Correlation analysis of airway-facial phenotype in Crouzon syndrome by geometric morphometrics: A promising method for non-radiation airway evaluation.

AIM: This study aimed to verify the correlation of the airway-facial phenotype and visualize the morphological variation in Crouzon syndrome patients. Additionally, to develop a non-radiation methodology for airway assessments. METHOD: In this study, 22 patients diagnosed with Crouzon syndrome (Age: 7.80 ± 5.63 years; Gender distribution: 11 females and 11 males) were analysed. The soft tissue surface and airway were three-dimensionally reconstructed, and the entire facial phenotype was topologized and converted into spatial coordinates. Geometric morphometrics was employed to verify the correlation and visualize dynamic phenotypic variation associated with airway volume. A total of 276 linear variables were automatically derived from 24 anatomical landmarks, and principal component analysis (PCA) identified the 20 most significant parameters for airway evaluation. Correlation analyses between parameters and airway volume were performed. Then, patients were classified into three groups based on airway volume, and the differences among the groups were compared for evaluating the differentiating effectiveness of parameters. RESULTS: The facial phenotype was strongly correlated with the airway (coefficient: 0.758). Morphological variation was characterized by (i) mandibular protrusion and anticlockwise rotation; (ii) midface retrusion; (iii) supraorbital frontward and (iv) lengthening of the facial height. All the anthropometric parameters were strongly associated with the airway, and the differences among the groups were statistically significant. CONCLUSION: This study confirmed the strong correlation between facial phenotype and airway parameters in Crouzon syndrome patients. Despite the development of the airway, pathological midface retrusion was still aggravated, suggesting that surgical intervention was inevitable. Three-dimensional facial anthropometry has potential as a non-radiation examination for airway evaluation.

Anthropometric 3D evaluation of the face in patients with sleep related breathing disorders.

PURPOSE: To evaluate craniofacial measurements on 3D-stereophotogrammetry and see if particular measurements are more typical in obstructive sleep apnea (OSA) and have a correlation with its severity. METHODS: Subjects included were adults undergoing a diagnostic polysomnography. Age, BMI, neck, abdominal and hip circumference (cm) were recorded. 3D-stereophotogrammetry was performed and landmarks were placed on the 3D-image. Different linear, angular and volume measurements were performed to gauge facial and neck anatomy. The relationship between these measurements and the severity of OSA, based on the obstructive apnea/hypopnea index (OAHI, events/h), was assessed by multiple linear regression, and adjusted for BMI and sex. RESULTS: Of 91 subjects included (61 male), mean age was 46 ± 12 years, BMI 30.1 ± 6.5 kg/m2, OAHI 19.3 ± 18.8/h. BMI was higher (p = 0.0145) in females (32.9 ± 7.7) than in males (28.6 ± 5.3). This was also true for hip circumference (118 ± 15 vs 107 ± 10, p = 0.0006), while the neck circumference was higher (p < 0.0001) in males (41 ± 4 vs 37 ± 4). The following parameters could predict the logOAHI (r2-adjusted = 0.51): sex (p < 0.0001), BMI (p = 0.0116), neck-depth/mandibular-length (p = 0.0002), mandibular-width angle (p = 0.0118), neck-depth euclidean distance/surface distance (E/S) (p = 0.0001) and the interaction terms between sex and neck-depth/mandibular-length (p = 0.0034), sex and neck-depth E/S (p = 0.0276) and BMI and neck-depth E/S (p = 0.0118). The interaction between sex and neck-depth/mandibular-length showed a steeper linear course in females. This is also true for the interaction term BMI with neck-depth E/S in patients with a higher BMI. With a same neck-depth ratio, the OAHI is larger in men. CONCLUSION: Measurements involving the width of the face and addressing the soft tissue in the upper neck were found to have a significant relation with OSA severity. We found remarkable differences between non-obese/obese subjects and between males and females.

Cognitive, Motor, and Language Development of Preschool Children With Craniofacial Microsomia.

