Craniofacial phenotyping with fetal MRI: a feasibility study of 3D visualisation, segmentation, surface-rendered and physical models.

This study explores the potential of 3D Slice-to-Volume Registration (SVR) motion-corrected fetal MRI for craniofacial assessment, traditionally used only for fetal brain analysis. In addition, we present the first description of an automated pipeline based on 3D Attention UNet trained for 3D fetal MRI craniofacial segmentation, followed by surface refinement. Results of 3D printing of selected models are also presented.Qualitative analysis of multiplanar volumes, based on the SVR output and surface segmentations outputs, were assessed with computer and printed models, using standardised protocols that we developed for evaluating image quality and visibility of diagnostic craniofacial features. A test set of 25, postnatally confirmed, Trisomy 21 fetal cases (24-36 weeks gestational age), revealed that 3D reconstructed T2 SVR images provided 66-100% visibility of relevant craniofacial and head structures in the SVR output, and 20-100% and 60-90% anatomical visibility was seen for the baseline and refined 3D computer surface model outputs respectively. Furthermore, 12 of 25 cases, 48%, of refined surface models demonstrated good or excellent overall quality with a further 9 cases, 36%, demonstrating moderate quality to include facial, scalp and external ears. Additional 3D printing of 12 physical real-size models (20-36 weeks gestational age) revealed good/excellent overall quality in all cases and distinguishable features between healthy control cases and cases with confirmed anomalies, with only minor manual adjustments required before 3D printing.Despite varying image quality and data heterogeneity, 3D T2w SVR reconstructions and models provided sufficient resolution for the subjective characterisation of subtle craniofacial features. We also contributed a publicly accessible online 3D T2w MRI atlas of the fetal head, validated for accurate representation of normal fetal anatomy.Future research will focus on quantitative analysis, optimizing the pipeline, and exploring diagnostic, counselling, and educational applications in fetal craniofacial assessment.

Craniofacial features of adult obese obstructive sleep apnoea patients in relation to the obesity onset - A pilot study.

INTRODUCTION: Obesity and craniofacial structures are aetiologies of obstructive sleep apnoea (OSA). The effect of obesity onset on the craniofacial development and growth of obese OSA subjects has been suggested, but supporting data were lacking. This study aimed to assess the craniofacial features of adult obese OSA patients in relation to their obesity onset. MATERIALS AND METHODS: A total of 62 adult OSA patients were included in the study, consisting of 12 early-onset (i.e. before puberty), 21 late-onset (i.e. after puberty) and 29 non-obese. All participants underwent a sleep study and cephalometric radiograph. Cephalometric analysis was conducted to measure the craniofacial features among the groups. RESULTS: The early obesity onset group (n = 12) showed a more prognathic mandible, longer lower facial height, protrusive incisors, a more caudal position of the hyoid bone and a wider lower airway. The late-onset group (n = 21) had more proclined and protrusive upper incisors, a shallower overbite, a more inferiorly positioned hyoid bone and an obtuse craniocervical angle. The overall obese group showed a combination of the findings above, plus a shorter soft palate and shorter airway length. There was no significant difference between early and late obesity onset groups. However, the early group showed a tendency for a shallower or decreased mandibular plane angle and deeper overbite. CONCLUSIONS: The current pilot study had many limitations but holds important information as a hypothesis generator. Craniofacial features of OSA patients with different obesity onset showed discrepancies and were distinguished from non-obese controls. Adult OSA patients with an early obesity onset showed a tendency for a more hypodivergent growth pattern than those with a late obesity onset.

"Liu-Liang-Chung" syndrome with multiple congenital anomalies and the distinctive craniofacial features caused by dominant ZEB2 gene gain mutation.

