Craniofacial syndromes and class III phenotype: common genotype fingerprints? A scoping review and meta-analysis.

Skeletal Class III (SCIII) is among the most challenging craniofacial dysmorphologies to treat. There is, however, a knowledge gap regarding which syndromes share this clinical phenotype. The aims of this study were to: (i) identify the syndromes affected by the SCIII phenotype; (ii) clarify the involvement of maxillary and/or mandibular structures; (iii) explore shared genetic/molecular mechanisms. A two-step strategy was designed: [Step#1] OMIM, MHDD, HPO, GeneReviews and MedGen databases were explored; [Step#2]: Syndromic conditions indexed in [Step#1] were explored in Medline, Pubmed, Scopus, Cochrane Library, WOS and OpenGrey. Eligibility criteria were defined. Individual studies were assessed for risk of bias using the New Ottawa Scale. For quantitative analysis, a meta-analysis was conducted. This scoping review is a hypothesis-generating research. Twenty-two studies met the eligibility criteria. Eight syndromes affected by the SCIII were targeted: Apert syndrome, Crouzon syndrome, achondroplasia, X-linked hypohidrotic ectodermal dysplasia (XLED), tricho-dento-osseous syndrome, cleidocranial dysplasia, Klinefelter and Down syndromes. Despite heterogeneity between studies [p < 0.05], overall effects showed that midface components were affected in Apert and Down Syndromes, lower face in Klinefelter Syndrome and midface and lower face components in XLED. Our review provides new evidence on the craniofacial characteristics of genetically confirmed syndromes exhibiting the SCIII phenotype. Four major regulatory pathways might have a modulatory effect on this phenotype. IMPACT: What does this review add to the existing literature? To date, there is no literature exploring which particular syndromes exhibit mandibular prognathism as a common trait. Through this research, it was possibly to identify the particular syndromes that share the skeletal Class III phenotype (mandibular prognathism) as a common trait highlighting the common genetic and molecular pathways between different syndromes acknowledging their impact in craniofacial development.

[Digital Concepts for the Care of Newborns with Craniofacial Anomalies]. / Digitale Konzepte für die Versorgung von Neugeborenen mit kraniofazialen Anomalien.

The treatment of newborns with craniofacial abnormalities such as cleft lip and/or palate poses special challenges for healthcare providers. Often, the collaboration of an interdisciplinary team of pediatricians, orthodontists, and oral and maxillofacial surgeons is necessary. Therapy using feeding or stimulation plates can improve feeding and strengthen orofacial muscle tone. The treatment of patients with cleft lip and palate using conventionally manufactured feeding plates as well as the treatment of patients with reduced orofacial muscle tone through stimulation plates therapy are established and widely used methods. The conventional production of these plate appliances can lead to serious complications such as swallowing of impression material and airway obstruction due to aspiration. Through an innovative, entirely digital workflow using computer-assisted design and manufacturing of the appliances in a 3D printer, risks can be minimized and time and costs can be saved. This article aims to explain the digital workflow of treating newborns with 3D CAD/CAM feeding and stimulation plates through two case studies.

Craniofacial Orthodontic Experience in CODA-Accredited Orthodontic Residency Programs.

To evaluate orthodontic care for patients with craniofacial anomalies (CFA) by identifying orthodontic residents' preparedness to treat certain conditions and willingness to receive more training in CFA.A 12-question survey was sent through the American Association of Orthodontics (AAO) organization to orthodontic residents. Questions were primarily designed to obtain information on the frequency with which they dealt with patients with CFA in their training, specific craniofacial conditions that orthodontic residents feel comfortable treating.A total of 150 participants out of 1066 responded. Of the 150 responses, 35% were first-year residents, 43% second year, and 22% were third-year residents. Thirty nine percent of residents saw 3 or more CFA patients during their residency followed by 24% that saw no patients with CFA. Forty five percent reported that 1 to 3 hours of lecture time was devoted to CFA per month. Sixty percent felt their training in CFA was not sufficient to feel comfortable treating these patients in practice. Specifically, 62% felt comfortable treating Down syndrome, 84% unilateral cleft lip and/or palate, and 64% bilateral cleft lip and/or palate, while the majority did not feel comfortable treating Pierre Robin sequence (68%), Cleidocranial dysplasia (65%), Crouzon syndrome (75%), Pfeiffer syndrome (80%), Treacher Collins syndrome (76%), Apert syndrome (76%), CHARGE syndrome (84%), and DiGeorge sequence (84%). Seventy eight percent of residents reported that they would like more training in treating craniofacial.Orthodontic residents did not feel comfortable treating patients with CFA. Majority of the residents felt that they would like to learn more about CFA.

