snRNP proteins in health and disease.

Split gene architecture of most human genes requires removal of intervening sequences by mRNA splicing that occurs on large multiprotein complexes called spliceosomes. Mutations compromising several spliceosomal components have been recorded in degenerative syndromes and haematological neoplasia, thereby highlighting the importance of accurate splicing execution in homeostasis of assorted adult tissues. Moreover, insufficient splicing underlies defective development of craniofacial skeleton and upper extremities. This review summarizes recent advances in the understanding of splicing factor function deduced from cryo-EM structures. We combine these data with the characterization of splicing factors implicated in hereditary or somatic disorders, with a focus on potential functional consequences the mutations may elicit in spliceosome assembly and/or performance. Given aberrant splicing or perturbations in splicing efficiency substantially underpin disease pathogenesis, profound understanding of the mis-splicing principles may open new therapeutic vistas. In three major sections dedicated to retinal dystrophies, hereditary acrofacial syndromes, and haematological malignancies, we delineate the noticeable variety of conditions associated with dysfunctional splicing and accentuate recurrent patterns in splicing defects.

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway.

Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans. We present the components of the RAS/ERK pathway implicated in craniofacial and orodental disorders through a series of human and animal studies. We attempt to unravel the specific molecular targets downstream of ERK that act on particular cell types and regulate key steps in the associated developmental processes. Finally we point to ambiguities in our current knowledge that need to be clarified before RAS/ERK-targeting therapeutic approaches can be implemented.

Coronal craniosynostosis due to TCF12 mutations in patients from Turkey.

Craniosynostosis consists of premature fusion of one or more cranial sutures and can be seen as part of a syndrome or diagnosed as nonsyndromic (isolated). Although more than 180 craniosynostosis syndromes have been identified, 70% of the cases are diagnosed as nonsyndromic. On the other hand, genetic causes of the cases are mostly unknown and the overall frequency of the genetic diagnosis is around 25%. In this study, we used targeted Next Generation Sequencing (NGS) analysis to identify the genetic variations of two craniosynostosis cases. We have identified two different truncating mutations, a known NM_207036.1:c.778_779delAT;p.(Met260Valfs*5) and a novel NM_207036.1:c.1102_1108delTCACCTC;p.(Pro369Glnfs*26) TCF12 variants. Additionally, upon physical examination of these two cases, we have observed some shared clinical similarities as well as differences such as bilateral simian crease and hidden cleft palate. This is the first study that reports the TCF12 mutations in Turkish patients with coronal suture synostosis.

A novel AXIN2 gene mutation in sagittal synostosis.

The bones of the skull are held together by fibrous joints called sutures. Premature fusion of these sutures leads to a pathologic condition called as craniosynostosis. Although at least 50 nuclear genes including FGFR2, TWIST1, TCF12, and SMAD6 were identified as causative of craniosynostosis; only 25% of the patients can be genetically diagnosed. Here, we report a 3-year-old Turkish Caucasian boy with sagittal craniosynostosis with a de novo loss-of-function mutation in exon 4 of the AXIN2 gene for the first time. The patient has frontal bossing, high anterior hair line, depressed nasal bridge, bilateral epicanthus and low set ears which are correlated with his scaphocephaly. As a negative regulator of the Wnt signaling pathway which is one of the key modulators of craniosynostosis syndrome, it has been shown in model organisms that Axin2 orchestrates the regulation of beta-catenin especially in the intramembranous ossification process. This clinical report adds value to the literature that AXIN2 gene mutations could be a potential cause in human calvarial malformations, especially for the sagittal synostosis.

Genetic Disorders of Dental Development: Tales from the Bony Crypt.

