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Caregiver and observer-reported measures are frequently used as outcomes for research on infants and young children who are unable to report on their own health. Our team developed the Infant with Clefts Observation Outcomes Instrument (iCOO) for infants with cleft lip with or without cleft palate. This exploratory study compared test-retest and interrater reliabilities to inform whether differences in caregiver perspective might affect the iCOO. This study is a secondary analysis comparing caregiver interrater agreement to test-retest reliability. Twenty-five pairs of caregivers completed the iCOO before surgery, 1 week later for test-retest reliability, 2 days after surgery, and 2 months after surgery. Reliability was assessed using intraclass correlations (ICCs) and t-tests were used to compare ratings between caregivers. Infants had cleft lip (28%) or cleft lip and palate (72%). Primary caregivers were predominantly mothers (92%) and secondary caregivers were predominantly fathers (80%). Test-retest reliability met psychometric standards for most items on the iCOO (81%-86% of items). Caregiver agreement on the iCOO items was lower than test-retest reliability (33%-46% of items met psychometric standards). Caregivers did not systematically differ in whether they rated infants as healthier or less healthy than the other caregiver (5%-16% of items had statistically significant differences). Caregivers used the measure consistently, but had different experiences and perceptions of their infant’s health and functioning. Future studies are needed to explore mechanisms for the differences in test-retest and interrater reliability. Whenever possible, the same caregiver should provide ratings of the infant, including on the iCOO.

Aim: This article provides a review of a decade of clinical research studies on clinical features, medical interventions, and surgical interventions for individuals with craniofacial microsomia (CFM). We also provide recommendations for future clinical research. Method: A systematic search of literature was conducted in Embase and PubMed/MEDLINE Ovid. All publications from 2010 to 2020 that included at least 10 individuals with CFM were considered relevant for this study. Results: A total of 91 articles were included. In the past decade, many new studies on CFM have been published providing more insight on the diagnosis and management of patients with CFM. This review encompasses findings on the clinical difficulties patients with CFM encounter, including the craniofacial and extracraniofacial characteristics of patients with CFM and its related clinical consequences on breathing, feeding, speech, and hearing. Conclusions: A considerable number of large multicenter studies have been published in recent years, providing new insights in the clinical consequences of CFM. The phenotypic variety between patients with CFM makes patient-specific treatment tailored to individual needs essential. The research and development of clinical care standards might be challenging because of the heterogeneity of CFM. Future research on clinical and patient-reported outcomes can help identify optimal treatment strategies. Cooperation between craniofacial centers, using uniform registration and outcome measurement tools, could enhance research and future care for these patients. Level of evidence: Level IV.

Objective We evaluated the measurement properties for item and domain scores of the Infant with Clefts Observation Outcomes Instrument (iCOO). Design Cross-sectional (before lip surgery) and longitudinal study (preoperative baseline and 2 days and 2 months after lip surgery). Setting Three academic craniofacial centers and national online advertisements. Participants Primary caregivers with an infant with cleft lip with or without cleft palate (CL ± P) scheduled to undergo primary lip repair. There were 133 primary caregivers at baseline, 115 at 2 days postsurgery, and 112 at 2 months postsurgery. Main Outcome Measure(s) Caregiver observation items ( n = 61) and global impression of health and function items ( n = 8) across eight health domains. Results Mean age at surgery was 6.0 months (range 2.7-11.8 months). Five of eight iCOO domains have scale scores, with Cronbach’s alphas ranging from 0.67 to 0.87. Except for the Facial Skin and Mouth domain, iCOO scales had acceptable intraclass correlation coefficients (ICCs) ranging from 0.76 to 0.84. The internal consistency of the Global Impression items across all domains was 0.90 and had acceptable ICCs (range 0.76-0.91). Sixteen out of 20 (nonscale) items had acceptable ICCs (range 0.66-0.96). As anticipated, iCOO scores 2 days postoperatively were generally lower than baseline and scores 2 months postsurgery were consistent with baseline or higher. The iCOO took approximately 10 min to complete. Conclusions The iCOO meets measurement standards and may be used for assessing the impact of cleft-related treatments in clinical research and care. More research is needed on its use in various treatment contexts.

Objective To evaluate the sensitivity to change of daily ratings of the comfort (COMF) and behavioral/emotional health (BEH) domains of the Infants with Clefts Observation Outcomes Instrument (iCOO) at 3 time points, and to assess the association of post-surgical interventions on iCOO ratings. Design The COMF and BEH domains were completed by caregivers before (T0), immediately after (T1), and 2-months after (T2) cleft lip (CL) surgery. Analyses included descriptive statistics, correlations, t-tests, and generalized estimating equations. Participants Caregivers ( N = 140) of infants with CL with/without cleft palate. Main Outcome Measures The COMF and BEH domain scores of the iCOO: Scale (SCALE), a summary of observable signs; and Global Impression (IMPR), a single item measuring caregivers’ overall impression. Results Daily COMF and BEH SCALE and IMPR scores changed significantly during T1 ( P's 0.05). After CL surgery, the combined use of immobilizers and nasal stents and the use of multiple feeding methods with treatment for gastroesophageal reflux were associated with lower daily scores in COMF and BEH SCALE and IMPR ( P's: 0.040 to Conclusions COMF and BEH iCOO scores were sensitive to daily changes in infant well-being following CL surgery. Future studies should further investigate impact of post-surgical treatments on infant well-being.

Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown.We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro.We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3.Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.