Adaptive correction of craniofacial defects in pre-metamorphic Xenopus laevis tadpoles involves thyroid hormone-independent tissue remodeling.

Although it is well established that some organisms can regenerate lost structures, the ability to remodel existing malformed structures has been less well studied. Therefore, in this study we examined the ability of pre-metamorphic Xenopus laevis tadpoles to self-correct malformed craniofacial tissues. We found that tadpoles can adaptively improve and normalize abnormal craniofacial morphology caused by numerous developmental perturbations. We then investigated the tissue-level and molecular mechanisms that mediate the self-correction of craniofacial defects in pre-metamorphic X. laevis tadpoles. Our studies revealed that this adaptive response involves morphological changes and the remodeling of cartilage tissue, prior to metamorphosis. RT-qPCR and RNA-seq analysis of gene expression suggests a thyroid hormone-independent endocrine signaling pathway as the potential mechanism responsible for triggering the adaptive and corrective remodeling response in these larvae that involves mmp1 and mmp13 upregulation. Thus, investigating how malformed craniofacial tissues are naturally corrected in X. laevis tadpoles has provided valuable insights into the maintenance and manipulation of craniofacial morphology in a vertebrate system. These insights may help in the development of novel therapies for developmental craniofacial anomalies in humans.

European Guideline on Craniofacial Microsomia: A Version for Patients and Families.

ABSTRACT: A European guideline on craniofacial microsomia was developed within the European Reference Network for rare and/or complex craniofacial anomalies and ear, nose, and throat disorders and published in 2020. The guideline provides an overview of optimal care provisions for patients with craniofacial microsomia and recommendations for the improvement of care. This document seeks to provide a tailored overview of this guideline for patients and their families.

Tessier Number 3 and 4 Clefts: Clinical Presentation and Associated Clefts in a South African Population.

INTRODUCTION: The defects found in Tessier clefts number 3 and number 4 come in various forms in different patients. These variations have to a great extent affected not only documentation of these craniofacial defects but invariably their treatment and communication amongst craniofacial researchers. This study has not only documented the clinical presentation of these clefts in a South African population but has also incorporated the clinical presentation of Tessier clefts number 3 and 4 from different regions of the world. METHODS: The records of 8 patients, who had been treated for either Tessier clefts number 3 or 4, were reviewed and compared with 16 studies pulled from the literature systematically. The defects recorded as well as associated clefts and other congenital malformations were documented, and findings were compared. RESULTS: The anatomical and clinical presentation of the patients was compared to the reviewed literature and the different parameters were documented. In addition, associated clefts were also recorded in the study-it was noted that the association pattern recorded in Tessier cleft number 4 in this study did not conform to its traditional counterpart. CONCLUSION: This study concluded that the clinical presentations of these clefts, however variable, seem to have a similar presentation worldwide. Additionally, associated clefts do not conform to the original Tessier classification system and therefore it is imperative for these patterns to be clearly mapped out.

Craniofacial Deformities in Patients With Beta-Thalassemia: Orthodontic Versus Surgical Correction-A Systematic Review.