PURPOSE OF REVIEW: The ebb and flow of genetic influence relative to the understanding of craniofacial and dental disorders has evolved into a tacit acceptance of the current genetic paradigm. This review explores the science behind craniofacial and dental disorders through the lens of recent past and current findings and using tooth agenesis as a model of advances in craniofacial genetics. RECENT FINDINGS: Contemporary studies of craniofacial biology takes advantage of the technological resources stemming from the genomic and post-genomic eras. Emerging data highlights the role of key genes and the epigenetic landscape controlling these genes, in causing dentofacial abnormalities. We also report here a novel Glu78FS MSX1 mutation in one family segregating an autosomal dominant form of severe tooth agenesis as an illustration of an evolving theme, i.e., different mutations in the same gene can result in a spectrum of dentofacial phenotypic severity. The future of clinical therapeutics will benefit from advances in genetics and molecular biology that refine the genotype-phenotype correlation. Indeed, the past century suggests a continued convergence of genetic science in the practice of clinical dentistry.

The chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development.

BACKGROUND: Heterozygous mutations in the chromatin remodeling gene CHD7 cause CHARGE syndrome, a developmental disorder with variable craniofacial dysmorphisms and respiratory difficulties. The molecular etiologies of these malformations are not well understood. Homozygous Chd7 null mice die by E11, whereas Chd7(Gt/+) heterozygous null mice are a viable and excellent model of CHARGE. We explored skeletal phenotypes in Chd7(Gt/+) and Chd7 conditional knockout mice, using Foxg1-Cre to delete Chd7 (Foxg1-CKO) in the developing eye, ear, nose, pharyngeal pouch, forebrain, and gut and Wnt1-Cre (Wnt1-CKO) to delete Chd7 in migrating neural crest cells. RESULTS: Foxg1-CKO mice exhibited postnatal respiratory distress and death, dysplasia of the eye, concha, and frontal bone, hypoplastic maxillary shelves and nasal epithelia, and reduced tracheal rings. Wnt1-CKO mice exhibited frontal and occipital bone dysplasia, hypoplasia of the maxillary shelves and mandible, and cleft palate. In contrast, heterozygous Chd7(Gt/+) mice had apparently normal skeletal development. CONCLUSIONS: Conditional deletion of Chd7 in ectodermal and endodermal derivatives (Foxg1-Cre) or migrating neural crest cells (Wnt1-Cre) results in varied and more severe craniofacial defects than in Chd7(Gt/+) mice. These studies indicate that CHD7 has an important, dosage-dependent role in development of several different craniofacial tissues.

A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis.

Disruptions in core cellular processes elicit stress responses that drive cell-state changes leading to organismal phenotypes. Perturbations in the splicing machinery cause widespread mis-splicing, resulting in p53-dependent cell-state changes that give rise to cell-type-specific phenotypes and disease. However, a unified framework for how cells respond to splicing perturbations, and how this response manifests itself in nuanced disease phenotypes, has yet to be established. Here, we show that a p53-stabilizing Mdm2 alternative splicing event and the resulting widespread downregulation of metabolic transcripts are common events that arise in response to various splicing perturbations in both cellular and organismal models. Together, our results classify a common cellular response to splicing perturbations, put forth a new mechanism behind the cell-type-specific phenotypes that arise when splicing is broadly disrupted, and lend insight into the pleiotropic nature of the effects of p53 stabilization in disease.

A critical analysis on quality-of-life in women with visible facial disfigurements.

AIMS: This study aimed to examine whether surgical treatment for a facial disfigurement influenced an individual's quality of life. METHODS AND RESULTS: One-on-one interviews were conducted with the aim of synthesizing participant's medical experiences into common themes. Additionally, participants completed the World Health Organization's Quality of Life Brief Version (WHOQOL-BREF) questionnaire. The WHOQL-BREF is a standardized testing instrument with four domains of 26 questions, meant to analyze participants' overall quality of health, physical health, psychological status, social relationships, and environmental health. Our study revealed that women with visible facial differences experienced a quality of life below the average of the general population. However, in those who reported above-average quality of life, a key theme emerged: active participation in the choice to undergo surgical treatment. Participants who felt this sense of agency in the decision-making process also reported a more positive healthcare experience. They felt more respected by others, indicating a strong connection between personal agency, surgical choices, and overall well-being. CONCLUSIONS: These findings reveal that personal agency plays an important role in the decision-making process for patients undergoing surgical treatment for facial differences, as it improves quality of life and has a positive impact on overall healthcare experience and well-being.