BACKGROUND: Contiguous gene gain syndrome including entire ZEB2 may be a novel syndrome. In the past, there were no easily distinct and recognizable features as a guide for precise clinical and genetic diagnosis of the syndrome. CASE PRESENTATION: We report a novel case with the syndrome with a novel de novo 22.16 Mb duplication at 2q21.2-q24.1. The syndrome is characterized by multiple anomalies including the same typical craniofacial phenotype that is entirely different from Mowat-Wilson syndrome (MWS), and other quite similar features of MWS consisting of development delay, congenital heart disease, abdominal abnormalities, urogenital abnormalities, behavioral problems and so on, in which the distinctive craniofacial features can be more easily recognized. CONCLUSIONS: Contiguous gene gain syndrome including entire ZEB2 characterized with similar multiple congenital anomalies of MWS and the distinctive craniofacial features is mainly caused by large 2q22 repeats including ZEB2 leading to dominant singe ZEB2 gene gain mutation, which is recommended to be named "Liu-Liang-Chung" syndrome. We diagnose this novel syndrome to distinguish it from MWS. Some variable additional features in the syndrome including remarkable growth and development retardation and protruding ears were recognized for the first time.

Craniofacial and dental features in children aged 3-5 years with congenital Zika syndrome.

OBJECTIVE: Zika virus infection has been associated to congenital zika syndrome (CZS) in newborns and is characterized by microcephaly, central/axial motor and sensory dysfunction, dysphagia among other previously described severe health complications. CZS is usually diagnosed postpartum by evident/apparent neural development problems. Although there are some reports of craniofacial/dentition development in CZS, several clinical oral aspects are still unknown. This study describes some structural and functional characteristics of facial and cranial growth and deciduous dentition in CZS-affected children. MATERIAL AND METHODS: Some cranial, facial and dental characteristics were determined in 14 children with CZS aged 3-5 years and compared them against 12 apparently healthy children paired by age and gender. RESULTS: Fourteen CZS cases presented microcephaly, maxillary prognathism, altered facial thirds, asymmetric pupillary line, bruxism (p = 0.006), deep and anterior open bite and distal step decidual molar relationship (p = 0.031). CZS children cannot feed by themselves and most cannot walk and have not develop coordinated and intelligible language according to their chronological age. In contrast, controls presented normal skull features, have autonomous locomotion skills, speak intelligible language, feed by themselves, presented a harmonic intermaxillary relationship and have symmetrical facial thirds. CONCLUSION: Microcephaly, dysphagia, bruxism, mandibular retrognathia, altered facial proportions and malocclusion are the main craniofacial and oral features at CZS. CLINICAL RELEVANCE: The complications of CZS including those related with the face and the oral cavity are still being identified. This study revealed some cranial, facial and oral features in children affected by CSZ. Interdisciplinary rehabilitation protocols must address these syndromic features that could improve children and parents living conditions.

Effect of genetic variants in UBE2O and TPK1 on facial morphology of Koreans.

Human face is a highly heritable and complex trait. Many genome-wide analyses have identified genetic variants influencing facial morphology. Genome-wide association studies (GWASs) investigating facial morphologies of different populations provide a comprehensive insight into the genetic basis of the human face. Here, we report a GWAS of normal facial variation in Koreans using an array optimized for the Korean population (KoreanChip). We found that novel genetic variants encompassing four loci reached the genome-wide significance threshold. They include LOC107984547, UBE2O, TPK1, and LINC01148 loci associated with facial angle, brow ridge protrusion, nasal height, and eyelid curvature. Our results also validated previously published genetic loci, including FAT4, SOX9, and TBX3 loci. All confirmed genetic variants showed phenotypic differences involving each facial trait based on the effect of the minor allele. The present study highlights genetic signals associated with normal human facial variation and provides candidates for functional studies. Key points: GWAS of normal facial variation in the Korean population was conducted using a Korean genome chip.Previously reported genetic signals associated with FAT4, SOX9, and TBX3 loci were replicated in the Korean populations.Genetic signals in UBE2O and TPK1 loci were identified as novel variants for corresponding facial features.

Anatomical phenotype of obstructive sleep apnea patients based on cluster analysis.