Rapid blood cell turnover and bone marrow expansion caused by beta-thalassemia (ßT) result in craniofacial and dentoalveolar anomalies. This report presents a systematic review of the literature over the past 50 years on orthodontic and surgical considerations in the management of ßT-affected patients. Seventeen publications encompassed 24 patients, 11 male individuals and 13 female individuals, 7 to 43 years of age. Eleven patients underwent only surgical treatment, eleven combined orthodontic-surgical treatment, and 2 orthodontic treatment. Surgical treatment primarily addressed typical maxillary overgrowth by maxillary reshaping, premaxillary segmental repositioning, or complete Le Fort I impaction and set back osteotomy. In severe maxilla-mandibular discrepancy and/or increased lower facial height, a bilateral sagittal split mandibular osteotomy is the treatment of choice. Although surgery involves risks of excessive bleeding, morbidity, and impaired nasal esthetics, little attention is given to the orthodontic modality. In conclusion, the current literature recommends early interceptive orthodontics aimed to decrease dentoskeletal deformities, severe malocclusion, and soft tissue imbalance. Treatment includes maxillo-mandibular orthopedic and functional manipulation with dentoalveolar treatment, which might either prevent orthosurgical procedures later or reduce its extent. This suggested a multidisciplinary approach comprising a hematologist, a pediatrician, a pediatric dentist, and an orthodontist, which might also significantly improve the patient's quality of life.

What Do Animal Models Teach Us About Congenital Craniofacial Defects?

The formation of the head and face is a complex process which involves many different signaling cues regulating the migration, differentiation, and proliferation of the neural crest. This highly complex process is very error-prone, resulting in craniofacial defects in nearly 10,000 births in the United States annually. Due to the highly conserved mechanisms of craniofacial development, animal models are widely used to understand the pathogenesis of various human diseases and assist in the diagnosis and generation of preventative therapies and treatments. Here, we provide a brief background of craniofacial development and discuss several rare diseases affecting craniofacial bone development. We focus on rare congenital diseases of the cranial bone, facial jaw bones, and two classes of diseases, ciliopathies and RASopathies. Studying the animal models of these rare diseases sheds light not only on the etiology and pathology of each disease, but also provides meaningful insights towards the mechanisms which regulate normal development of the head and face.

Implications for the Multi-Disciplinary Management of Children With Craniofrontonasal Syndrome.

The purpose of this retrospective study was to assess the genetic and phenotypic features of patients with craniofrontonasal syndrome (CFNS), and the implications of the condition for multidisciplinary management.The subjects were 25 female patients with a mutation of EFNB1, who presented to the Oxford Craniofacial Unit during a 38-year period. Medical records were reviewed for genetic and phenotypic information. Mean duration of follow-up was 12.6 years (range 0-30.7 years).This study examines neurodevelopment in constituent parts, with specific reference to speech, language, and cognition in relation to genotype. Three children had deletions extending beyond the EFNB1 gene; the 2 with available data presented with speech, language, or cognitive delay. The remaining 25 patients had intragenic mutations of EFNB1. Of these 25, those assessed in detail showed variable difficulties with speech and language development; 57% had receptive language difficulties (n = 4/7) and 88% had expressive language difficulties (n = 8/9). 55% presented with speech difficulties (n = 6/11). 2/3 patients with abnormal hearing had speech difficulties; 4/5 with normal hearing had normal speech development. Cognitive assessments indicated that IQ is variable; with full scale IQ ranging from 69 to 100.The complex, multifactorial presentation of patients with CFNS contributed to 41% (n = 7/17) of patients requiring additional educational support.Our results demonstrated significant multidisciplinary input is required, including Speech and Language Therapy, Plastic and Reconstructive Surgery, Genetics, Ear, Nose and Throat, Maxillofacial, Orthodontic, Orthopaedic, Clinical Psychology and Orthoptic teams. The results of this study reinforce the importance of multi-disciplinary long-term follow-up of children with CFNS.

Barriers to Accessing Medical Care for Hispanic Individuals With Craniofacial Conditions.

In the United States, having limited access to health care has been an ongoing concern that could cause detrimental effects for minority populations, specifically the Hispanic population. Numerous barriers to accessing health care were identified for both pediatric and adult Hispanic patients who were born with craniofacial conditions. Barriers that were determined to impact Hispanic patients with craniofacial conditions from receiving medical and health services included language and communication, patient-health care provider relationships, socioeconomic status and finances, insurance status, timely access to appointments, citizenship and immigration status, and lack of family and social support. Interventions for these barriers were also proposed to increase support for Hispanic patients. Lamentably, there is scant research that investigates how these barriers affect this special population, despite the limitations that they have in their ability to access health care. In addition, these barriers to treatment have dire consequences for individuals with craniofacial conditions. The findings and proposed interventions discussed in this review article provide measures to minimize these barriers and define ways to benefit Hispanic patients with craniofacial conditions.