Is there relationship between temporomandibular disorders and head and cervical posture? A systematic review.

The objective of this systematic review was to find sufficient evidence to deny or accept the association between the head and cervical posture and temporomandibular disorders (TMDs), and thus assist health professionals in the evaluation and treatment of patients with TMDs. A search was conducted through all publications written in English about this topic using the databases from Medline, ISI Web of Science, EMBASE, PubMed and Lilacs. The abstracts that fulfilled the initial guideline were retrieved and evaluated to ensure they met the inclusion criteria. To assess the methodological quality of the studies, we developed a questionnaire considering the following criteria: participant's eligibility, control group, diagnosis of TMDs, posture diagnosis and randomisation. Twenty-two studies were selected as potential studies based on their abstracts. Only seventeen studies actually fulfilled the inclusion criteria. The search provided information about the methodological quality of the studies, in which several methodological defects were found. The evidence presented in this systematic review shows that the relation between TMDs and the head and neck posture is still controversial and unclear. The insufficient number of articles considered of excellent methodological quality is a factor that hinders the acceptance or denial of this association.

Effect of Midface Surgery on Ocular Outcomes in Patients with Orbital and Midface Malformations.

(1) Background: Orbital and midface malformations occur in multiple craniofacial disorders. Depending on the deformity, surgical corrections include orbital box osteotomy (OBO), Le Fort III (LFIII), monobloc (MB), and facial bipartition (FB). The aim of this study was to determine the effect of these procedures on ocular outcomes. (2) Methods: A retrospective analysis was performed. All patients with craniofacial disorders who had previously undergone midface surgery were included. The Wilcoxon signed ranks test was used for statistical analysis. (3) Results: In total, 63 patients were included: two patients were treated by OBO, 20 by LFIII, 26 by MB, and 15 by FB. Pre-operatively, strabismus was present in 39 patients (61.9%), in whom exotropia was most common (n = 27; 42.9%), followed by esotropia (n = 11; 17.5%). Postoperatively, strabismus significantly worsened (p = 0.035) in the overall population (n = 63). Pre-operative binocular vision (n = 33) was absent in nine patients (27.3%), poor in eight (24.2%), moderate in 15 (45.5%), and good in one (3.0%). Postoperatively, binocular vision significantly improved (p < 0.001). Before surgery, the mean visual acuity (VA) in the better eye was 0.16 LogMAR (Logarithm of the Minimum Angle of Resolution), and 0.31 LogMAR in the worse eye. Furthermore, pre-operative astigmatism was present in 46 patients (73.0%) and hypermetropia in 37 patients (58.7%). No statistical difference was found for VA (n = 51; p = 0.058) postoperatively. (4) Conclusions: Midface surgery has a direct and indirect substantial effect on several ocular outcomes. This study emphasizes the importance of appropriate ophthalmological evaluation in patients with craniofacial disorders undergoing midface surgery.

Prevalence of Ocular Anomalies in Craniosynostosis: A Systematic Review and Meta-Analysis.

BACKGROUND: The aim of this study was to describe the ophthalmic abnormalities and their prevalence in craniosynostosis prior to craniofacial surgery. METHODS: A systematic search was conducted on Medline OVID, Embase, Cochrane, Google Scholar, Web of Science Core Collection. Inclusion criteria were English papers, children aged <18 years with non-syndromic and syndromic craniosynostosis, case reports, case series, and case-control studies. A system of domains was established consisting of an anatomic and functional ophthalmic domain. A meta-analysis of single proportions was carried out using random effects model and pooled mean proportions with 95% confidence intervals (CI) were calculated. RESULTS: Thirty-two papers analyzing 2027 patients were included. Strabismus was the most common anomaly in non-syndromic craniosynostosis: Horizontal strabismus was highest prevalent in unicoronal craniosynostosis (UCS) 19% (95% CI 9-32), followed by vertical strabismus 17% (95% CI 5-33). In syndromic craniosynostosis, horizontal strabismus was most prevalent in Crouzon syndrome 52% (95 CI 26-76), followed by Apert syndrome 50% (95% CI 42-58). Vertical strabismus was most prevalent in Saethre-Chotzen 60% followed by Muenke's syndrome 36%. Furthermore, astigmatism was the second most reported outcome in non-syndromic craniosynostosis and highest prevalent in UCS 35% (95% CI 21-51). In syndromic craniosynostosis, astigmatism was most frequently seen in Crouzon syndrome 43% (95% CI 22-65), followed by Apert syndrome 34% (95% CI 14-58). Moreover, in syndromic craniosynostosis, 5-40% had a decrease in visual acuity (VA) ≤ 0.3 LogMAR in the better eye and 11-65% had a VA ≤ 0.3 LogMAR in at least one eye. DISCUSSION: This review demonstrates the high prevalence of ocular anomalies in non-syndromic and syndromic craniosynostosis. A multidisciplinary and systematic approach is needed for the screening and optimal treatment of these conditions in a timely manner.