OBJECTIVES: To generate a novel subtype of obstructive sleep apnea (OSA) based on anatomical features and verify the differences in the response of different subtypes to orthodontic treatment, thus providing a theoretical reference for clinical decision-making. MATERIALS AND METHODS: A K-means cluster analysis was performed for this retrospective serial study, which includes 722 OSA patients, aged 44.0 (36.0, 54.0) years, 80.2% male, with apnea-hypopnea index (AHI) of 23.2 (13.4, 39.6) events·h-1 , and body mass index (BMI) of 25.47 ± 3.00 kg·m-2 . All samples were divided into three subtypes based on AHI, BMI, and five variables of craniofacial measurements. Sixty-seven cases with mandibular advancement devices (MAD) therapeutic results were further applied to validate the efficacy and side effects of this treatment in different subtypes. RESULTS: Two hundred and thirty patients (31.9%) were characterized as cluster 1: AHI of 17.65 (11.80, 30.42) events·h-1 , BMI of 23.65 ± 2.62 kg·m-2 , with skeletal Class II high-angle shape. Cluster 2 included 278 patients (38.5%): AHI of 17.00 (11.00, 26.48) events·h-1 , BMI of 25.36 ± 2.53 kg·m-2 , soft palate length (SPL) of 39.25 mm (36.12, 42.20), with basically normal skeleton and normal airway size. Cluster 3, consisting of 214 patients (29.6%), exhibited a combination of anatomical deformity and obesity, with the highest AHI and BMI of 45.35 (30.42, 62.53) events·h-1 and 27.57 ± 2.59 kg·m-2 respectively, but less deformity degree than cluster 1. Cluster 2 had the highest response rate and relatively mild side effects with MAD. CONCLUSIONS: Orthodontic treatment based on anatomical morphology could exert a better effect on mild-moderate OSA patients with mild skeletal deformity.

KBG syndrome: Clinical features and molecular findings in seven unrelated Korean families with a review of the literature.

BACKGROUND: KBG syndrome is a rare genetic disorder involving macrodontia of the upper central incisors, craniofacial, skeletal, and neurologic symptoms, caused either by a heterozygous variant in ANKRD11 or deletion of 16q24.3, including ANKRD11. Diagnostic criteria were proposed in 2007 based on 50 cases, but KBG syndrome remains underdiagnosed. METHODS: Whole exome sequencing (WES) and array comparative genomic hybridization (array CGH) were conducted for genetic analysis and patient phenotypes were characterized based on medical records. RESULTS: Eight patients from seven unrelated families were confirmed with KBG syndrome. All patients (8/8, 100%) had some degree of craniofacial dysmorphism and developmental delay or intellectual disabilities. Triangular face, synophrys, anteverted nostril, prominent ears, long philtrum, and tented upper lip, which are typical facial dysmorphism findings in patients with KBG syndrome, were uniformly identified in the eight patients participating in this study, with co-occurrence rates of 4/8 (50%), 4/8 (50%), 4/8 (50%), 4/8 (50%), 5/8 (62.5%), and 5/8 (62.5%), respectively. Various clinical manifestations not included in the diagnostic criteria were observed. Six patients had point mutations in ANKRD11, one had an exonic deletion of ANKRD11, and one had a 16q24.3 microdeletion. According to the ACMG guidelines, all mutations were classified as pathogenic. The c.2454dup (p.Asn819fs*1) mutation in Pt 4 was reported previously. The remaining variants (c.397 + 1G>A, c.226 + 1G>A, c.2647del (p.Glu883Argfs*94), and c.4093C>T (p.Arg1365Ter)) were novel. CONCLUSION: The clinical and molecular features of eight patients from seven unrelated Korean families with KBG syndrome described here will assist physicians in understanding this rare genetic condition.

Oral and cephalometric study in Brazilian Rubinstein-Taybi syndrome patients.

