Neurocognitive, behavioral and socio-adaptive functioning assessment in a case of Coffin-Siris syndrome: A holistic approach/perspective beyond the identification of the disorder.

PURPOSE: Coffin-Siris syndrome (CSS) is a rare genetic disorder characterized by the presence of particular facies, congenital malformations, intellectual developmental disorder, behavioral issues, and speech and language impairment. Thorough neuropsychological assessments in the case of CSS have been reported infrequently, and its subdomains are poorly defined. A detailed description of the clinical, neurocognitive, behavioral, socio-adaptive sequelae of the patient with CSS is provided. RESULTS: The clinical diagnosis in the patient was confirmed by genetic analysis, which identified the presence of mutation of ARID1B gene; the parents' Sanger sequencing reported normal. The neuropsychological assessments revealed borderline intellectual functioning (IQ-75, verbal > performance) with a mild socio-adaptive deficit score of 64 as suggested by the adaptive scale. The behavioral profile reported that the child had significant difficulties in the attention subdomain with concern in social and thought subdomains. The child met the profile for mild severity of Autism Spectrum Disorder and did not meet the criteria for Attention Deficit Hyperactivity Disorder. In addition, the child had scholastic difficulties in reading and mathematical skills. CONCLUSION: Neurocognitive, behavioral, socio-adaptive functioning and comorbidity assessment in order to provide holistic management of such children after thorough evaluation is essential for their overall functioning.

Large-scale open-source three-dimensional growth curves for clinical facial assessment and objective description of facial dysmorphism.

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.

The Prevalence of Clinical Features in Patients with Aarskog-Scott Syndrome and Assessment of Genotype-Phenotype Correlation: A Systematic Review.

Aarskog-Scott syndrome is a genetically and clinically heterogeneous rare condition caused by a pathogenic variant in the FGD1 gene. A systematic review was carried out to analyse the prevalence of clinical manifestations found in patients, as well as to evaluate the genotype-phenotype correlation. The results obtained show that clinical findings of the craniofacial, orthopaedic, and genitourinary tract correspond to the highest scores of prevalence. The authors reclassified the primary, secondary, and additional criteria based on their prevalence. Furthermore, it was possible to observe, in accordance with previous reports, that the reported phenotypes do not present a direct relation to the underlying genotypes.

Three-dimensional scanners for soft-tissue facial assessment in clinical practice.

INTRODUCTION: The quantitative assessment of facial appearance and function is critical in the process of restoring normality and thus minimising morbidity in patients with facial deformities. Three-dimensional (3D) scanners have increasingly been applied in clinical settings to circumvent the issues associated with standard approaches, namely, subjectivity. This study aimed to summarise the current literature on the accuracy, reliability, and usability of 3D scanning technologies for soft-tissue facial assessment. METHODOLOGY: Medline, EMBASE, and Web of Science were searched for studies assessing the accuracy, reliability, and/or clinical usability of 3D scanners in assessing facial morphology. All results were filtered by title, abstract, and finally by full text for relevance. RESULTS: Eight hundred and thirty-seven results were filtered down to 41 articles that were included in this review. Articles were categorised depending on the 3D visualising principle of the scanner being tested: laser-based scanning, stereophotogrammetry, structured-light scanning, or RGB-D (red, green, blue-depth) sensors. DISCUSSION: Of the traditional 3D scanners evaluated in the literature, stereophotogrammetric systems most consistently demonstrate excellent accuracy and reliability in the collection of 3D facial scans. Due to their cost, size, and complexity, these systems are often unsuitable for incorporation into clinical environments with limited availability of resources, space, and time. Recently developed RGB-D sensors can collect accurate static and dynamic 3D facial scans without many of these disadvantages. Still, further improvements in their technical specifications and a greater focus on the development of automated facial assessment software is needed before RGB-D sensors can be universally accepted as a new gold-standard for soft-tissue facial assessment.

Classifying dysmorphic syndromes by using artificial neural network based hierarchical decision tree.

Dysmorphic syndromes have different facial malformations. These malformations are significant to an early diagnosis of dysmorphic syndromes and contain distinctive information for face recognition. In this study we define the certain features of each syndrome by considering facial malformations and classify Fragile X, Hurler, Prader Willi, Down, Wolf Hirschhorn syndromes and healthy groups automatically. The reference points are marked on the face images and ratios between the points' distances are taken into consideration as features. We suggest a neural network based hierarchical decision tree structure in order to classify the syndrome types. We also implement k-nearest neighbor (k-NN) and artificial neural network (ANN) classifiers to compare classification accuracy with our hierarchical decision tree. The classification accuracy is 50, 73 and 86.7% with k-NN, ANN and hierarchical decision tree methods, respectively. Then, the same images are shown to a clinical expert who achieve a recognition rate of 46.7%. We develop an efficient system to recognize different syndrome types automatically in a simple, non-invasive imaging data, which is independent from the patient's age, sex and race at high accuracy. The promising results indicate that our method can be used for pre-diagnosis of the dysmorphic syndromes by clinical experts.