Objective Our goal was to compare data collected from 3- and 7-day Infant with Clefts Observation Outcomes (iCOO) diaries. Design Secondary data analysis of an observational longitudinal cohort study. Caregivers completed the daily iCOO for 7 days before cleft lip surgery (T0) and for 7 days after cleft lip repair (T1). We compared 3- and 7-day diaries collected at T0 and 3- and 7-day diaries collected at T1. Setting United States. Participants Primary caregivers of infants with cleft lip with and without cleft palate (N = 131) planning lip repair and enrolled in original iCOO study. Main Outcomes Measure(s) Mean differences and Pearson correlation coefficients. Results Correlation coefficients were high for global impressions (>0.90) and scaled scores (0.80–0.98). Mean differences were small across iCOO domains at T0. T1 comparisons reflected the same pattern. Conclusions Three-day diary data is comparable to 7-day diaries for measuring caregiver observations using iCOO across T0 and T1.

To estimate nutritional status in a large cohort of infants with orofacial clefts in the US, overall and by cleft type from birth to 6 months of age.We conducted a cross-sectional study in infants with orofacial clefts by examining growth by month between birth and 6 months of age. Infants with at least one weight measurement at a single US regional tertiary care pediatric hospital with an interdisciplinary cleft team between 2010 and 2020 were included. We calculated the average weight-for-age z-scores and weight-for-length z-scores. We calculated the proportion of infants underweight and wasting with z-scores below -2 standard deviations monthly from birth -6 months of age. We used t-tests to compare the distribution of WAZ and WLZ among children with orofacial clefts to a normal distribution.We included 883 infants with orofacial clefts. Compared with expected proportion of underweight infants (2.3%), a larger proportion of infants with orofacial clefts were underweight between birth -1 months (10.6%), peaking between 2-3 months (27.1%) and remaining high between 5-6 months (16.3%). Compared with the expected proportion of infants with wasting (2.3%), a higher proportion of infants with orofacial clefts experienced wasting between birth -1 month (7.3%), peaking between 2-3 months (12.8%) and remaining high between 5-6 months (5.3%). Similar findings were observed for all cleft types and regardless of comorbidities.A substantial proportion of infants with orofacial clefts compared with normative peers have malnutrition in the first 6 months of life in the United States.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.

Objectives Few evidence-based psychosocial programs exist within craniofacial care. This study (a) assessed feasibility and acceptability of the Promoting Resilience in Stress Management-Parent (PRISM-P) intervention among caregivers of children with craniofacial conditions and (b) described barriers and facilitators of caregiver resilience to inform program adaptation. Design In this single-arm cohort study, participants completed a baseline demographic questionnaire, the PRISM-P program, and an exit interview. Participants Eligible individuals were English-speaking legal guardians of a child Intervention PRISM-P included 4 modules (stress-management, goal-setting, cognitive-restructuring, meaning-making) delivered in 2 one-on-one phone or videoconference sessions 1–2 weeks apart. Main Outcome Measures Feasibility was defined as >70% program completion among enrolled participants; acceptability was defined as >70% willingness to recommend PRISM-P. Intervention feedback and caregiver-perceived barriers and facilitators of resilience were summarized qualitatively. Results Twenty caregivers were approached and 12 (60%) enrolled. The majority were mothers (67%) of a child Conclusions PRISM-P was acceptable among caregivers of children with craniofacial conditions but not feasible based on program completion rates. Barriers and facilitators of resilience support the appropriateness of PRISM-P for this population and inform adaptation.

Children with craniofacial microsomia (CFM) are at increased risk for educational and social concerns. This study describes intervention services and frequency of teasing in a multinational population of children with CFM. Caregivers of children with CFM ages 3 to 18 years in the US and South America were administered a questionnaire. Additional information was gathered from medical charts and photographs. Participants (N = 169) had an average age of 10.1 ± 6.2 years, were primarily male (60%), and from the US (46%) or Colombia (32%). Most participants had microtia and mandibular hypoplasia (70%). They often had unilateral (71%) or bilateral (19%) hearing loss and 53% used a hearing aid. In the US, special education services were provided for 48% of participants enrolled in school; however, similar services were rare (4%) in South America and reflect differences in education systems. Access to any intervention service was higher in the US (80%) than in South America (48%). Caregivers reported children showed diagnosis awareness by an average age of 4.4 ± 1.9 years. Current or past teasing was reported in 41% of the children, starting at a mean age of 6.0 ± 2.4 years, and most often took place at school (86%). As half of the US participants received developmental and academic interventions, providers should screen for needs and facilitate access to services. Given diagnosis awareness at age 4 and teasing at age 6, providers are encouraged to assess for psychosocial concerns and link to resources early in treatment.

BACKGROUND Postoperative computed tomography scans allow for evaluation of the structural results of cranial vault reconstruction and potential surgical concerns. The authors evaluated the clinical utility of routine postoperative scans to identify relevant surgical findings in children treated for craniosynostosis. METHODS The authors conducted a retrospective study of postoperative computed tomography reports for patients with craniosynostosis following cranial vault reconstruction during a 9-year period at their tertiary care pediatric hospital. They categorized postoperative computed tomography findings as typical, atypical, or indeterminate. Images with reported indeterminate or atypical findings were reviewed and verified by a pediatric neuroradiologist and a pediatric neurological surgeon. Clinical outcomes of patients with abnormal postoperative images were assessed with chart review for clinical relevance. RESULTS Postoperative computed tomography radiology reports for 548 operations in 506 participants were included. Most participants had single-suture craniosynostosis (89 percent), were male (64 percent), and under 1 year of age (78 percent). Surgically concerning scans were described in 52 reports (

The cause of occipital asymmtery can be either extrinsic or intrinsic. Intrinsic causes include lambdoid craniosynsotosis. This condition is generally treated with cranial vault expansion surgery. Extrinsic causes include deformational plagiocephaly, which became commonplace after the "Back to Sleep Campaign" instituted in the 1980s by the American Academy of Pediatrics. The treatment of this condition is non surgical. Dr. Joseph Gruss was instumental in differentiating between these conditions and reducing the number of unnecessary surgeries that were previously being performed.

