Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Parental Reports of Intervention Services and Prevalence of Teasing in a Multinational Craniofacial Microsomia Pediatric Study.

ABSTRACT: 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 ±â€Š6.2 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 ±â€Š1.9 years. Current or past teasing was reported in 41% of the children, starting at a mean age of 6.0 ±â€Š2.4 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.

Behavioral Adjustment of Preschool Children With and Without Craniofacial Microsomia.

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.

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.

Methods and Challenges in a Cohort Study of Infants and Toddlers With Craniofacial Microsomia: The Clock Study.

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.

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.

In Their Own Words: Caregiver and Patient Perspectives on Stressors, Resources, and Recommendations in Craniofacial Microsomia Care.

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 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 ±â€Š6 years. Most children were male (71%) with an average age of 7 ±â€Š4 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.

Hearing Loss in Children With Craniofacial Microsomia.

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.

Phenotypic characterization of epibulbar dermoids.

The purpose of this study was to characterize the phenotypic presentation, clinical course, and outcomes of epibulbar dermoids (EpDs) which are the most common congenital eye tumor in children. Sixty-eight dermoids were identified in 58 eyes of 48 patients of Seattle Children's Hospital between 1981 and 2014 via electronic medical record search. Patients were organized into: "EpD-Only" [patients without other congenital anomalies (n = 13)], "EpD-CFM" [patients with a craniofacial microsomia (CFM) diagnosis (n = 25)], and "EpD-Other" [patients with other congenital anomalies (n = 10)]. All EpD in the EpD-Only group were unilateral and singular, while the EpD-CFM group had six cases with multiple unilateral EpD and five cases with bilateral EpD. In the EpD-Only group, 69 % of EpD were left sided, whereas in the EpD-CFM group, there was no side predisposition. Among both groups, the majority of EpD were limbal or lipodermoids in the inferotemporal quadrant of the eye. Surgery was more common and at a younger age in the EpD-CFM group than the EpD-Only group (56 vs. 38 %, 5.2 vs. 7.0 years). Follow-up surgeries occurred only in the EpD-CFM group (21 %). EpDs were most commonly associated with preauricular tags, congenital heart defects, genitourinary, and nervous system anomalies. Whereas the location and type of EpDs did not significantly differ between the groups, the phenotype in the EpD-Only group appears to be less complex. This may indicate an important difference between EpDs in isolation and those within CFM. Additional studies will further characterize these phenotypes and outcomes.

Characterizing facial features in individuals with craniofacial microsomia: A systematic approach for clinical research.

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.

Phenotypic sub-grouping in microtia using a statistical and a clinical approach.

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.

Perspectives and challenges in advancing research into craniofacial anomalies.

Development of the craniofacial region is a remarkably complex and tightly orchestrated process. It is therefore not surprising that genetic and environmental insults frequently result in craniofacial anomalies. Nonetheless, our knowledge of their etiology and pathogenesis is still scarce, limiting our efforts at prevention. Furthermore, few standardized protocols have been developed to guide clinical and surgical interventions. In this Issue of the Seminars, reviews on the most recent research advances on craniofacial conditions, from genomics and epigenetics to ontology and medical care are discussed with emphasis on the most common anomalies of the craniofacial region: orofacial clefts, craniosynostosis, craniofacial microsomia, facial dysostosis, Robin sequence, jaw and dentition anomalies, and anterior neural tube defects. Phenotypic variability and the importance of detailed characterization using standardized terminology to better distinguish between phenotypes, new technologies (and their limitations) for genetic diagnosis, and the use of mouse models to study these conditions in both their complex phenotypic and genetic aspects are highlighted.

Preferential associated anomalies in 818 cases of microtia in South America.

The etiology of microtia remains unknown in most cases. The identification of patterns of associated anomalies (i.e., other anomalies that occur with a given congenital anomaly in a higher than expected frequency), is a methodology that has been used for research into the etiology of birth defects. We conducted a study based on cases of microtia that were diagnosed from more than 5 million live (LB)- and stillbirths (SB) examined in hospitals participating in ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 1967 and 2009. We identified 818 LB and SB with microtia and at least one additional non-related major congenital anomaly (cases) and 15,969 LB and SB with two or more unrelated major congenital anomalies except microtia (controls). A logistic regression analysis was performed to identify the congenital anomalies preferentially associated with microtia. Preferential associations were observed for 10 congenital anomalies, most of them in the craniofacial region, including facial asymmetry, choanal atresia, and eyelid colobomata. The analysis by type of microtia showed that for anomalies such as cleft lip and palate, macrostomia, and limb reduction defects, the frequency increased with the severity of the microtia. In contrast, for other anomalies the frequency tended to be the same across all types of microtia. Based on these results we will integrate data on the developmental pathways related to preferentially associated congenital anomalies for future studies investigating the etiology of microtia.