Fibrous Dysplasia With Aneurysmal Bone Cyst Presenting as Sinonasal Mass.

Craniofacial involvement in fibrous dysplasia is a rare occurrence and complications of it are even rarer. Involvement of the sinonasal region can pose a challenge in both diagnosis and management. We hereby present a case of craniofacial fibrous dysplasia complicated with secondary aneurysmal bone cyst formation in a 15-year-old male patient.

Diagnostic approaches to respiratory abnormalities in craniofacial syndromes.

Craniofacial syndromes are a complex cluster of genetic conditions characterized by embryonic perturbations in the developmental trajectory of the upper airway and related structures. The presence of reduced airway size and maladaptive neuromuscular responses, particularly during sleep, leads to significant alterations in sleep architecture and overall detrimental gas exchange abnormalities that can be life-threatening. The common need for multi-stage therapeutic interventions for these craniofacial problems requires careful titration of anatomy and function, and the latter is currently evaluated by overnight polysomnography in sleep laboratories. The cost, inconvenience, and scarcity of pediatric sleep laboratories preclude the frequent evaluations that could optimize the overall process of treatment and corresponding outcomes. Here, we critically examine reductionist approaches to polysomnography in children to establish the parallel approximation of such techniques to infant with craniofacial disorders. The need for prospective longitudinal multicenter studies with side-by-side comparisons aimed at identifying an optimal diagnostic and long-term monitoring paradigm for these potentially life-threatening conditions is emphasized.

Recent Advances in Craniosynostosis.

Craniosynostosis is a pathologic craniofacial disorder and is defined as the premature fusion of one or more cranial (calvarial) sutures. Cranial sutures are fibrous joints consisting of nonossified mesenchymal cells that play an important role in the development of healthy craniofacial skeletons. Early fusion of these sutures results in incomplete brain development that may lead to complications of several severe medical conditions including seizures, brain damage, mental delay, complex deformities, strabismus, and visual and breathing problems. As a congenital disease, craniosynostosis has a heterogeneous origin that can be affected by genetic and epigenetic alterations, teratogens, and environmental factors and make the syndrome highly complex. To date, approximately 200 syndromes have been linked to craniosynostosis. In addition to being part of a syndrome, craniosynostosis can be nonsyndromic, formed without any additional anomalies. More than 50 nuclear genes that relate to craniosynostosis have been identified. Besides genetic factors, epigenetic factors like microRNAs and mechanical forces also play important roles in suture fusion. As craniosynostosis is a multifactorial disorder, evaluating the craniosynostosis syndrome requires and depends on all the information obtained from clinical findings, genetic analysis, epigenetic or environmental factors, or gene modulators. In this review, we will focus on embryologic and genetic studies, as well as epigenetic and environmental studies. We will discuss published studies and correlate the findings with unknown aspects of craniofacial disorders.

Modeling human craniofacial disorders in Xenopus.