OBJECTIVE: The purpose of this study was to describe a detailed investigation of craniofacial and dental characteristics in a group of Brazilian Rubinstein-Taybi syndrome (RSTS) patients. METHODS AND RESULTS: Thirteen RSTS patients treated in a special care dental clinic after 10 years were studied. Panoramic radiographs were obtained from all patients, and cephalometric analysis was performed in eight patients. Five male and eight white female patients with a median age of 11.7 years were analyzed. All the RSTS patients were mouth breathers and presented malocclusion, transverse hypoplastic maxilla, nine subjects (9/13; 69.2%) had posterior crossbite, and eight (61.53%) exhibited talon cusps. Most patients presented class II skeletal pattern and were brachycephalic. Regarding systemic disorders, one patient (7.69%) reported seizure episodes during childhood, and four patients (30.76%) presented heart valve disorders. All patients presented reduced attention span, low intolerance to dental interventions, impulsiveness, and irritability. CONCLUSIONS: Since RSTS exhibits oral and skeletal changes, early dental treatment is essential for these patients. Dentists must be aware of medical problems related to heart disease and persist in conditioning techniques to obtain cooperation and avoid dental care under general anesthesia.

Three-Dimensional Assessment of Craniofacial Features in Patients With Down Syndrome During the Mixed Dentition Period: A Case-Control Study.

OBJECTIVES: Down syndrome (DS) is a common congenital chromosomal disorder related to trisomy 21. Lateral cephalometric radiography studies have shown that patients with DS have characteristic craniofacial morphology; however, no 3-dimensional analysis studies have been performed to investigate the craniofacial features, including volumetric aspects, of patients with DS. The present study was performed to evaluate the craniofacial features, including volumetric aspects, of patients with DS and to compare these findings with control participants using cone beam computed tomography (CBCT). MATERIALS AND METHODS: The study sample consisted of 12 patients with DS and 12 control participants. All participants were examined by means of CBCT; the resulting images were used for evaluation of maxillary and mandibular volume, cranial base, and craniofacial measurements. Differences between patients with DS and control participants were statistically analyzed using Student t test. RESULTS: Compared to control participants, patients with DS exhibited statistically significant reductions in maxillary and mandibular volumes. Both sagittal and axial cranial base linear measurements were shorter in patients with DS than in control participants. In contrast, the cranial base angle was enhanced in patients with DS, compared with control participants. Moreover, condylion (Co)-gnathion, anterior nasal spine-menton, and Co-subspinale (point A) measurements were shorter in patients with DS than in control participants; the sella-nasion-mandibular plane angle was significantly reduced in patients with DS, compared with control participants. CONCLUSION: Our results suggest that patients with DS have distinct skeletal volume and craniofacial morphology features, relative to individuals without DS.

A Novel 4q32.3 Deletion in a Child: Additional Signs and the Role of MARCH1.

The 4q deletion syndrome is an uncommon condition manifesting with broad clinical expression and phenotypic variability. We report a 5-year-old boy affected by 4q deletion syndrome who showed minor craniofacial features, growth failure, mild developmental delay, severe speech delay, and marked irascibility and aggressivity. Moreover, he showed precocious and crowded primary dentition, digital hyperlaxity, and congenital bilateral adducted thumbs, signs which were previously unreported in the syndrome. The array comparative genomic hybridization analysis revealed a 4q partial terminal deletion of ∼329.6 kb extending from 164.703.186 to 165.032.803 nt, which includes part of MARCH1 (membrane associated ring-CH-type finger 1) gene (OMIM#613331). Same rearrangement was found in his healthy mother. Clinical phenotype of the child and its relationship to the deleted region is presented with a revision of the cases having the same copy number losses from the literature and genomic variant databases.

Craniofacial features of 3q29 deletion syndrome: Application of next-generation phenotyping technology.

3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next-generation phenotyping algorithm DeepGestalt (Face2Gene by FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls and all other recognized syndromes. Area under the curve of receiver operating characteristic curves (AUC-ROC) was used to determine the capacity of Face2Gene to identify 3q29del cases against controls. In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC-ROC value of 0.873 (p = 0.006) and led to the inclusion of 3q29del as one of the supported syndromes. This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next-generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.

Analyzing Effects of Sickle Cell Disease on Morphometric and Cranial Growth in Indian Population.