Three-dimensional assessment of facial asymmetry in preschool patients with orofacial clefts after neonatal cheiloplasty.

OBJECTIVES: To evaluate facial asymmetry changes in pre-school patients with orofacial clefts after neonatal cheiloplasty and to compare facial asymmetry with age-matched healthy controls. METHODS AND MATERIALS: The sample consisted of patients with unilateral cleft lip (UCL), unilateral cleft lip and palate (UCLP), and bilateral cleft lip and palate (BCLP). The patients were divided in two age groups with a mean age of 3 years (n = 51) and 4.5 years (n = 45), respectively, and 78 age-matched individuals as controls. Three-dimensional (3D) facial scans were analyzed using geometric morphometry and multivariate statistics. RESULTS: Geometric morphometry showed positive deviations from perfect symmetry on the right side of the forehead in the intervention groups and the controls. The UCL groups showed the greatest asymmetric nasolabial area on the cleft-side labia and the contralateral nasal tip. The UCLP group showed, moreover, asymmetry in buccal region due to typical maxillar hypoplasia, which was accentuated in the older group. The BCLP groups showed slightly similar but greater asymmetry than the control groups, except for the philtrum region. CONCLUSIONS: Asymmetry of each of the cleft groups significantly differed from the controls. Except for the buccal region in the UCLP and BCLP groups, asymmetry did not significantly increase with age.

The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance.

Kabuki syndrome (KS) is caused by mutations in KMT2D, which is a histone methyltransferase involved in methylation of H3K4, a histone marker associated with DNA methylation. Analysis of >450,000 CpGs in 24 KS patients with pathogenic mutations in KMT2D and 216 controls, identified 24 genomic regions, along with 1,504 CpG sites with significant DNA methylation changes including a number of Hox genes and the MYO1F gene. Using the most differentiating and significant probes and regions we developed a "methylation variant pathogenicity (MVP) score," which enables 100% sensitive and specific identification of individuals with KS, which was confirmed using multiple public and internal patient DNA methylation databases. We also demonstrated the ability of the MVP score to accurately reclassify variants of unknown significance in subjects with apparent clinical features of KS, enabling its potential use in molecular diagnostics. These findings provide novel insights into the molecular etiology of KS and illustrate that DNA methylation patterns can be interpreted as 'epigenetic echoes' in certain clinical disorders.

Need for uniqueness as a mediator of the relationship between face consciousness and status consumption in China.

Strong economic development in China has led to a surge in status consumption as a means of gaining face. In Eastern culture, people interpret uniqueness as status distinction rather than separateness or deviance. This type of uniqueness can be used to meet others' expectations and gain social approval. Thus its relationship with face consciousness and status consumption is to be expected. This study investigates 2 hypotheses: (a) Face consciousness has a positive effect on status consumption and (b) Consumer need for uniqueness mediates the relationship between face consciousness and status consumption. Two-hundred and forty-six working respondents in eastern China completed a survey. Regression analysis of the results supported both hypotheses.

Optimizing Hybrid Occlusion in Face-Jaw-Teeth Transplantation: A Preliminary Assessment of Real-Time Cephalometry as Part of the Computer-Assisted Planning and Execution Workstation for Craniomaxillofacial Surgery.

BACKGROUND: The aesthetic and functional outcomes surrounding Le Fort-based, face-jaw-teeth transplantation have been suboptimal, often leading to posttransplant class II/III skeletal profiles, palatal defects, and "hybrid malocclusion." Therefore, a novel technology-real-time cephalometry-was developed to provide the surgical team instantaneous, intraoperative knowledge of three-dimensional dentoskeletal parameters. METHODS: Mock face-jaw-teeth transplantation operations were performed on plastic and cadaveric human donor/recipient pairs (n = 2). Preoperatively, cephalometric landmarks were identified on donor/recipient skeletons using segmented computed tomographic scans. The computer-assisted planning and execution workstation tracked the position of the donor face-jaw-teeth segment in real time during the placement/inset onto recipient, reporting pertinent hybrid cephalometric parameters from any movement of donor tissue. The intraoperative data measured through real-time cephalometry were compared to posttransplant measurements for accuracy assessment. In addition, posttransplant cephalometric relationships were compared to planned outcomes to determine face-jaw-teeth transplantation success. RESULTS: Compared with postoperative data, the real-time cephalometry-calculated intraoperative measurement errors were 1.37 ± 1.11 mm and 0.45 ± 0.28 degrees for the plastic skull and 2.99 ± 2.24 mm and 2.63 ± 1.33 degrees for the human cadaver experiments. These results were comparable to the posttransplant relations to planned outcome (human cadaver experiment, 1.39 ± 1.81 mm and 2.18 ± 1.88 degrees; plastic skull experiment, 1.06 ± 0.63 mm and 0.53 ± 0.39 degrees). CONCLUSION: Based on this preliminary testing, real-time cephalometry may be a valuable adjunct for adjusting and measuring "hybrid occlusion" in face-jaw-teeth transplantation and other orthognathic surgical procedures.