OBJECTIVE: To examine neurodevelopment in preschool-aged children with craniofacial microsomia (CFM) relative to unaffected peers. DESIGN: Multisite, longitudinal cohort study. SETTING: Tertiary care centers in the United States. PARTICIPANTS: We included 92 children with CFM ("cases") through craniofacial centers and clinics. Seventy-six children without CFM (controls) were included from pediatric practices and community advertisements. This study reports on outcomes assessed when participants were an average age of 38.4 months (SD = 1.9). MAIN OUTCOME MEASURES: We assessed cognitive and motor skills using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), and language function using subtests from the Clinical Evaluation of Language Fundamentals-Preschool, second edition (CELF-P2). RESULTS: Case-control differences were negligible for Bayley-III cognitive (effect sizes [ES] = -0.06, P = .72) and motor outcomes (ES = -0.19, P = .25). Cases scored lower than controls on most scales of the CELF-P2 (ES = -0.58 to -0.20, P = .01 to .26). Frequency counts for "developmental delay" (ie, one or more scores > 1 SD below the normative mean) were higher for cases (39%) than controls (15%); however, the adjusted odds ratio = 1.73 (P = 0.21) was not significant. Case-control differences were most evident in children with microtia or other combinations of CFM-related facial features. CONCLUSIONS: Cognitive and motor scores were similar for preschool-aged children with and without CFM. However, children with CFM scored lower than controls on language measures. We recommend early monitoring of language to identify preschoolers with CFM who could benefit from intervention.

Obstructive Sleep Apnea in School-Aged Children Presented with Nocturnal Enuresis.

OBJECTIVES: We aimed to detect obstructive sleep apnea (OSA) among school-age children presented with nocturnal enuresis (NE) and to identify the possible risk factors for OSA in them. METHODS: Sixty-six children aged > 5-16 years presented with NE were enrolled in the study. Children with urinary tract anatomical abnormalities or infection, intellectual disabilities, genetic syndromes, psychological issues, and diabetes mellitus were excluded. They were clinically examined, scored using sleep clinical record score (SCR), and subjected for full-night polysomnogram (PSG). Children with obstructive apnea/hypopnea index (AHI) ≥ 2 episodes/hour (h) were considered as OSA. RESULTS: Fifty-four children (81.8% of the recruited children) aged 8.3 ± 2.8 years agreed to undergo PSG as 68.5% had OSA with median obstructive AHI of 6.1 (3.7-13.2) episodes/h, median oxygen saturation of 97% and nadir of 88%. Thirty-three percent were obese with significantly higher AHI [7.0 (3.7-12.4) vs. 2.4 (1.3-6.1) episodes/h; p = 0.023]. SCR score correlated significantly with AHI (r2 = 0.462, p = 0.001) with 91% sensitivity in detecting OSA ≥ 5 episodes/h. Nasal obstruction, adenoid/adult facial phenotype, and arched palate were associated with OSA (p < 0.05). CONCLUSION: NE is commonly associated with OSA especially in obese children. Nasal obstruction, abnormal facial phenotype, and high-arched palate were common risk factors.

Parsing the craniofacial phenotype: effect of weight change in an obstructive sleep apnoea population.

PURPOSE: Craniofacial structure is an important risk factor in the development of obstructive sleep apnoea. Most craniofacial imaging methods are not feasible for large-scale studies or the clinic. Craniofacial photography is a high-throughput technique for facial phenotyping; however, derived measurements are a composite of skeletal and soft tissue craniofacial information. Weight change is a paradigm to help determine which facial measurements most relate to regional soft tissue (i.e. change with weight) versus skeletal structure (i.e. stable with weight changes). We aimed to assess the association between weight change and changes in key facial measurements from facial photography. METHODS: Calibrated frontal and profile photographs were taken of participants in weight loss studies (N = 106). Univariate linear regression was used to assess whether weight change explained changes in facial dimensions. RESULTS: Patients lost 11.7 ± 10.8 kg body weight and 2.0 ± 2.0 cm of neck circumference. Weight changes influenced face width (r = 0.3, p < 0.001), mandibular width (r = 0.4, p < 0.001) and cervicomental angle (r = 0.3, p = 0.001). Facial angles, facial heights and mandibular length were not influenced by weight change. CONCLUSIONS: A weight loss paradigm suggests that face and mandibular width and cervicomental angle most strongly reflect regional adiposity. Facial angles and heights are insensitive to weight change and could be more representative of craniofacial skeletal structure. This study informs the interpretation of facial phenotype assessed by this craniofacial photographic method which can be applied to future studies of craniofacial phenotype in OSA.

Neurodevelopment of Infants with and without Craniofacial Microsomia.