PURPOSE OF REVIEW: Craniofacial disorders are among the most common human birth defects and present an enormous health care and social burden. The development of animal models has been instrumental to investigate fundamental questions in craniofacial biology and this knowledge is critical to understand the etiology and pathogenesis of these disorders. RECENT FINDINGS: The vast majority of craniofacial disorders arise from abnormal development of the neural crest, a multipotent and migratory cell population. Therefore, defining the pathogenesis of these conditions starts with a deep understanding of the mechanisms that preside over neural crest formation and its role in craniofacial development. SUMMARY: This review discusses several studies using Xenopus embryos to model human craniofacial conditions, and emphasizes the strength of this system to inform important biological processes as they relate to human craniofacial development and disease.

La descodificación biológica y las alteraciones craneofaciales, una mirada desde las ciencias básicas / Biological decoding and craniofacial alterations, a view from basic sciences

Antecedentes: La Descodificación Biológica propone la correspondencia entre el estrés ante una situación desbordante y la aparición de síntomas. La ciencia ha logrado profundizar en los componentes biológicos de los trastornos del desarrollo que podrían explicar lo queocurre en algunos preceptos de esta teoría. Objetivo: Determinar a partir de la revisión de literatura científica, la relación entre el estrés y algunas hormonas, con las alteraciones craneofaciales. Materiales y métodos: Se realizó una búsqueda en SciELO, PubMed y SCOPUS buscando artículos relacionados conel estrés, trastornos fisiológicos y esqueléticos y la hormona de crecimiento. Resultados: Se encontraron 17 artículos que relacionan el estrés con alteraciones fisiológicas, 18 artículos que muestran del el papel de los el estrés en el sistema nervioso central y la alteración de la hormona de crecimiento, además 16 artículos que relacionan la hormona de crecimiento con alteraciones esqueléticas craneofaciales. Conclusión: Se encontró evidencia que muestran cómo algunos supuestos de la teoría de la "Descodificación biológica" pueden ser explicados a partir del papel del estrés y de los estresores que podrían estimular respuestas a nivel del sistema nervioso central y llevar a cambios en estructuras óseas en pacientes en periodo de crecimiento o maduración ósea.

Background: Biological Decoding proposes the correspondence between stress in an overwhelming situation and the appearance of symptoms. Science has managed to investigate into the biological components of developmental disorders that could explain what happens in some precepts of this theory. Objective: To determine from the review of scientific literature, the relationship between stress and some hormones, with craniofacial alterations.Materials and methods: A search was carried out in SciELO, PubMed and SCOPUS looking for articles related to stress, physiological and skeletal disorders and growth hormone. Results: 17 articles were found that relate stress with physiological alterations, 18 articles that show the role of stress in the central nervous system and alteration of growth hormone, in addition 16 articles that relate growth hormone with alterations craniofacial skeletal. Conclusion: Evidence was found that shows how some assumptions of the "biological decoding" theory can be explained from the role of stress and stressors that could stimulate responses at the level of the central nervous system and lead to changes in bone structures in patients in a period of bone growth or maturation.

Crouzon syndrome: relationship of rectus muscle pulley location to pattern strabismus.

PURPOSE: Investigate the relationship between the extorsion of the rectus muscle pulleys and the V-pattern exotropia and "overelevation in adduction" observed in Crouzon syndrome. METHODS: Twenty children with Crouzon syndrome had assessment of eye alignment. The horizontal and vertical positions of the four rectus muscle pulleys were estimated from coronal CT images. Eye alignment was simulated in Orbit 1.8 software by shifting the corresponding location of the rectus muscle pulley array. RESULTS: Eleven of the 20 patients had a V-pattern exotropia with displacements of each rectus muscle pulley ranging from 2 to 7 mm. The remaining nine patients were orthotropic with <2 mm displacement of the rectus muscle pulleys. Simulated displacements (>2 mm) of either the horizontal or vertical rectus muscle pulleys produced a similar strabismus pattern. The amount of V-pattern exotropia observed clinically was highly correlated with the amount predicted by pulley displacements in Orbit 1.8 (r(2) = 0.63; P < 0.0001). The displacement of vertical and horizontal rectus muscle pairs was significantly higher for patients having overelevation in adduction. CONCLUSIONS: Rotation of the four rectus muscle pulleys relative to the corresponding rotation planes of the globe changes the direction and magnitude of their active and passive pulling forces in a gaze-dependent manner. Extorsion of the horizontal and vertical rectus muscle pulleys in Orbit 1.8 reproduces the pattern strabismus observed in Crouzon syndrome. The high correlation between the predicted magnitude of the V-pattern exotropia and observed exotropia indicates that extorsion of the rectus muscle pulleys primarily accounts for the pattern strabismus.