Barriers to Accessing Medical Care for Hispanic Individuals With Craniofacial Conditions.

In the United States, having limited access to health care has been an ongoing concern that could cause detrimental effects for minority populations, specifically the Hispanic population. Numerous barriers to accessing health care were identified for both pediatric and adult Hispanic patients who were born with craniofacial conditions. Barriers that were determined to impact Hispanic patients with craniofacial conditions from receiving medical and health services included language and communication, patient-health care provider relationships, socioeconomic status and finances, insurance status, timely access to appointments, citizenship and immigration status, and lack of family and social support. Interventions for these barriers were also proposed to increase support for Hispanic patients. Lamentably, there is scant research that investigates how these barriers affect this special population, despite the limitations that they have in their ability to access health care. In addition, these barriers to treatment have dire consequences for individuals with craniofacial conditions. The findings and proposed interventions discussed in this review article provide measures to minimize these barriers and define ways to benefit Hispanic patients with craniofacial conditions.

The Society for Craniofacial Genetics and Developmental Biology 41st Annual Meeting.

The mission of the Society for Craniofacial Genetics and Developmental Biology (SCGDB) is to promote education, research, and communication about normal and abnormal development of the tissues and organs of the head. The SCGDB welcomes as members undergraduate students, graduate students, postdoctoral researchers, medical and dental practitioners, scientists, and academicians who possess an interest in craniofacial biology. Each year our members come together to share their novel findings, build upon, and challenge current knowledge of craniofacial biology.

Obstructive sleep apnea and craniofacial appearance in MPS type I-Hurler children after hematopoietic stem cell transplantation.

OBJECTIVES: Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder characterized by severe multi-systemic organ manifestations including obstructive sleep apnea syndrome (OSAS). Hematopoietic stem cell transplantation (HSCT) is the treatment of choice in severe MPS I (MPS IH, Hurler syndrome). However, the effect of HSCT on OSAS in MPS IH still remains unclear. The purpose of this study was to analyze respiratory patterns during sleep following HSCT in MPS IH children and to relate these findings to craniofacial abnormalities. METHODS: Overnight polysomnographies of nine MPS IH children (mean age: 8.2 years) previously treated with HSCT were retrospectively analyzed. Magnetic resonance images of the head were assessed with regard to soft and hard tissue abnormalities of the upper respiratory tract. RESULTS: The mean apnea hypopnea index (AHI) was 5.3 events/h (range, 0.3-12.2), and the majority of apnea/hypopneas were obstructive. Whereas two patients had severe OSAS (AHI > 10) and two moderate OSAS (5 > AHI < 10), five patients had no evidence of OSAS (AHI < 2.0). Donor cell chimerism was significantly lower in MPS IH patients with OSAS as compared to patients without OSAS (p < 0.001). The upper airway space and the maxilla were significantly smaller and the adenoids larger in MPS IH patients with OSAS as compared to those of non-OSAS patients. CONCLUSION: OSAS was only observed in MPS IH patients with graft failure or low donor cell chimerism. Conversely, successful HSCT seems to ameliorate adenoid hyperplasia and maxillary constriction in MPS IH patients and thereby minimizes the risk of OSAS at least at younger ages.

Altered FGF signalling in congenital craniofacial and skeletal disorders.

The fibroblast growth factor (FGF) signalling pathway has been the focus of intense genetic and functional research for several decades. The emerging data implicate FGF signalling in diverse regulatory processes, both in the developing embryo as well as in the adult organism. Alterations in this tightly regulated pathway can lead to a number of pathological conditions, ranging from well-recognized congenital disorders to cancer. In order to mediate their cellular processes, FGFs signal through a subfamily of tyrosine kinase receptors, called FGF receptors (FGFRs). In humans, four FGFRs are described, and, to date, mutations in FGFR1, FGFR2, and FGFR3 have been shown to underlie human developmental disorders. FGFs/FGFRs are known to be key players in both endochondral and intramembranous bone development. In this review, we focus on the major developmental craniofacial and skeletal disorders which result from altered FGF signalling.