OBJECTIVES: To determine whether infant cases with craniofacial microsomia (CFM) evidence poorer neurodevelopmental status than demographically similar infants without craniofacial diagnoses ("controls"), and to examine cases' neurodevelopmental outcomes by facial phenotype and hearing status. STUDY DESIGN: Multicenter, observational study of 108 cases and 84 controls aged 12-24 months. Participants were assessed by the Bayley Scales of Infant and Toddler Development-Third Edition and the Preschool Language Scales-Fifth Edition (PLS-5). Facial features were classified with the Phenotypic Assessment Tool for Craniofacial Microsomia. RESULTS: After adjustment for demographic variables, there was little difference in Bayley Scales of Infant and Toddler Development-Third Edition or Preschool Language Scales-Fifth Edition outcomes between cases and controls. Estimates of mean differences ranged from -0.23 to 1.79 corresponding to standardized effect sizes of -.02 to 0.12 (P values from .30 to .88). Outcomes were better among females and those with higher socioeconomic status. Among cases, facial phenotype and hearing status showed little to no association with outcomes. Analysis of individual test scores indicated that 21% of cases and 16% of controls were developmentally delayed (OR 0.68, 95% CI 0.29-1.61). CONCLUSIONS: Although learning problems have been observed in older children with CFM, we found no evidence of developmental or language delay among infants. Variation in outcomes across prior studies may reflect differences in ascertainment methods and CFM diagnostic criteria.

Craniofacial phenotyping for prediction of obstructive sleep apnoea in a Chinese population.

BACKGROUND AND OBJECTIVE: Craniofacial morphology is a risk factor for obstructive sleep apnoea (OSA). Facial photography has previously shown utility in predicting OSA in a Caucasian sleep clinic. However, ethnic differences in OSA risk factors may influence these facial predictors. Our aim was to assess phenotypical facial measurements for OSA prediction in a Chinese population. METHODS: Calibrated frontal and profile facial photographs were taken before polysomnography. Photographs were analysed to derive head, face and neck measurements. Demographical, anthropometrical and facial photographical variables were considered in prediction models for OSA. OSA prediction models were derived using logistic regression and classification and regression tree techniques. RESULTS: Two-hundred subjects were recruited (146 OSA, 54 controls). The OSA group contained more men (77% vs 61%) and were more obese. Logistic regression modelling found cervicomental angle (OR 1.06/degree, 95% CI: 1.03-1.09, P < 0.001) and face width (OR 1.7/cm, 95% CI: 1.1-2.7, P = 0.02) predicted OSA (area under the receiver operating characteristics curve 0.76). Classification and regression tree analysis identified cricomental space area, mandibular width, mandibular plane angle and neck soft tissue area as predictors (area under receiver operating characteristics curve 0.81). CONCLUSION: In a Hong Kong Chinese sleep clinic, facial photographical measurements had predictive utility for OSA. Prediction models had similar accuracy and included variables to a previous Caucasian population.

Characterization of facial phenotypes of children with congenital hypopituitarism and their parents: a matched case-control study.

Congenital Hypopituitarism (CH) has traditionally been associated with specific facial phenotypes subsumed under the term midface retrusion, based on cephalometric studies. In this study, we used a systematic anthropometric approach to facial morphology in 37 individuals with CH and their parents, primarily of French Canadian ancestry, and compared them to a control group of 78 French Canadian patients with well-controlled type 1 diabetes and their parents. We were able to demonstrate clear morphological differences, which were more prevalent in the affected group than in the control group. More specifically, we showed the presence of a shorter skull base width (P < 0.001) and reduced inner canthal distance (P = 0.006) in the CH face, as well as a relative underdevelopment of the mandible (P = 0.001). These findings were present in individuals of all ages, and were independent of the duration of growth hormone treatment (median treatment 90.8 months; range 7.2-175.8 months). In addition, skull base width was significantly reduced in both mothers and fathers of affected children compared to the parents of the controls (P < 0.001), despite comparable parental heights, supporting an underlying genetic etiology. Such extensive phenotypic studies have not been done in congenital hypopituitarism and will provide further opportunities for data mining.

Can intraoral and facial photos predict obstructive sleep apnea in the general and clinical population?