The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology and was predicted bioinformatically to have a deleterious effect on protein function. Notably, NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. Findings from this study expanded our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in several novel genes.

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10−10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases., Despite being a common congenital facial anomaly, the genetic etiology of craniofacial microsomia (CFM) is not well understood. Here, the authors use exome and genome sequencing of 146 individuals with CFM to identify haploinsufficient variants in SF3B2 as a prevalent underlying cause.

Background Craniofacial microsomia (CFM), also known as the oculo‐auriculo‐vertebral spectrum, comprises a variable phenotype with the most common features including microtia and mandibular hypoplasia on one or both sides, in addition to lateral oral clefts, epibulbar dermoids, cardiac, vertebral, and renal abnormalities. The etiology of CFM is largely unknown. The MYT1 gene has been reported as a candidate based in mutations found in three unrelated individuals. Additional patients with mutations in this gene are required to establish its causality. We present two individuals with CFM that have rare variants in MYT1 contributing to better understand the genotype and phenotype associated with mutations in this gene. Methods/Results We conducted genetic analysis using whole‐exome and ‐genome sequencing in 128 trios with CFM. Two novel MYT1 mutations were identified in two participants. Sanger sequencing was used to confirm these mutations. Conclusion We identified two additional individuals with CFM who carry rare variants in MYT1, further supporting the presumptive role of this gene in the CFM spectrum., We conducted genetic analysis using whole‐exome and ‐genome sequencing in 128 trios with CFM. Two novel MYT1 mutations were identified in two participants, further supporting the presumptive role of this gene in the CFM spectrum.

Objective: The study aim was to assess behavioral adjustment in preschool children with and without craniofacial microsomia (CFM). Design: Multisite cohort study of preschoolers with CFM (“cases”) or without CFM (“controls”). Participants: Mothers (89%), fathers (9%), and other caregivers (2%) of 161 preschoolers. Outcome Measure: Child Behavior Check List (CBCL 1.5-5); linear regressions with standardized effect sizes (ES) adjusted for sociodemographic confounds. Results: Child Behavior Check Lists for 89 cases and 72 controls (average age 38.3 ± 1.9 months). Children were male (54%), white (69%), and of Latino ethnicity (47%). Cases had microtia with mandibular hypoplasia (52%), microtia only (30%), or other CFM-associated features (18%). Nearly 20% of cases had extracranial anomalies. Composite CBCL scores were in the average range compared to test norms and similar for cases and controls. On the subscales, cases’ parents reported higher Anxious/Depressed scores (ES = 0.35, P = .04), Stress Problems (ES = 0.40, P = .04), Anxiety Problems (ES = 0.34, P = .04), and Autism Spectrum Problems (ES = 0.41, P = .02); however, the autism subscale primarily reflected speech concerns. Among cases, more problems were reported for children with extracranial anomalies and certain phenotypic categories with small ES. Conclusions: Behavioral adjustment of preschoolers with CFM was comparable to peers. However, parental reports reflected greater concern for internalizing behaviors; thus, anxiety screening and interventions may benefit children with CFM. Among cases, more problems were reported for those with more complex presentations of CFM. Craniofacial microsomia–related speech problems should be distinguished from associated psychosocial symptoms during developmental evaluations.

Objective An increasing number of patients use social media for health-related information and social support. This study's objective was to describe the content posted on Facebook groups for individuals with microtia and/or craniofacial microsomia (CFM) and their families in order for providers to gain insight into patient and family needs and experiences to inform clinical care. Methods Two months of posts, images, comments, and “like” responses from two Facebook groups in the US and the UK were recorded and analyzed using content analysis. A secondary analysis identified statements of emotion. Results Posts (N = 254) had a total of 7912 “like” responses, 2245 comments, and 153 images. There were three categories of posts: seeking guidance (43%; 9 themes), promoting events/news (33%; 5 themes), and sharing experiences (24%; 3 themes). Across categories, 16% of posts had emotional content. Most comments were responding to posts seeking guidance, including medical care (20%), surgical care (9%), and hearing aids (5%). Promotional posts often aimed to increase CFM awareness. Posts sharing experiences were generally positive, with the highest number of “likes”. Conclusions Facebook groups members frequently exchanged health-related information, suggesting value placed on input from other families and the convenience of seeking information online. Posts also promoted awareness and shared experiences. Clinical care implications include the need for easily accessible accurate and tailored CFM-related health education. Additionally, providers should demonstrate awareness of health information on social media and may address the potential emotional impact of CFM by facilitating access to resources for social support.