The social penalty of facial lesions: new evidence supporting high-quality reconstruction.

IMPORTANCE: To date, there have been no studies attempting to measure the multidimensional impact of facial lesions, before and after reconstruction, on social conversation. OBJECTIVE: To measure the direct social impact of facial lesions before and after surgical reconstruction. DESIGN, SETTING, AND PARTICIPANTS: Prospective randomized controlled experiment at an academic tertiary referral center. One hundred twenty casual observers viewed images of faces with lesions of varying sizes and locations before and after reconstruction as well as faces without lesions (normal faces) for comparison. MAIN OUTCOMES AND MEASURES: Observers rated faces using a battery of metrics, including how comfortable they would be having a conversation with the participant in each facial image. The conversation questions were answered on a scale from 0 to 100, where the higher the score, the more comfortable the observer would be conversing with the subject. RESULTS: The mean (SD) conversation score for participants with normal faces was 85.02 (17.95) of 100 points. Facial lesions had a negative effect (or, a penalty) on conversation (61.63 [29.50]). Structural equation modeling showed this conversation penalty varied with lesion size and location, with large and central lesions generating the greatest penalty. Reconstructive surgery increased observers' comfort and willingness to converse with individuals with facial lesion by an average of 19.83 (95% CI, 17.49-22.17), an improvement that also varied with preoperative lesion size and location. Planned hypothesis testing showed that reconstructive surgery normalized observer comfort in communicating with people with small peripheral, small central, and large peripheral lesions. However, substantial discomfort communicating with patients with large central lesions remained after surgery. Observer-rated facial attractiveness, affect, and perceived quality of life also influenced this social communication measure. CONCLUSIONS AND RELEVANCE: Facial lesions induce a significant social penalty as rated by the casual observer. Specifically, observers are less comfortable communicating with people who have facial lesions. Surgical reconstruction of facial lesions increased observers' comfort in conversing with people with facial lesions, an impact that varied with lesion size and location. LEVEL OF EVIDENCE: NA.

Immunologic assessment and KMT2D mutation detection in Kabuki syndrome.

Kabuki or Niikawa-Kuroki syndrome (KS) is a rare disorder with multiple malformations and recurrent infections, especially otitis media. This study aimed to investigate the genetic defects in Kabuki syndrome and determine if immune status is related to recurrent otitis media. Fourteen patients from 12 unrelated families were enrolled in the 9-year study period (2005-2013). All had Kabuki faces, cleft palate, developmental delay, mental retardation, and the short fifth finger. Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. Immunologic analysis revealed lower memory CD19+ cells (11/13), lower memory CD4+ cells (8/13), undetectable anti-HBs antibodies (7/13), and antibody deficiency (7/13), including lower IgA (4), IgG (2), and IgG2 (1). Naïve emigrant lymphocytes, lymphocyte proliferation function, complement activity, and superoxide production in polymorphonuclear cells were all normal. All the patients had KMT2D mutations and 10 novel mutations of R1252X, R1757X,Y1998C, P2550R fs2604X, Q4013X, G5379X, E5425K, R5432X, R5432W, and R5500W. Resembling the phenotype of common variable immunodeficiency, KS patients with antibody deficiency, decreased memory cells, and poor vaccine response increased susceptibility to recurrent otitis media. Large-scale prospective studies are warranted to determine if regular immunoglobulin supplementation decreases the frequency of otitis media and severity of hearing impairment.

Fetal alcohol spectrum disorders: an overview for pediatric and adolescent care providers.