STUDY OBJECTIVES: This study aimed to evaluate and compare measurements of standardized craniofacial and intraoral photographs between clinical and general population samples, between groups of individuals with an apnea-hypopnea index (AHI) ≥ 15 and AHI < 15, and their interaction, as well as the relationship with the presence and severity of obstructive sleep apnea (OSA). METHODS: We used data from 929 participants from Sleep Apnea Global Interdisciplinary Consortium, in which 309 patients from a clinical setting and 620 volunteers from a general population. RESULTS: AHI ≥ 15 were observed in 30.3% of the total sample and there were some interactions between facial/intraoral measures with OSA and both samples. Mandibular volume (p < 0.01) and lateral face height (p = 0.04) were higher in the AHI ≥ 15 group in the clinical sample compared to the AHI ≥ 15 group in the general population and AHI < 15 group in the clinical sample. When adjusted for sex and age, greater mandible width (p < 0.01) differed both in the clinical and in the general population samples, reflecting AHI severity and the likelihood of OSA. The measure of smaller tongue curvature (p < 0.01) reflected the severity and probability of OSA in the clinical sample and the higher posterior mandibular height (p = 0.04) showed a relationship with higher AHI and higher risk of OSA in the general population. When adjusted for sex, age, and body mass index, only smaller tongue curvature (p < 0.01) was associated with moderate/severe OSA. CONCLUSIONS: Measures of greater tongue and mandible were associated with increased OSA risk in the clinical sample and craniofacial measurement was associated in the general population sample.

Thermal facial image analyses reveal quantitative hallmarks of aging and metabolic diseases.

Although human core body temperature is known to decrease with age, the age dependency of facial temperature and its potential to indicate aging rate or aging-related diseases remains uncertain. Here, we collected thermal facial images of 2,811 Han Chinese individuals 20-90 years old, developed the ThermoFace method to automatically process and analyze images, and then generated thermal age and disease prediction models. The ThermoFace deep learning model for thermal facial age has a mean absolute deviation of about 5 years in cross-validation and 5.18 years in an independent cohort. The difference between predicted and chronological age is highly associated with metabolic parameters, sleep time, and gene expression pathways like DNA repair, lipolysis, and ATPase in the blood transcriptome, and it is modifiable by exercise. Consistently, ThermoFace disease predictors forecast metabolic diseases like fatty liver with high accuracy (AUC > 0.80), with predicted disease probability correlated with metabolic parameters.

Cockayne syndrome-xeroderma pigmentosum complex with demyelination: A rare association.

Xeroderma pigmentosum-Cockayne syndrome (XP-CS) includes facial freckling and early skin cancers typical of XP and some features typical of CS, such as mental retardation, spasticity, short stature, and hypogonadism. XP-CS does not include skeletal involvement, the facial phenotype of CS, or CNS demyelination and calcifications. We present a rare patient whose genome probably harbored a specific combination of mutations producing a rare double syndrome of XP-CS, with facial phenotype of CS, and CNS demyelination.

Classification of facial phenotypes in Asian patients with obstructive sleep apnea.

BACKGROUD: The facial phenotypes of Asian obstructive sleep apnea (OSA) patients remain unclear. OBJECTIVES: (1) To describe the facial features of OSA patients. (2) To develop a model based on facial contour indicators to predict OSA. (3) To classify the facial phenotypes of Asian OSA patients. MATERIALS AND METHODS: 110 patients with OSA (apnea-hypopnea index [AHI] ≥ 10/h) and 50 controls (AHI< 10/h) were selected to measure facial contour indicators. Indicators were compared between OSA patients and the control group. We used multivariable linear regression analysis to predict OSA severity and K-means cluster analysis to classify OSA patients into different phenotypes. RESULTS: We built a model to predict OSA which explained 49.1% of its variance and classified OSA patients into four categories. Cluster 1 (Skeletal type) had the narrowest facial width indicators with narrowing of the retroglossal airway. Cluster 2 (Obese type) had the widest face, and narrowest hard palate, retropalatal, and hypopharyngeal airways. Cluster 3 (Nose type) had the narrowest nasal cavity. Cluster 4 (Long type) had the longest airway length. CONCLUSIONS AND SIGNIFICANCE: Patients with OSA were classified into four categories, each of which identified different anatomic risk factors that can be used to select the treatment.

A theoretical analysis of longitudinal temporomandibular joint compressive stresses and mandibular growth.