Nablus syndrome: Easy to diagnose yet difficult to solve.

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.

Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.

Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene­phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.

The society for craniofacial genetics and developmental biology 39th annual meeting.

The Society for Craniofacial Genetics and Developmental Biology (SCGDB) aims to promote education, research, and communication, about normal and abnormal development of the tissues and organs of the head. Membership of the SCGDB is broad and diverse-including clinicians, orthodontists, scientists, and academics-but with all members sharing an interest in craniofacial biology. Each year, the SCGDB hosts a meeting where members can share their latest research, exchange ideas and resources, and build on or establish new collaborations. © 2017 Wiley Periodicals, Inc.

Electrospun 3D composite scaffolds for craniofacial critical size defects.

Critical size defects in the craniofacial region can be effectively treated using three dimensional (3D) composite structures mimicking natural extra cellular matrix (ECM) and incorporated with bioactive ceramics. In this study we have shown that the dynamic liquid bath collector can be used to form electrospun polycaprolactone (PCL)-hydroxyapatite (HA) composite structure as unique 3D scaffold. The structure was found to have three distinct sections (base, stem and head) based on the mechanism of its formation and morphology. The size of the head portion was around 15 mm and was found to vary with the process parameters. Scanning electron microscopy (SEM) analysis revealed that the base had random fibres while the fibres in stem and head sections were aligned but perpendicular to each other. X-ray diffraction (XRD) analysis also showed an increase in the crystallinity index of the fibres from base to head section. Cytotoxicity and cytocompatibility studies using human osteosarcoma (HOS) cells showed good cell adhesion and proliferation indicating the suitability of the 3D structure for craniofacial graft applications.

A Patient Information Leaflet Reduces Parental Anxiety Before Their Child's First Craniofacial Multidisciplinary Outpatient Appointment.

INTRODUCTION: It is expected that a child's first outpatient appointment with a craniofacial multidisciplinary team (MDT) instills anxiety in parents. Limited data exist on the aspects of the appointment that parents are most concerned about and what information they desire. The effect of written information provision on this cohort is unstudied. METHODS: Parents attending their child's first outpatient appointment with the Birmingham Children's Hospital Craniofacial MDT between September and December 2012 completed a questionnaire to identify concerns they had relating to the appointment. A patient information leaflet was subsequently developed and distributed. From September 2015 to January 2016, questionnaires completed by parents assessed the usefulness of the leaflet and whether it reduced parental anxiety. RESULTS: Twenty-six initial questionnaires were returned. Seventeen respondents (65%) reported that they were concerned about some aspect of their child's appointment. Twenty-two (86%) expressed a desire for more information surrounding their child's appointment. Thirteen (50%) requested for this information to be provided using a patient information leaflet. After the introduction of the leaflet, 30 questionnaires were returned. All 30 (100.0%) found the leaflet easy to understand. Twenty-nine (96.7%) felt the leaflet provided helpful information. Eighteen (60.0%) felt less worried about the appointment after reading the leaflet. CONCLUSIONS: The majority of parents of children referred to a craniofacial MDT appointment displayed concerns that related to the appointment itself. Specific information relating to the appointment process itself was desired. A purpose-built leaflet successfully provided parents with desired information and lowered anxiety among the majority of attendees.

Craniofacial Morphology in Midline Cervical Cleft: Case Report and Review of Literature.

Congenital midline cervical cleft is a rare anomaly of the neck. This paper presents the case of a boy diagnosed with this disorder in which a preliminary orthodontic treatment was implemented. The craniofacial anomalies associated with this malformation produced a defect that could only be successfully treated through the implementation of orthodontic and surgical treatments. In this case, congenital midline cervical cleft was accompanied by certain disorders within the facial structures of the skull, primarily mandibular retrusion, flattening of the contour of the mandibular base, and a steep angle between the cranial base and the mandibular plane.