Objective: To develop an outcomes instrument that assesses observations that can be reliably reported by caregivers and can be used to assess health of infants with a cleft lip or cleft lip and cleft palate (CL±P) and impacts of treatments. Design: Cross-sectional, mixed methods study. Setting: Caregivers and health-care providers were recruited from 3 academic craniofacial centers and national advertisements. Most interviews were conducted by telephone, and surveys were completed online. Participants: Caregivers had a child less than 3 years of age with CL±P and spoke either English or Spanish. Health-care providers were members of a cleft team. Caregivers (n = 492) and health-care professionals (n = 75) participated in at least one component of this study. Main Outcome Measure(s): Caregivers and health-care providers participated in tasks related to instrument development: concept elicitation for items within relevant health domains, prioritization of items, and item review. Results: We identified 295 observations of infant well-being across 9 health areas. Research staff and specialists evaluated items for clarity, specificity to CL±P, and responsiveness to treatment. Caregivers and health-care providers rated the resulting list of 104 observations and developed the final instrument of 65 items. Conclusions: In this phase of development of the Infant with Clefts Observation Outcomes (iCOO) instrument, items were developed to collect caregiver observations about indicators of children’s health and well-being across multiple domains allowing for psychometric testing, sensitivity to changes associated with treatment, and documentation of the effects of treatment.

Objective: To explore, using semistructured qualitative interviews, parent observations of their infant’s health as they relate to having a cleft lip or cleft lip and cleft palate (CL±P) and/or associated treatments. Design: Cross-sectional, qualitative study across 3 sites. Setting: Parents were recruited from 3 academic craniofacial centers. Most interviews were conducted over the telephone, audio-recorded, and transcribed. Participants: Forty-one parents (31 English-, 10 Spanish-speaking) were interviewed. Parents had a child ages 1 to 35 months diagnosed with CL±P. Main Outcome Measure(s): Twelve domains reflecting infant health and well-being, likely affected by a CL±P and/or associated treatments, were identified from clinical experience and literature review. Study investigators conducted semistructured interviews based on 12 identified domains. After transcripts of the interviews were reviewed, our multidisciplinary team selected illustrative quotes from each domain that reflected consistent observations made by parents. Results: Parents’ responses covered all 12 domains. Specifically, parents discussed the domain of feeding most frequently, followed by observations about sleep, development, comfort, breathing, and vocalization. Conclusions: We found that parents of infants with clefts provided caregiver-centered language useful in describing their daily observations. No additional domains of infant health were noted by parents. We will use these observations and language to develop and validate a parent-reported observation diary that can augment assessments of the impacts of interventions on infants who are receiving care for CL±P.

Objective: The objective was to assess differences in psychosocial adjustment between adolescents with and without craniofacial microsomia (CFM). Design: This is a case-control follow-up study in adolescents with and without CFM. Setting: Participants were originally recruited as infants from 26 cities across the United States and Canada. Participants: Participants included 142 adolescents with CFM (cases) and 316 peers without CFM (controls), their caregivers, and their teachers. Main Outcome Measures: Social and behavior measures from the Achenbach System of Empirically Based Assessments (ASEBA), the PedsQL: Core Version, and the Children’s Communication Checklist–2nd edition (CCC-2) were used. Linear regression was used to estimate case-control differences and corresponding standardized effect sizes (ES) and 95% confidence intervals after adjustment for sociodemographic confounds. We also examined case-control differences by facial phenotype and hearing status. Results: The magnitude and direction of case-control differences varied across assessment and respondent, but were generally modest (ES = –0.4 to 0.02, P values ranged from .003 to .85). There was little evidence for variation in case-control differences across different facial phenotypes or as a function of hearing status. Conclusions: Our results suggest that in spite of multiple risk factors, adolescents with CFM exhibit behavior problems no more frequently than their peers without CFM. Future studies of individuals with CFM should focus on resilience and social coping mechanisms, in addition to maladjustment.

Objective To evaluate the association between craniofacial phenotype and hearing loss in children with craniofacial microsomia. Design Retrospective cohort study. Setting Tertiary care children's hospital. Patients Individuals with craniofacial microsomia. Main Outcome Measures Ear-specific audiograms and standardized phenotypic classification of facial characteristics. Results A total of 79 participants were included in the study. The mean age was 9 years (range, 1 to 23 years) and approximately 60% were boys. Facial anomalies were bilateral in 39 participants and unilateral in 40 participants (24 right, 16 left). Microtia (hypoplasia of the ear) was the most common feature (94%), followed by mandibular hypoplasia (76%), soft tissue deficiency (60%), orbital hypoplasia or displacement (53%), and facial nerve palsy (32%). Sixty-five individuals had hearing loss (12 bilateral and 53 unilateral). Hearing loss was conductive in 73% of affected ears, mixed in 10%, sensorineural in 1%, and indeterminate in 16%. Hypoplasia of the ear or mandible was frequently associated with ipsilateral hearing loss, although contralateral hearing loss occurred in 8% of hemifaces. Conclusions Hearing loss is strongly associated with malformations of the ipsilateral ear in craniofacial microsomia and is most commonly conductive. Hearing loss can occur contralaterally to the side with malformations in children with apparent hemifacial involvement. Children with craniofacial microsomia should receive early diagnostic hearing assessments.

Purpose Youth with craniofacial microsomia (CFM) have anomalies and comorbidities that increase their risk for speech, language, and communication deficits. We examined these outcomes in youth with and without CFM and explored differences as a function of CFM phenotype and hearing status. Method Participants included youth ages 11–17 years with CFM ( n = 107) and demographically similar controls ( n = 306). We assessed speech intelligibility, articulation, receptive and expressive language, and parent and teacher report measures of communication. Hearing status was also screened at the study visit. Group differences were estimated using linear regression analyses with standardized effect sizes (ES) adjusted for demographic characteristics (adjusted ES) or negative binomial regression. Results Youth with CFM scored lower than unaffected peers on most measures of intelligibility, articulation, expressive language, and parent- and-teacher-rated communication. Differences were most pronounced among participants with CFM who had mandibular hypoplasia plus microtia (adjusted ES = −1.15 to −0.18). Group differences were larger in youth with CFM who failed the hearing screen (adjusted ES = −0.73 to 0.07) than in those who passed the hearing screen (adjusted ES = −0.34 to 0.27). Conclusions Youth with CFM, particularly those with mandibular hypoplasia plus microtia and/or hearing loss, should be closely monitored for speech and language concerns. Further research is needed to identify the specific needs of youth with CFM as well as to document the course of speech and language development in children with CFM.