OBJECTIVES: To determine if temporomandibular joint (TMJ) compressive stresses during incisor biting (1) differed between growing children over time, and (2) were correlated with Frankfort Horizontal-mandibular plane angle (FHMPA, °) and ramus length (Condylion-Gonion (Co-Go), mm). MATERIALS AND METHODS: Three-dimensional anatomical geometries, FHMPA and Co-Go, were measured longitudinally from lateral and posteroanterior cephalographs1 of children aged 6 (T1), 12 (T2), and 18 (T3) years. Geometries were used in numerical models to estimate subject-specific TMJ eminence shape and forces for incisor bite-forces of 3, 5, and 8 Newtons at T1, T2, and T3, respectively. TMJ compressive stresses were estimated via two steps: First, TMJ force divided by age-dependent mandibular condylar dimensions, and second, modified by loading surfaces' congruency. Analysis of variance and Tukey honest significant difference post-hoc tests, plus repeated measures and mixed effects model analyses were used to evaluate differences in variables between facial groups. Regression analyses tested for correlation between age-dependent compressive stresses, FHMPA, and Co-Go. RESULTS: Sixty-five of 842 potential subjects had T1-T3 cephalographs and were grouped by FHMPA at T3. Dolichofacial (FHMPA ≥ 27°, n = 36) compared to meso-brachyfacial (FHMPA< 27°, n = 29) subjects had significantly larger FHMPA at T1-T3, shorter Co-Go at T2 and T3 (all P < .01), and larger increases in TMJ compressive stresses with age (P < .0001). Higher compressive stresses were correlated with larger FHMPA (all R2 ≥ 0.41) and shorter Co-Go (all R2 ≥ 0.49). CONCLUSIONS: Estimated TMJ compressive stress increases from ages 6 to 18 years were significantly larger in dolichofacial compared to meso-brachyfacial subjects and correlated to FHMPA and Co-Go.

Does Father Christmas Have a Distinctive Facial Phenotype?

We investigated whether Father Christmas has a distinguishable facial phenotype by performing a cross-sectional cohort study examining the facial feature vectors of all publicly available photographs obtained from a google image search of individuals meeting our eligibility criteria presenting as Father Christmas compared with other adult and elderly bearded men. Facial feature vectors were determined using the open-source OpenFace facial recognition system and assessed by support vector machines (SVM). SVM classifiers were trained to distinguish between the facial feature vectors from our groups. Accuracy, precision, and recall results were calculated and the area under the curve (AUC) of the receiver operating characteristic (ROC) were reported for each classifier. SVM classifiers were able to distinguish the face of Father Christmas from other adult men with a high degree of accuracy and could discriminate Father Christmas from elderly bearded men but with lower accuracy. Father Christmas appears to have a distinct facial phenotype when compared to adult men and elderly bearded men. This will be reassuring to children who may be keen to recognise him but raises some interesting questions about the careful use of two-dimensional facial analysis, particularly when employed to explore the relationships between genotype and facial phenotype in a clinical dysmorphology setting.

High facial specificity and positive predictive value are required to diagnose fetal alcohol syndrome when prenatal alcohol exposure is unknown.

BACKGROUND: Facial criteria with high specificity and positive predictive value (PPV) to prenatal alcohol exposure (PAE) are required to diagnose fetal alcohol syndrome (FAS) when documentation of PAE is unavailable. Not all fetal alcohol spectrum disorder (FASD) diagnostic guidelines appear to meet these criteria. METHODS: A dataset generated from a 10-year FAS screening of 1,602 children in fostercare conducted by the University of Washington FAS Diagnostic & Prevention Network was used to determine how well the FAS facial phenotype, microcephaly and growth deficiency (individually and in combination at varying levels of magnitude) predicted PAE. RESULTS: The 4-Digit-Code Rank 4 FAS facial phenotype was the only outcome that provided sufficient PPV and specificity to PAE (100%) to allow the facial phenotype to serve as confirmation of PAE in a diagnostic setting when PAE is unknown. Even minimal relaxation of the phenotype (e.g., Face Rank 3) resulted in PPV (35%) and specificity (88.7%) values too low to use as confirmation of PAE. Further relaxation of the facial criteria, as defined by the Hoyme et al., 2016 FASD guidelines, resulted in even lower PPV (17.9%) and specificity (76.6%); both too low to serve as confirmation of PAE in a diagnostic setting. The presence of all three physical features of FAS (Hoyme et al FAS facial phenotype, growth and OFC ≤10th percentile) did not increase PPV beyond chance (52%). CONCLUSIONS: FASD diagnostic guidelines that use relaxed criteria for the FAS facial phenotype risk misdiagnosing and over-diagnosing FAS and partial FAS when PAE is unknown.

Contribution of a better maxillofacial phenotype in Silver-Russell syndrome to define a better orthodontics and surgical management.