"Mandibulofacial dysostosis with microcephaly" caused by EFTUD2 mutations: expanding the phenotype.

Heterozygous mutations in the EFTUD2 were identified in 12 individuals with a rare sporadic craniofacial condition termed Mandibulofacial dysostosis with microcephaly (MIM 610536). We present clinical and radiographic features of three additional patients with de novo heterozygous mutations in EFTUD2. Although clinical features overlap with findings of the original report (choanal atresia, cleft palate, maxillary and mandibular hypoplasia, and microtia), microcephaly was present in two of three patients and cognitive impairment was milder in those with head circumference proportional to height. Our cases expand the phenotypic spectrum to include epibulbar dermoids and zygomatic arch clefting. We suggest that craniofacial computed tomography studies to assess cleft of zygomatic arch may assist in making this diagnosis. We recommend consideration of EFTUD2 testing in individuals with features of oculo-auriculo-vertebral spectrum and bilateral microtia, or individuals with atypical CHARGE syndrome who do not have a CHD7 mutation, particularly those with a zygomatic arch cleft. The absence of microcephaly in one patient indicates that it is a highly variable phenotypic feature.

Interrater reliability of a phenotypic assessment tool for the ear morphology in microtia.

The Elements of Morphology Standard Terminology working group published standardized definitions for external ear morphology. The primary objective of our study was to use these descriptions to evaluate the interrater reliability for specific features associated with microtia. We invited six raters from three different subspecialities to rate 100 ear photographs on 32 features. We calculated overall and within specialty and professional experience intraclass correlation coefficients (ICC) and 95% confidence intervals. A total of 600 possible observations were recorded for each feature. The overall interrater reliability ranged from 0.04 (95% CI: 0.00-0.14) for the width of the antihelix inferior crus to 0.93 (95% CI: 0.91-0.95) for the presence of the inferior crux of the antihelix. The reliability for quantitative characteristics such as length or width of an ear structure was generally lower than the reliability for qualitative characteristics (e.g., presence or absence of an ear structure). Categories with very poor interrater reliability included anti-helix inferior crux width (0.04, 95% CI: 0.00-0.14), crux helix extension (0.17, 95% CI 0.00-0.37), and shape of the incisura (0.14, 95% CI: 0.01-0.27). There were no significant differences in reliability estimates by specialty or professional experience for most variables. Our study showed that it is feasible to systematically characterize many of structures of the ear that are affected in microtia. We incorporated these descriptions into a standardized phenotypic assessment tool (PAT-Microtia) that might be used in multicenter research studies to identify sub-phenotypes for future studies of microtia.

Risk factors and demographics for microtia in South America: a case-control analysis.

BACKGROUND: The etiopathogenesis of microtia is still unknown in the majority of the cases, particularly for individuals presenting with isolated microtia. Our aim was to evaluate potential risk factors for this condition using a case-control approach. METHODS: We analyzed data from 1,194 live births with isolated microtia enrolled in the ECLAMC study (Estudio Colaborativo Latino Americano de Malformaciones Congénitas) from 1982 to 2011 and their respective controls. Odds ratios (ORs) were estimated with logistic regression models along with 95% confidence intervals for the resulting OR estimates controlling for the effects of potential confounders (sex, maternal age, hospital, and year of birth) for an adjusted OR (aOR). RESULTS: Multiparity was associated with a higher risk of microtia compared with primiparity (aOR, 1.5; 95% confidence interval [CI], 1.2-1.8), with women who had eight or more prior pregnancies having the highest risk (aOR, 2.8; 95% CI, 1.6-5.2). Women who presented with cold-like symptoms were at higher risk for microtia (aOR, 2.2; 95% CI, 1.2-3.9) as well as those that used tobacco or alcohol during pregnancy (aOR, 1.7; 95% CI, 1.1-2.6 and aOR, 1.4; 95% CI, 0.9-2.1, respectively). The association with alcohol use appeared to be limited to those women who reported binge drinking during pregnancy (aOR, 1.4; 95% CI, 0.7-3.1). Cases from hospitals at low altitude (<2500 m) tended to have more severe types of microtia than those from hospitals at high altitude. CONCLUSION: These results support the hypothesis that, in addition to teratogens, other nongenetic risk factors contribute to the occurrence of isolated microtia.