BACKGROUND: Sickle cell disease is the most pervasive autosomal recessive hereditary blood diseases and is characterized by the presence of sickle hemoglobin (HbS), which in turn gives rise to pathophysiological consequences. This HbS reduces the agility of erythrocytes plummeting their ability to pass through small vascular channels, which in turn results in increased blood viscosity and congestion of vascular beds, causing ischemia, local infarction, and hemolysis. OBJECTIVES: The current study was conducted to carry out the morphometric analysis in patients with sickle cell disease. MATERIALS AND METHODS: This study was conducted on 75 subjects detected with sickle cell disease aged between 8 and 16.5 years. The study involved 38 males and 37 females. All the subjects were subjected to lateral cephalogram for the calculation of various angular and linear dimensions of the craniofacial structures. The linear measurements made were nasion-menton height, anterior nasal spine (ANS)-menton height, and nasion-ANS height, whereas the angular measurements made were Frankfurt mandibular plane angle, Frankfort mandibular incisor angle, and incisor mandibular plane angle. RESULTS: Major chunk of the subjects had retruded mandible and vertical growth pattern. Few subjects exhibited with maxillary protrusion. CONCLUSION: It is concluded that early diagnosis and management of dental malocclusion in patients with sickle cell disease plays a pivotal role in an attempt to endow with a better quality of life to these individuals.

Knockout of the gene encoding the extracellular matrix protein SNED1 results in early neonatal lethality and craniofacial malformations.

BACKGROUND: The extracellular matrix (ECM) is a fundamental component of multicellular organisms that orchestrates developmental processes and controls cell and tissue organization. We previously identified the novel ECM protein SNED1 as a promoter of breast cancer metastasis and showed that its level of expression negatively correlated with breast cancer patient survival. Here, we sought to identify the roles of SNED1 during murine development. RESULTS: We generated two novel Sned1 knockout mouse strains and showed that Sned1 is essential since homozygous ablation of the gene led to early neonatal lethality. Phenotypic analysis of the surviving knockout mice revealed a role for SNED1 in the development of craniofacial and skeletal structures since Sned1 knockout resulted in growth defects, nasal cavity occlusion, and craniofacial malformations. Sned1 is widely expressed in embryos, notably by cell populations undergoing epithelial-to-mesenchymal transition, such as the neural crest cells. We further show that mice with a neural-crest-cell-specific deletion of Sned1 survive, but display facial anomalies partly phenocopying the global knockout mice. CONCLUSIONS: Our results demonstrate requisite roles for SNED1 during development and neonatal survival. Importantly, the deletion of 2q37.3 in humans, a region that includes the SNED1 locus, has been associated with facial dysmorphism and short stature.

Craniofacial and occlusal features of children with sickle cell disease compared to normal standards: a clinical and radiographic study of 50 paediatric patients.

PURPOSE: To evaluate craniofacial and occlusal features of children with sickle cell disease and compare them with the normal healthy children. METHODS: A total of 50 children diagnosed with sickle cell disease (Group I) and 50 normal healthy children (Group II) between age 10 and 18 years were included in the study. Dental casts were obtained, occlusal traits were recorded and DAI and DHC-IOTN were calculated. Cephalometric parameters were measured. Obtained data were compared between the two groups. RESULTS: In children with sickle cell disease, 24% had definite malocclusion according to DAI and only 4% of them had normal occlusion as per the DHC-IOTN index. Also, children with sickle cell had significant retruded mandible and vertical growth pattern when compared with normal children. CONCLUSIONS: Children with sickle cell disease showed delayed eruption of teeth, a tendency towards Class II molar relationship, with increased crowding in the lower anterior region, increased overjet and open bite when compared to the normal children. Children with sickle cell disease had severe and handicapping malocclusion as per DAI and DHC-IOTN indices and a tendency towards skeletal Class II with a vertical growth pattern.

The Orthodontic Management of an Adult with Sickle Cell Disease.