Fetal alcohol spectrum disorder (FASD) is a term used to describe the spectrum of conditions associated with prenatal alcohol exposure. These are characterized by facial dysmorphia, growth deficits and central nervous system abnormalities. FASDs are the most common preventable cause of intellectual disability in the United States and have high financial costs. Therefore, efforts at prevention are paramount. When an individual with an FASD goes undiagnosed and when appropriate interventions are not instituted, secondary disabilities such as substance abuse, school dropout, and criminal involvement are common with corresponding suffering endured by both the affected individual and the family. The diagnostic process opens up access to existing tools and resources, including the new American Academy of Pediatrics (AAP) FASD algorithm for the evaluation of FASDs, the new AAP FASD toolkit and evidence-based interventions specific to FASDs. Pediatric and adolescent clinicians are challenged to participate in the continuum of care from FASD prevention to identification, diagnosis, and management, including provision of supportive services for families in order for clinicians to make a difference in this 100% preventable disorder.

Three-dimensional assessment of facial asymmetry among pre-pubertal class III subjects: a controlled study.

BACKGROUND/OBJECTIVE: Facial asymmetry is very common in adult class III patients; however, the degree of facial asymmetry in growing class III subjects has been poorly investigated. Therefore, the aim was to assess the degree of facial asymmetry of growing class III subjects and to compare it with a sample of growing subjects without malocclusion, recorded using a three-dimensional laser scanning method and classified according to the dentition phase. SUBJECTS/METHODS: A group of 156 Caucasian subjects, 52 with class III malocclusion (28 females and 24 males) and 104 without malocclusion (control, 51 females and 53 males), with an overall mean age 6.7±1.4 years (range 4.3-10.3 years), were included. The subjects were further subdivided according to the presence of either primary or early/intermediate mixed dentitions. Facial asymmetry was assessed on three-dimensional surface facial images obtained using a laser scanning device in terms of mirrored face distances and percentages of asymmetry. Multivariate analyses were used to assess the differences among class III and control groups. RESULTS: Complete facial symmetry was not seen in any subject. No significant differences of facial asymmetry were observed between the class III and control groups, neither in the primary nor in the early/intermediate mixed dentition phases. LIMITATIONS: No conclusions about longitudinal changes in the degree of facial asymmetry among class III subjects could be drawn from the present cross-sectional study. CONCLUSIONS: Based on three-dimensional facial asymmetry analysis, class III subjects do not show clinically relevant facial asymmetry, at least during the pre-pubertal growth period.

[Radiological evaluation of transverse maxillofacial disparity].

Graphical model is established based on frontal cephalometric for differential diagnostic of transverse morphological and functional abnormalities of the mandible. Eight graphical models are made which cover and dinstinguish possible transverse variations of mandible position and morphology taking into account the asymmetry of the mandible, rotation and translation of the joints and the combinations thereof. With these eight detailed models an orthodontist can accurately differentiate the problem and choose an adequate treatment plan.

Assessment of health-related quality of life in Turkish patients with facial prostheses.

BACKGROUND: Facial prostheses are intended to provide a non-operative rehabilitation for patients with acquired facial defects. By improving aesthetics and quality of life (QOL), this treatment involves reintegration of the patient into family and social life. The aim of this study was to evaluate the perception of QOL in adult patients with facial prostheses and to compare this perception with that of a control group. METHODS: The study participants consisted of 72 patients, who were divided into three equal-sized groups according to the type of prosthesis (OP- orbital prosthesis, AP- auricular prosthesis, NP - nasal prosthesis) and 24 healthy control participants without any congenital or acquired deformity of face or body. Clinical and socio-demographic data were gathered from each person's medical chart. Participants completed the Turkish version of the World Health Organization Quality of Life Instrument, Short Form (WHOQOL-BREF). Descriptive statistics, independent sample t-tests, Pearson's chi-square test, ANOVA, ANCOVA, and Pearson correlation were used to analyse the data. RESULTS: Compared with the control participants, patients with NP scored lower on the all domains of QOL and all three patient groups had lower scores on overall QOL and its domains of physical and environmental health. Patients with OP reported significantly lower physical health scores than those with AP, while patients with NP reported significantly lower overall QOL and psychological health scores than those with AP. Female patients had lower environmental domain scores than did male patients. The patient's age and income correlated with social relationships QOL, while the patient's income and the age of facial prosthesis were correlated with environmental QOL. CONCLUSION: Patients with facial prostheses had lower scores in overall QOL, physical and environmental health domains than the control participants. Socio-demographic and clinical characteristics such as age, gender, income, localization of the defect, and age of facial prosthesis were associated with patients' QOL. These findings may provide valuable information about the specific health needs of these patients that may affect their well-being. Further studies are needed to confirm these results. Use of the WHOQOL-BREF may provide valuable information for determining patients' needs and priorities as well as for planning and developing comprehensive prosthetic rehabilitation programs.