Objective:The Craniofacial microsomia: Longitudinal Outcomes in Children pre-Kindergarten (CLOCK) study is a longitudinal cohort study of neurobehavioral outcomes in infants and toddlers with craniofacial microsomia (CFM). In this article, we review the data collection and methods used to characterize this complex condition and describe the demographic and clinical characteristics of the cohort.Setting:Craniofacial and otolaryngology clinics at 5 study sites.Participants:Infants with CFM and unaffected infants (controls) ages 12 to 24 months were recruited from the same geographical regions and followed to age 36 to 48 months.Methods:Phenotypic, neurodevelopmental, and facial expression assessments were completed during the first and third waves of data collection (time 1 and time 3, respectively). Medical history data were taken at both of these time points and during an intermediate parent phone interview (time 2).Results:Our cohort includes 108 cases and 84 controls. Most cases and controls identified as white and 55% of cases and 37% of controls identified as Hispanic. Nearly all cases had microtia (95%) and 59% had mandibular hypoplasia. Cases received extensive clinical care in infancy, with 59% receiving care in a craniofacial clinic and 28% experiencing at least one surgery. Study visits were completed at a study site (92%) or at the participant’s home (8%).Conclusions:The CLOCK study represents an effort to overcome the challenges of characterizing the phenotypic and neurodevelopmental outcomes of CFM in a large, demographically and geographically diverse cohort.

Objectives Craniofacial microsomia (CFM) is a congenital condition that typically involves hypoplasia of the ear and jaw. It is often associated with adverse effects such as hearing loss and sleep-disordered breathing. There is little research on its etiology. Methods We conducted a case-control study from maternal interview data collected from mothers of infants with and without CFM. The study included 108 children with and 84 children without CFM. Logistic regression with adjustment for demographic factors was used to evaluate associations between maternal exposures of interest and risk for CFM overall, as well as for different phenotypic sub-groups of children on the CFM spectrum. Results We found a statistically significant association between diabetes mellitus (DM) and CFM (OR 4.01, 95% CI 1.6-10.5). The association was slightly attenuated after adjustment for BMI. Higher parity was also associated with increased risk for CFM (OR 2.0, 95% CI 1.0-4.0). Vitamin A consumption and/or liver consumption was associated with a 70% lower risk compared with non-users (OR 0.3, 95% 0.1-0.8). Maternal age at the time of pregnancy was not associated with CFM. Conclusions These analyses contribute evidence linking maternal DM with an elevated risk of having an infant with CFM, which is consistent with previous research and adds to the body of knowledge about the strength of this association. Further study is warranted to understand the potential mechanisms underlying the effect of DM in the developing embryo.

Supplemental Digital Content is available in the text., Background: Craniofacial microsomia (CFM) is a congenital condition associated with malformations of the bone and soft tissue of the face and the facial nerves, all of which have the potential to impair facial expressiveness. We investigated whether CFM-related variation in expressiveness is evident as early as infancy. Methods: Participants were 113 ethnically diverse 13-month-old infants (n = 63 cases with CFM and n = 50 unaffected matched controls). They were observed in 2 emotion induction tasks designed to elicit positive and negative effects. Facial and head movement was automatically measured using a computer vision–based approach. Expressiveness was quantified as the displacement, velocity, and acceleration of 49 facial landmarks (eg, lip corners) and head pitch and yaw. Results: For both cases and controls, all measures of expressiveness strongly differed between tasks. Case–control differences were limited to infants with microtia plus mandibular hypoplasia and other associated CFM features, which were the most common phenotypes and were characterized by decreased expressiveness relative to control infants. Conclusions: Infants with microtia plus mandibular hypoplasia and those with other associated CFM phenotypes were less facially expressive than same-aged peers. Both phenotypes were associated with more severe involvement than microtia alone, suggesting that infants with more severe CFM begin to diverge in expressiveness from controls by age 13 months. Further research is needed to both replicate the current findings and elucidate their developmental implications.

Shared decision-making (SDM) has emerged as the preferred decision-making model in the clinician-patient relationship. Through collaboration, SDM helps to facilitate evidence-based medical decisions that are closely aligned with patient or surrogate preferences, values, and goals. How to implement SDM in clinical pediatric practice, however, remains elusive, in part because SDM in pediatrics is complicated by the involvement of parents as a special class of surrogate decision-maker. A provisional framework for the process of SDM in pediatrics was recently proposed by Opel to help facilitate its implementation. To identify aspects of the framework that require refinement, we applied it across a diverse range of clinical cases from multiple pediatric specialties. In doing so, several questions surfaced that deserve further scrutiny: (1) For which medical decisions is consideration of SDM required? (2) What is considered medically reasonable when there is variability in standard practice? (3) Can an option that is not consistent with standard practice still be medically reasonable? (4) How should public health implications be factored into SDM? (5) How should variability in preference sensitivity be approached? (6) How should the developing autonomy of adolescents be integrated into SDM?; and (7) How should SDM address parental decisional burden for emotionally charged decisions? We conduct a brief analysis of each question raised to illustrate key areas for future research.