INTRODUCTION: Maxillofacial phenotype for SRS is incompletely described in literature. The aim of this study was to describe a maxillofacial phenotype for SRS, to determine a better treatment. MATERIALS AND METHODS: A retrospective study was conducted including 37 patients with SRS. 24-control patients had been included and appareled. The subjective clinical examination included analyzes of SRS defined criteria. Frontal and lateral photographs had been reviewed, according to Farkas analysis; dental photographs had been examined for the deep-bite and the crowding severity. Radiologic cephalometric analysis had been reviewed. RESULTS: Maxillofacial examination showed protruding forehead (55%), anteverted ears (55%) and low-set ears (16%), small triangular face (48%); retrognatia (29%) and micrognathia (13%). SSR patients presented a lower forehead transverse growth, forehead height, and higher sagittal and transverse mandibular growth than control patients. Deep-bite was present in 21 patients of patient, and crowding in 17 patients. Cephalometric analysis showed 18 patients with the skeletal class II. We did not note a correlation between sleep apnea and retrognatia, neither between genetic anomalies and craniofacial phenotype. CONCLUSION: In this study, we showed new SRS characteristics: small forehead, small mandible, skeletal class II and a dental phenotype, leading to a specific maxillofacial and orthopedic management.

Craniofacial Phenotyping in Chinese and Caucasian Patients With Sleep Apnea: Influence of Ethnicity and Sex.

STUDY OBJECTIVES: Craniofacial abnormalities are a risk factor for obstructive sleep apnea (OSA). We have previously shown that phenotypic information derived from craniofacial photographs predict OSA in sleep clinic populations. However, there are likely ethnic and sex differences in craniofacial phenotypes related to OSA. We aimed to assess the use of craniofacial photography to identify interactions between OSA, ethnicity, and sex in craniofacial phenotype. METHODS: Frontal and profile craniofacial photographs were analyzed from two sleep clinic populations of different ethnicity (Hong Kong Chinese, Australian Caucasians). OSA was defined as apnea-hypopnea index (AHI) > 10 events/h. Ten craniofacial measurements (three angles relating to jaw position and seven ratios describing proportions of the face) were examined for interactions between OSA status and sex or ethnicity) using factorial analysis of variance. RESULTS: A total of 363 subjects (25% female) were included (n = 200 Chinese, n = 163 Caucasian), of which 33% were controls. There were two-way interactions for OSA with both sex (mandibular plane angle [F = 7.0, P = .009], face / eye width ratio [F = 4.7, P = .032], maxillary / mandibular volume ratio [F = 9.2, P = .003]) and ethnicity (face / nose width ratio [F = 4.0, P = .045], mandibular width / length ratio [F = 5.1, P = .024], maxillary / mandibular volume ratio [F = 11.0, P = .001]). CONCLUSIONS: We provide evidence of ethnic and sex differences in facial phenotype related to OSA. Furthermore, we demonstrate that craniofacial photography can be used as a phenotypic tool to assess these differences and allow investigation of OSA phenotypes in large samples. This has relevance to personalizing OSA recognition strategies across different populations.

Investigating facial phenotype in autism spectrum conditions: The importance of a hypothesis driven approach.

Atypical facial characteristics have been observed in many disorders associated with developmental disability. While autism spectrum conditions (ASC) have not previously been thought to be associated with a distinct facial phenotype, an emerging research literature is casting doubt on this assumption. The identification of differences in the facial phenotype of individuals with ASC may contribute to efforts to promote early identification of the condition and help elucidate etiological pathways. With the aim of identifying facial phenotypes associated with ASC, this commentary evaluated facial features purported to distinguish ASC from typical development. Although there is little consensus across the reviewed studies for the majority of facial characteristics described, preliminary evidence suggests increased facial asymmetry may be more common in ASC. There is also evidence to suggest that there are morphologically distinct subgroups within ASC that correspond with different cognitive and behavioral symptomatology. However, in light of the various inconsistencies in the reported literature, and based on an accumulating understanding of etiological pathways proposed to be associated with ASC, we propose an alternative paradigm for investigating facial phenotypes in ASC. A series of studies are outlined to demonstrate the promise of a research program that has taken a hypothesis-driven approach to examine facial phenotypes associated with increased exposure to prenatal testosterone and to ASC. Autism Res 2017, 10: 1910-1918. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This commentary reviewed studies that found differences in the facial features of individuals with autism spectrum conditions (ASC) compared to typically developing individuals. While there is little agreement between studies, there is some support for asymmetrical facial features associated with ASC, and preliminary evidence that particular facial features relate to specific patterns of cognitive and behavioral symptoms. However, in light of inconsistencies between studies and based on accumulating understanding of etiological pathways, we propose an alternative approach to investigating facial differences in ASC.