Características cranianas, faciais e dentárias em indivíduos acondroplásicos / Craniofacial and dental features in achondroplastic individuals

A acondroplasia é a forma mais comum de nanismo por encurtamento dos membros. É uma síndrome hereditária de caráter autossômico dominante, que também pode ser causada por novas mutações genéticas. A formação óssea endocondral é defeituosa e leva a alterações craniofaciais e dentárias típicas. Os pacientes acometidos apresentam macroencefalia, calota craniana volumosa, base do crânio encurtada, nariz em sela e estreitamento de vias aéreas, além de retrognatia maxilar, discrepância entre arcos dentários e maloclusões acentuadas. O presente artigo tem como objetivo apresentar as características craniofaciais e dentárias de pacientes acondroplásicos, por meio de revisão de literatura.

Achondroplasia is the most common hereditary form of dwarfism. The syndrome is inherited in an autosomal dominant manner but it can also be a result of a new gene mutation. The defective endochondral bone formation causes typical craniofacial and dental features such as enlarged calvarium, short posterior cranial base, depressed nasal bridge, short upper airway, retrognathic maxilla and malocclusion. The aim of the present article is to introduce the craniofacial and dental features of achondroplastic patients, by reviewing the literature.

Análise genética de problemas craniofaciais: revisão da literatura e diretrizes para investigações clínico-laboratoriais (parte 2) / Genetic analysis of craniofacial problems: a review of the literature and some guidelines for clinical and laboratorial investigation (part 2)

OBJETIVO: esse artigo tem como objetivo ser uma fonte de informação acerca das técnicas e análises genéticas mais utilizadas em investigações clínicas e laboratoriais visando a identificação e a caracterização de genes relacionados a doenças ou distúrbios complexos, especialmente os que atingem as estruturas do crânio e da face. METODOLOGIA: são traçadas algumas diretrizes para guiar os futuros pesquisadores nos processos de seleção de amostras e obtenção de heredogramas para estudos genéticos e fornecidos conceitos e princípios gerais que norteiam métodos de análises genéticas. Tais métodos exigem conhecimento a respeito de transmissão gênica, genética molecular e utilização de marcadores moleculares, assim como envolvem o domínio de técnicas laboratoriais como, por exemplo, reações de polimerização em cadeia (PCR), eletroforese e seqüenciamento de DNA. RESULTADOS E CONCLUSÕES: as análises genéticas, em especial as análises de segregação e de ligação, representam importantes ferramentas à disposição dos pesquisadores na tentativa de relacionar fenótipos a genes específicos e na busca da exata localização cromossômica dos mesmos. Espera-se com esse artigo que os cirurgiões-dentistas clínicos possam começar a perceber a importância do assunto e buscar se aprofundar nessa área.

AIM: The aim of this paper is to inform the reader about genetic techniques and analysis used in clinical and laboratorial investigations for the identification and characterization of the genetic determinants for complex disorders, especially those that attain craniofacial structures. METHODS: General concepts and principles of important methods of genetic analysis are given as well as some guidelines for future researchers, concerning sample gathering and pedigrees construction. These methods described here require knowledge about genetic transmission, molecular genetics and DNA markers, and involve the ability to deal with the current laboratorial techniques, including polymerase chain reactions, agarose or polyacrilamide gel and the use of DNA sequencers. RESULTS AND CONCLUSIONS: Those genetic analysis, mainly the segregation and the linkage analysis, are considered important tools in the attempt to make the relationship between some phenotypes and specific genotypes, and to search for the exact chromosomal localization of each one of these genes. The knowledge of these information can help clinical dentists to understand the important role played by genetics, leading them to get deeper into the subject.