Objective Quantitative measures of facial form to evaluate treatment outcomes for cleft lip (CL) are currently limited. Computer-based analysis of three-dimensional (3D) images provides an opportunity for efficient and objective analysis. The purpose of this study was to define a computer-based standard of identifying the 3D midfacial reference plane of the face in children with unrepaired cleft lip for measurement of facial symmetry. Participants The 3D images of 50 subjects (35 with unilateral CL, 10 with bilateral CL, five controls) were included in this study. Interventions Five methods of defining a midfacial plane were applied to each image, including two human-based (Direct Placement, Manual Landmark) and three computer-based (Mirror, Deformation, Learning) methods. Main Outcome Measure Six blinded raters (three cleft surgeons, two craniofacial pediatricians, and one craniofacial researcher) independently ranked and rated the accuracy of the defined planes. Results Among computer-based methods, the Deformation method performed significantly better than the others. Although human-based methods performed best, there was no significant difference compared with the Deformation method. The average correlation coefficient among raters was .4; however, it was .7 and .9 when the angular difference between planes was greater than 6° and 8°, respectively. Conclusions Raters can agree on the 3D midfacial reference plane in children with unrepaired CL using digital surface mesh. The Deformation method performed best among computer-based methods evaluated and can be considered a useful tool to carry out automated measurements of facial symmetry in children with unrepaired cleft lip.

Background Craniofacial microsomia (CFM) is a congenital condition with wide phenotypic variability, including hypoplasia of the mandible and external ear. We assembled a cohort of children with facial features within the CFM spectrum and children without known craniofacial anomalies. We sought to develop a standardized approach to assess and describe the facial characteristics of the study cohort, using multiple sources of information gathered over the course of this longitudinal study and to create case subgroups with shared phenotypic features. Methods Participants were enrolled between 1996 and 2002. We classified the facial phenotype from photographs, ratings using a modified version of the Orbital, Ear, Mandible, Nerve, Soft tissue (OMENS) pictorial system, data from medical record abstraction, and health history questionnaires. Results The participant sample included 142 cases and 290 controls. The average age was 13.5 years (standard deviation, 1.3 years; range, 11.1-17.1 years). Sixty-one percent of cases were male, 74% were white non-Hispanic. Among cases, the most common features were microtia (66%) and mandibular hypoplasia (50%). Case subgroups with meaningful group definitions included: (1) microtia without other CFM-related features (n = 24), (2) microtia with mandibular hypoplasia (n = 46), (3) other combinations of CFM- related facial features (n = 51), and (4) atypical features (n = 21). Conclusion We developed a standardized approach for integrating multiple data sources to phenotype individuals with CFM, and created subgroups based on clinically-meaningful, shared characteristics. We hope that this system can be used to explore associations between phenotype and clinical outcomes of children with CFM and to identify the etiology of CFM. Birth Defects Research (Part A) 106:915-926, 2016.© 2016 Wiley Periodicals, Inc.

With the current widespread use of three-dimensional (3D) facial surface imaging in clinical and research environments, there is a growing demand for high-quality craniofacial norms based on 3D imaging technology. The principal goal of the 3D Facial Norms (3DFN) project was to create an interactive, Web-based repository of 3D facial images and measurements. Unlike other repositories, users can gain access to both summary-level statistics and individual-level data, including 3D facial landmark coordinates, 3D-derived anthropometric measurements, 3D facial surface images, and genotypes from every individual in the dataset. The 3DFN database currently consists of 2454 male and female participants ranging in age from 3 to 40 years. The subjects were recruited at four US sites and screened for a history of craniofacial conditions. The goal of this article is to introduce readers to the 3DFN repository by providing a general overview of the project, explaining the rationale behind the creation of the database, and describing the methods used to collect the data. Sex- and age-specific summary statistics (means and standard deviations) and growth curves for every anthropometric measurement in the 3DFN dataset are provided as a supplement available online. These summary statistics and growth curves can aid clinicians in the assessment of craniofacial dysmorphology.

This study describes stressors, resources, and recommendations related to craniofacial microsomia (CFM) care from the perspective of caregivers of children with CFM and adults with CFM in order to inform improved quality of healthcare delivery. A mixed method design was used with fixed-response and open-ended questions from an online survey in English. The survey included demographics, CFM phenotypic information, and items about CFM-related experiences across settings. Themes were identified by qualitative analysis of responses to open-ended questions. Respondents (N = 51) included caregivers (n = 42; 90% mothers) and adults with CFM (n = 9; 78% female), who had a mean age of 45±6 years. Most children were male (71%) with an average age of 7±4 years. Respondents were primarily white (80%), non-Hispanic (89%), from the United States (82%), had a college degree (80%), and had private health insurance (80%). Reflecting the high rate of microtia (84%) in the sample, themes centered on the impact of hearing difficulties across settings with related language concerns. Negative social experiences were frequently described and school needs outlined. Multiple medical stressors were identified and corresponding suggestions included: providers need to be better informed about CFM, treatment coordination among specialists, and preference for a family-centered approach with reassurance, empathy, and clear communication. Advice offered to others with CFM included positive coping strategies. Overall, caregivers’ and patients’ responses reflected the complexity of CFM treatment. Incorporating these perspectives into routine CFM care has the potential to reduce family distress while improving their healthcare. Key words: craniofacial microsomia; family stressors; family resources; qualitative analysis

The Facial Asymmetry Collaborative for Interdisciplinary Assessment and Learning (FACIAL) network applies key principles of established team science while using equity-based approaches that advance career development and accelerating collaborative research in craniofacial microsomia. Team science is an effort to leverage a challenge in science by using professionals of different backgrounds and expertise.