The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases.

Coffin-Siris syndrome (CSS) is a rare, clinically heterogeneous disorder often considered in the setting of cognitive/developmental delay and 5th finger/nail hypoplasia. Due to the clinical variability of facial and other features, this diagnosis is often difficult to confirm clinically and the existence of this disorder as a specific diagnosis has been at times an issue of debate. In an effort to further delineate the spectrum and key phenotypic features, we reviewed 80 previously reported cases to define features in patients that most closely correlated with a convincing diagnosis. There appear to be two subtypes of CSS, one which displays the "classic" coarse facial features previously described; another displays "variant" facial features which are less striking. Using these features, we defined an algorithm to rank the confidence of diagnosis and applied it to 15 additional patients who had been previously characterized by chromosome microarray. This approach will also facilitate uniform categorization for whole-exome analysis.

Alagille syndrome in a Vietnamese cohort: mutation analysis and assessment of facial features.

Alagille syndrome (ALGS, OMIM #118450) is an autosomal dominant disorder that affects multiple organ systems including the liver, heart, eyes, vertebrae, and face. ALGS is caused by mutations in one of two genes in the Notch Signaling Pathway, Jagged1 (JAG1) or NOTCH2. In this study, analysis of 21 Vietnamese ALGS individuals led to the identification of 19 different mutations (18 JAG1 and 1 NOTCH2), 17 of which are novel, including the third reported NOTCH2 mutation in Alagille Syndrome. The spectrum of JAG1 mutations in the Vietnamese patients is similar to that previously reported, including nine frameshift, three missense, two splice site, one nonsense, two whole gene, and one partial gene deletion. The missense mutations are all likely to be disease causing, as two are loss of cysteines (C22R and C78G) and the third creates a cryptic splice site in exon 9 (G386R). No correlation between genotype and phenotype was observed. Assessment of clinical phenotype revealed that skeletal manifestations occur with a higher frequency than in previously reported Alagille cohorts. Facial features were difficult to assess and a Vietnamese pediatric gastroenterologist was only able to identify the facial phenotype in 61% of the cohort. To assess the agreement among North American dysmorphologists at detecting the presence of ALGS facial features in the Vietnamese patients, 37 clinical dysmorphologists evaluated a photographic panel of 20 Vietnamese children with and without ALGS. The dysmorphologists were unable to identify the individuals with ALGS in the majority of cases, suggesting that evaluation of facial features should not be used in the diagnosis of ALGS in this population. This is the first report of mutations and phenotypic spectrum of ALGS in a Vietnamese population.

Smith-Lemli-Opitz syndrome: Objective assessment of facial phenotype.

Smith-Lemli-Opitz syndrome (SLOS), is an autosomal recessive condition caused by cholesterol synthesis deficiency which results in a wide phenotypic spectrum which includes multiple malformations, distinctive facial appearance, and intellectual disability. This anthropometric and observational study was carried out to define the key facial characteristics of individuals with SLOS and to evaluate evolution of the facial phenotype with age. Clinical photographs were obtained on 51 subjects with SLOS and standardized facial anthropometry was performed on 42; the ages ranged from 6 months to 20 years. For each individual, 22 standardized cranial and facial measurements were obtained and compared to published age- and sex-matched controls. Craniofacial pattern profiles were compared between sexes, various age groups, plasma cholesterol concentration at the time of diagnosis, and physical severity score. Mean-Z, a measurement of overall facial size, and craniofacial variability index (CVI), a summary anthropometric measure of craniofacial deviation from the norm, were calculated and compared according to methods published previously. A characteristic craniofacial pattern profile was universally present: narrow forehead, brachycephaly, short palpebral fissures, short nasal ridge, anteverted nares, flat face, normal jaw width, and retrognathia. The facial measurements of subjects with SLOS had higher deviations from the norm with mean CVI of 2.11; SD = 0.47 (controls: Mean = 0.76, SD = 0.19; <0.0001) than age- and sex-matched controls. Their faces were also smaller than controls: 70% of subjects had mean-Z values 2 SD below the mean for controls; average Z-score was -1.64; SD = 0.85 (controls: mean = 0, SD = 0.64; <0.0001). There were no significant differences in the craniofacial pattern profile between the sexes or clinical severity as measured by either plasma cholesterol level at the time of diagnosis or the physical severity score. Patients with a lower weight at the time of assessment and patients with higher physical severity score had higher CVI measures (P < 0.001 and P < 0.002, respectively), suggesting that the degree of deviation from craniofacial norms is a function of the overall physical severity.