Sickle cell disease (SCD) is a hereditary blood disorder characterized by abnormally shaped red cells. SCD frequently exhibits multisystemic manifestations including oral and craniofacial disorders. Craniofacial features such as maxillary protrusion and more forward growth of the mandible with significantly retruded maxillary and mandibular incisors are common. When a patient with Sickle Cell Disease (SCD) needs orthodontic treatment, it is important for the practitioner involved to know about the disease and the respective treatment because of the importance of complete blood supply after application of intraoral and extraoral forces. This article describes a sickle cell HbSS patient with orthodontic problems and how she was successfully managed at the University of Ghana Dental School.

Comparative evaluation of craniofacial anthropometric measurements in Indian adult patients with and without obstructive sleep apnea: A pilot study.

AIMS: The study aimed to compare the craniofacial features of North Indian patients suffering from obstructive sleep apnea (OSA) to that of normal North Indian population. MATERIALS AND METHODS: Selected 25 North Indian subjects (age: 18-65 years) were divided into two groups (OSA group [n = 14] and non-OSA group [n = 9]) according to the results of full night polysomnographic sleep study. Body mass index (BMI), neck circumference (NC), and lateral cephalograms were recorded for each subject in both groups and total 22 parameters of craniofacial anthropometric features were measured on lateral cephalograms for each subject. The differences in BMI, NC, and craniofacial features between the OSA and non-OSA groups were compared statistically. RESULTS: Independent sample t-test was used to compare the differences between OSA group and non-OSA group. The results showed that the BMI, NC, bulk of tongue (tongue length, tongue height, and tongue area) and length of the soft palate (PNS-U) were significantly higher in OSA group. OSA group was also found to have inferior positioning of hyoid bone (MP-H, ANS-H, PNS-H, ANS-Eb), narrower superior and middle airway space (SPAS and MAS), antero-inferior positioning of mandible (Gn-C3, ANS-Me, SNB, N-Me) and lower cranial base flexure angle (N-S-Ba). CONCLUSION: Craniofacial features, which play an important role in the pathophysiology of OSA, differ significantly between North Indian patients suffering from OSA and normal North Indian population.

Craniofacial and dental manifestations of triple X syndrome associated with congenital hypothyroidism: a case report.

Triple X syndrome (47,XXX) is a numerical chromosomal alteration that affects 1/1,000 women, in which the woman is born with an extra X chromosome. Some oral changes have been reported in the literature, as hypodontia, influence on deposition of crown enamel and discrepancies in cephalometric measurements. Other systemic complications may lead to oral abnormalities similar to those seen in triple X patients, such as congenital hypothyroidism (CH). This paper reports a triple X syndrome case associated with CH later treated. Besides delay in cognitive and intellectual development, the patient had changes in teeth development and in cephalometric measurements with deficiencies in the maxilla and mandible. This is the first report of a triple X syndrome associated with CH. Both conditions may result in changes in dentofacial development.

Do children with Wilson's disease have distinct craniofacial morphology? A cephalometric study.

OBJECTIVES: Patients with Wilson's disease (WD) develop osseous changes such as osteoporosis, spontaneous fractures, areas of sclerosis and demineralization of maxillary and mandibular bones, and neurologic symptoms including swallowing dysfunctions, which may affect dento-facial growth. However, dento-maxillo-facial structures of these patients have never been investigated. The present study aimed to discover if subjects with WD have different dentofacial structures. METHODS: Lateral cephalometric films of 13 children (5 males and 8 females) with WD and of 15 normal subjects (6 males and 9 females) were evaluated. Mean ages of the patients and controls were 12.62 ± 3.09 years and 12.01 ± 1.38 years, respectively. Lateral cephalometric cranial films of all subjects were taken in the same cephalostat in a habitual and unstrained body posture. Thirteen linear and 11 angular parameters were measured to describe the craniofacial characteristics of the subjects. RESULTS: Statistical analysis showed that there is no statistically significant difference between parameters of normal children and children with WD, with the exception of palatal plane inclination. The inclination of palatal plane was higher in children with WD than in normal subjects. CONCLUSIONS: Children with WD and healthy children have approximately the same dento-maxillo-facial structures. However, increased palatal plane inclination may be a finding of WD.