The shape of the cranial vault, a region comprising interlocking flat bones surrounding the cerebral cortex, varies considerably in humans. Strongly influenced by brain size and shape, cranial vault morphology has both clinical and evolutionary relevance. However, little is known about the genetic basis of normal vault shape in humans. We performed a genome-wide association study (GWAS) on three vault measures (maximum cranial width [MCW], maximum cranial length [MCL], and cephalic index [CI]) in a sample of 4419 healthy individuals of European ancestry. All measures were adjusted by sex, age, and body size, then tested for association with genetic variants spanning the genome. GWAS results for the two cohorts were combined via meta-analysis. Significant associations were observed at two loci: 15p11.2 (lead SNP rs2924767, p = 2.107 × 10-8) for MCW and 17q11.2 (lead SNP rs72841279, p = 5.29 × 10-9) for MCL. Additionally, 32 suggestive loci (p < 5x10-6) were observed. Several candidate genes were located in these loci, such as NLK, MEF2A, SOX9 and SOX11. Genome-wide linkage analysis of cranial vault shape in mice (N = 433) was performed to follow-up the associated candidate loci identified in the human GWAS. Two loci, 17q11.2 (c11.loc44 in mice) and 17q25.1 (c11.loc74 in mice), associated with cranial vault size in humans, were also linked with cranial vault size in mice (LOD scores: 3.37 and 3.79 respectively). These results provide further insight into genetic pathways and mechanisms underlying normal variation in human craniofacial morphology.

Background:. Premature fusion of the metopic suture (ie, metopic craniosynostosis) can be difficult to discriminate from physiological closure of the metopic suture with ridging (MR). Yet, MCS is treated surgically, whereas MR is treated nonsurgically. Often, the diagnosis can be made by physical examination alone, but in difficult cases, a computed tomography (CT) scan can add additional diagnostic information. Methods:. We de-identified, randomized, and analyzed the CT scans of patients with MCS (n = 52), MR (n = 20) and age-matched normative controls (n = 52) to identify specific findings helpful in distinguishing between MCS and MR. Four expert clinicians were blinded to the clinical diagnosis and assessed each CT for features of the orbits, frontal bones, and inner table of calvaria. Results:. Although no single feature was diagnostic of MCS, we identified several signs that were correlated with MCS, MR, or controls. Features such as “posteriorly displaced frontal bone” and “frontal bone tangent to mid-orbit or medial” demonstrated higher correlation with MCS than MR and the addition of other features improves the accuracy of diagnosis as did inclusion of the interfrontal divergence angle. Conclusion:. The presence of a closed metopic suture in addition to other CT scan findings may improve the accuracy of diagnosing MCS, MR, and normocephaly.

© 2018 Elsevier B.V. Objective: Craniofacial microsomia (CFM) is primarily characterized by underdevelopment of the ear and mandible, with several additional possible congenital anomalies. Despite the potential burden of care and impact of CFM on multiple domains of functioning, few studies have investigated patient and caregiver perspectives. The objective of this study was to explore the diagnostic, treatment-related, and early psychosocial experiences of families with CFM with the aim of optimizing future healthcare delivery. Methods: Forty-two caregivers and nine adults with CFM responded to an online mixed-methods survey. Descriptive statistics and qualitative methods were used for the analysis. Results: Survey respondents reported high rates of subspecialty evaluations, surgeries, and participation in therapies. Some participants reported receiving inaccurate or incomplete information about CFM and experienced confusion about etiology. Communication about CFM among family members included mostly positive messages. Self-awareness of facial differences began at a mean age of three years and teasing at mean age six, with 43% of individuals four years or older reporting teasing. Teasing often involved name-calling and frequent reactions were ignoring and negative emotional responses. Participants ranked “understanding diagnosis and treatment” as a top priority for future research and had the most questions about etiology and treatment guidance. Conclusions: The survey results on the healthcare and psychosocial experiences from birth through adulthood of individuals with CFM reinforce the need for ongoing psychological assessment and intervention. Healthcare provision could be improved through establishing diagnostic criteria and standardized treatment guidelines, as well as continued investigation of CFM etiology.

Objective:To compare facial expressiveness (FE) of infants with and without craniofacial microsomia (cases and controls, respectively) and to compare phenotypic variation among cases in relation to FE.Design:Positive and negative affect was elicited in response to standardized emotion inductions, video recorded, and manually coded from video using the Facial Action Coding System for Infants and Young Children.Setting:Five craniofacial centers: Children’s Hospital of Los Angeles, Children’s Hospital of Philadelphia, Seattle Children’s Hospital, University of Illinois–Chicago, and University of North Carolina–Chapel Hill.Participants:Eighty ethnically diverse 12- to 14-month-old infants.Main Outcome Measures:FE was measured on a frame-by-frame basis as the sum of 9 observed facial action units (AUs) representative of positive and negative affect.Results:FE differed between conditions intended to elicit positive and negative affect (95% confidence interval = 0.09-0.66, P = .01). FE failed to differ between cases and controls (ES = –0.16 to –0.02, P = .47 to .92). Among cases, those with and without mandibular hypoplasia showed similar levels of FE (ES = –0.38 to 0.54, P = .10 to .66).Conclusions:FE varied between positive and negative affect, and cases and controls responded similarly. Null findings for case/control differences may be attributable to a lower than anticipated prevalence of nerve palsy among cases, the selection of AUs, or the use of manual coding. In future research, we will reexamine group differences using an automated, computer vision approach that can cover a broader range of facial movements and their dynamics.

