Collins syndrome: etiology, pathogenesis and prevention.

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.

Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function.

Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1-mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1-driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.

Teratological studies on craniofacial malformations.

Craniofacial malformations cause great human suffering. The purpose of the experimental studies was to investigate teratogenically induced craniofacial malformations in the rat, and to study if vitamin B6 could prevent the teratogenically induced malformations in the rat. The aim of the clinical investigation was to compare mandibulofacial dysostosis (MFD) with hemifacial microsomia (HFM) and thalidomide-induced malformations restricted to the first and second branchial arches. In the experimental studies we used two different teratogenic agents, etretinate and BAPN (beta-aminoproprionitrile). Vitamin B6 was administered one day prior to and simultaneously with the teratogenic agent. The induced malformations were observed by direct microscopy, histology, differential staining, microdissection and enzyme histochemistry. Knowledge of isoenzymic differentiation was obtained by isoelectric focusing and polyacrylamide gel electrophoresis. The clinical features of 29 patients with MFD, 26 with HFM and seven with thalidomide-induced malformations were investigated. The patients underwent clinical investigations, radiography, tomography, computed tomography, surgical exploration and audiograms. The etretinate-induced syndrome in the rat shows similarities to first and second branchial arch syndromes in man. Defective formation of Meckel's cartilage and the cartilaginous skull base, the zygoma and the middle ear ossicles were prominent features of the observed malformations. The induced malformations were accompanied by increased staining for alkaline phosphatase (APase) in the skull and skull base cartilages and Meckel's cartilage. BAPN induced cleft palate in 95% of the cases and the teratogenically induced cleft palate was accompanied by a pathological differentiation pattern that could be traced by determination of isoenzymes in the palatal shelves as well as in amniotic fluid. Vitamin B6 could prevent the teratogenic malformations induced by etretinate and BAPN in the rat. Comparing MFD, HFM and thalidomide-induced malformations, all syndromes included patients with external, middle and inner ear malformations. Cranial nerve palsy/paresis was only seen in HFM and thalidomide-induced malformations. A relationship between disturbed neural crest cell migration and defects of the first and second branchial arches seems possible.