Comparison of two-dimensional and three-dimensional images for phenotypic assessment of craniofacial microsomia.

Background and Purpose : Three-dimensional surface imaging is used in many craniofacial centers. However, few data exist to indicate whether such systems justify their cost. Craniofacial microsomia is associated with wide phenotypic variability and can affect most facial features. The purpose of this study is to compare three-dimensional versus two-dimensional images for classification of facial features in individuals with craniofacial microsomia. Methods : We obtained a series of two-dimensional and three-dimensional images of 50 participants, aged 0-20 years, diagnosed with craniofacial microsomia, microtia, or Goldenhar syndrome. Three clinicians classified the craniofacial features on each image, and ratings were compared by calculating kappa statistics. We also evaluated image quality using a 5-point Likert scale. Results : Reliability estimates were high for most features using both two-dimensional and three-dimensional image data. Our three-dimensional protocol did not allow for scoring of facial animation, occlusal cant, or tongue anomalies. Image quality scores for the mandible and soft tissue assessment were higher for three-dimensional images. Raters preferred two-dimensional photographs for assessment of the ear, ear canal, and eyes. Conclusions : Both three-dimensional and two-dimensional images provide useful data for objective characterization of the craniofacial features affected in craniofacial microsomia. A series of two-dimensional images has relative advantages for assessment of some specific features, such as the ear, though three-dimensional images may have advantages for quantitative analysis and qualitative assessment of deformities of the jaw and soft tissue. These results should apply to any assessment of these features with or without a craniofacial microsomia diagnosis.

Microtia: epidemiology and genetics.

Microtia is a congenital anomaly of the ear that ranges in severity from mild structural abnormalities to complete absence of the ear, and can occur as an isolated birth defect or as part of a spectrum of anomalies or a syndrome. Microtia is often associated with hearing loss and patients typically require treatment for hearing impairment and surgical ear reconstruction. The reported prevalence varies among regions, from 0.83 to 17.4 per 10,000 births, and the prevalence is considered to be higher in Hispanics, Asians, Native Americans, and Andeans. The etiology of microtia and the cause of this wide variability in prevalence are poorly understood. Strong evidence supports the role of environmental and genetic causes for microtia. Although some studies have identified candidate genetic variants for microtia, no causal genetic mutation has been confirmed. The application of novel strategies in developmental biology and genetics has facilitated elucidation of mechanisms controlling craniofacial development. In this paper we review current knowledge of the epidemiology and genetics of microtia, including potential candidate genes supported by evidence from human syndromes and animal models. We also discuss the possible etiopathogenesis in light of the hypotheses formulated to date: Neural crest cells disturbance, vascular disruption, and altitude.

Evaluation of ICD-9-CM codes for craniofacial microsomia.

BACKGROUND: Craniofacial microsomia (CFM) is a congenital condition characterized by microtia and mandibular underdevelopment. Healthcare databases and birth defects surveillance programs could be used to improve knowledge of CFM. However, no specific International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code exists for this condition, which makes standardized data collection challenging. Our aim was to evaluate the validity of existing ICD-9-CM codes to identify individuals with CFM. METHODS: Study sample eligibility criteria were developed by an expert panel and matched to 11 ICD-9-CM codes. We queried hospital discharge data from two craniofacial centers and identified a total of 12,254 individuals who had ≥1 potentially CFM-related code(s). We reviewed all (n = 799) medical records identified at the University of North Carolina (UNC) and 500 randomly selected records at Seattle Children's Hospital (SCH). Individuals were classified as a CFM case or non-case. RESULTS: Thirty-two individuals (6%) at SCH and 93 (12%) at UNC met the CFM eligibility criteria. At both centers, 59% of cases and 95% of non-cases had only one code assigned. At both centers, the most frequent codes were 744.23 (microtia), 754.0 and 756.0 (nonspecific codes), and the code 744.23 had a positive predictive value (PPV) >80% and sensitivity >70%. The code 754.0 had a sensitivity of 3% (PPV <1%) at SCH and 36% (PPV = 5%) at UNC, whereas 756.0 had a sensitivity of 38% (PPV = 5%) at SCH and 18% (PPV = 26%) at UNC. CONCLUSIONS: These findings suggest the need for a specific CFM code to facilitate CFM surveillance and research.