The clinical presentation of microtia varies widely from minimal morphological abnormalities to complete absence of the ear. In this study we sought to identify and characterize sub-groups of microtia using a statistical and a clinical approach. Photographs of 86 ears were classified in relation to all the external ear components. We used cluster analysis and rater's clinical opinion to identify groups with similar phenotypes in two separate analyses. We used Cramer's Phi coefficient of association to assess the similarity among the clinician's groupings as well as among the statistical sub-phenotypic groups and each of the clinician's groupings. The cluster analysis initially divided the 86 ears into a more and a less severe group. The less severe group included two sub-groups that included ears classified as normal and a group that had very few anomalous components. The group of 48 more affected ears all had abnormalities of the helix crus; antihelix-stem, -superior crus and -inferior crus; and antitragus. These were further divided into 4 sub-phenotypes. There was a moderate degree of association among the raters' groupings (Cramer's Phi: 0.64 to 0.73). The statistical and clinical groupings had a lower degree of association (Cramer's Phi: 0.49 to 0.58). Using standardized characterization of structural abnormalities of the ear we identified six distinct phenotypic groups; correlations with clinicians' groupings were moderate. These clusters may represent groups of ear malformations associated with the same etiology, similar time of insult or target cell population during embryonic development. The results will help inform investigations on etiology. © 2015 Wiley Periodicals, Inc.

Action unit detection in infants relative to adults presents unique challenges. Jaw contour is less distinct, facial texture is reduced, and rapid and unusual facial movements are common. To detect facial action units in spontaneous behavior of infants, we propose a multi-label Convolutional Neural Network (CNN). Eighty-six infants were recorded during tasks intended to elicit enjoyment and frustration. Using an extension of FACS for infants (Baby FACS), over 230,000 frames were manually coded for ground truth. To control for chance agreement, inter-observer agreement between Baby-FACS coders was quantified using free-margin kappa. Kappa coefficients ranged from 0.79 to 0.93, which represents high agreement. The multi-label CNN achieved comparable agreement with manual coding. Kappa ranged from 0.69 to 0.93. Importantly, the CNN-based AU detection revealed the same change in findings with respect to infant expressiveness between tasks. While further research is needed, these findings suggest that automatic AU detection in infants is a viable alternative to manual coding of infant facial expression.

Background: The authors compared the IQ and academic achievement of adolescents with craniofacial microsomia (cases) and unaffected children (controls). Among cases, the authors analyzed cognitive functioning by facial phenotype. Methods: The authors administered standardized tests of intelligence, reading, spelling, writing, and mathematics to 142 cases and 316 controls recruited from 26 cities across the United States and Canada. Phenotypic classification was based on integrated data from photographic images, health history, and medical chart reviews. Hearing screens were conducted for all participants. Results: After adjustment for demographics, cases’ average scores were lower than those of controls on all measures, but the magnitude of differences was small (standardized effect sizes, −0.01 to −0.3). There was little evidence that hearing status modified case-control group differences (Wald p > 0.05 for all measures). Twenty-five percent of controls and 38 percent of cases were classified as having learning problems (adjusted OR, 1.5; 95 percent CI, 0.9 to 2.4). Comparison of cases with and without learning problems indicated that those with learning problems were more likely to be male, Hispanic, and to come from lower income, bilingual families. Analyses by facial phenotype showed that case-control group differences were largest for cases with both microtia and mandibular hypoplasia (effect sizes, −0.02 to −0.6). Conclusions: The highest risk of cognitive-academic problems was observed in patients with combined microtia and mandibular hypoplasia. Developmental surveillance of this subgroup is recommended, especially in the context of high socioeconomic risk and bilingual families. Given the early stage of research on craniofacial microsomia and neurodevelopment, replication of these findings is needed. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Background Surgical and orthodontic treatment of unilateral cleft lip +/- palate can produce dramatic changes in nasolabial form; however, the lack of ideal methods with which to objectively document three-dimensional form limits the ability to assess treatment outcomes. The purpose of this study was to determine the reliability of three-dimensional stereophotogrammetry for anthropometric assessment of the unilateral cleft lip +/- palate deformity in infants before cleft lip repair. Methods Preoperative three-dimensional images were acquired from 26 consecutive patients with unrepaired unilateral cleft lip +/- palate. Three raters performed indirect anthropometry on each image on two separate occasions, with at least 1 week between rating sessions. One rater performed direct measurements on participants before surgery while in the operating room. Twenty-six linear and angular measurements were considered, and intrarater, interrater, and intermethod reliability were assessed. Results Regarding intrarater and interrater reliability, most measurements had Pearson coefficients greater than 0.75, mean differences less than 0.8 mm, and mean proportional differences less than 0.1. For measurements involving vermilion height, nostril remnants, or Cupid's bow width, Pearson coefficients ranged from 0.3 to 0.75, mean differences ranged from 0.4 to 0.9 mm, and mean proportional differences ranged from 0.1 to 0.3. Regarding intermethod reliability, correlation coefficients ranged from 0.4 to 0.75 for most measurements. The mean differences for nose and lip measurements were less than 1 mm and between 0.8 and 1.3 mm, respectively. Conclusion Three-dimensional stereophotogrammetry provides a reliable method for many anthropometric measurements of nasolabial form in infants with unrepaired unilateral cleft lip +/- palate. Clinical question/level of evidence Diagnostic, II.

Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM.