Carrie L. Heike

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.

3D digital stereophotogrammetry: a practical guide to facial image acquisition

The use of 3D surface imaging technology is becoming increasingly common in craniofacial clinics and research centers. Due to fast capture speeds and ease of use, 3D digital stereophotogrammetry is quickly becoming the preferred facial surface imaging modality. These systems can serve as an unparalleled tool for craniofacial surgeons, proving an objective digital archive of the patients face without exposure to radiation. Acquiring consistent high-quality 3D facial captures requires planning and knowledge of the limitations of these devices. Currently, there are few resources available to help new users of this technology with the challenges they will inevitably confront. To address this deficit, this report will highlight a number of common issues that can interfere with the 3D capture process and offer practical solutions to optimize image quality.

Picture perfect? Reliability of craniofacial anthropometry using three-dimensional digital stereophotogrammetry.

Background: Quantification of facial characteristics is important for research in dysmorphology, otolaryngology, oral and maxillofacial, and plastic surgical disciplines, among others. Three-dimensional surface imaging systems offer a quick and practical method for quantifying craniofacial variation and appear to be highly reliable. However, some sources of measurement error have not yet been thoroughly evaluated. Methods: The authors assessed the reliability of using stereophotogrammetry for measuring craniofacial characteristics in 40 individuals, including 20 without craniofacial conditions and 20 with 22q11.2 deletion syndrome. The authors recruited staff and relatives of staff, and individuals with a laboratory-confirmed 22q11.2 deletion. Thirty anthropometric measurements were obtained on participants and on three-dimensional images. Results: Intrarater and interrater reliability for most interlandmark distances on three-dimensional images had intraclass correlation coefficients greater than 95 percent, mean absolute differences of less than 1 mm, relative error measurement less than 5, and technical error of measurement less than 1 mm. The Pearson correlation coefficients of greater than 0.9 for most distances suggest high intermethod reliability between direct and image-based measurements. Three-dimensional image-based measurements were systematically larger for the head length and width, forehead, and skull base widths, and upper and lower facial widths. Conclusions: This study provides further evidence of the high reliability of three-dimensional imaging systems for several craniofacial measurements, including landmarks and interlandmark distances not included in previous studies. The authors also discuss possible errors introduced with palpable landmarks and when working with less compliant participants, such as children. The authors offer guidelines for establishing protocols that can be tailored to each population and research question to maximize the accuracy of image-based measurements.

Development at Age 36 Months in Children With Deformational Plagiocephaly

OBJECTIVES: Infants and toddlers with deformational plagiocephaly (DP) have been shown to score lower on developmental measures than unaffected children. To determine whether these differences persist, we examined development in 36-month-old children with and without a history of DP. METHODS: Participants included 224 children with DP and 231 children without diagnosed DP, all of who had been followed in a longitudinal study since infancy. To confirm the presence or absence of DP, pediatricians blinded to children’s case status rated 3-dimensional cranial images taken when children were 7 months old on average. The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was administered as a measure of child development. RESULTS: Children with DP scored lower on all scales of the BSID-III than children without DP. Differences were largest in cognition, language, and parent-reported adaptive behavior (adjusted differences = –2.9 to –4.4 standard score points) and smallest in motor development (adjusted difference = –2.7). Children in the control group who did not have previously diagnosed DP but who were later rated by pediatricians to have at least mild cranial deformation also scored lower on the BSID-III than unaffected controls. CONCLUSIONS: Preschool-aged children with a history of DP continue to receive lower developmental scores than unaffected controls. These findings do not imply that DP causes developmental problems, but DP may nonetheless serve as a marker of developmental risk. We encourage clinicians to screen children with DP for developmental concerns to facilitate early identification and intervention.

Three Patients With Oculo-Auriculo-Vertebral Spectrum and Microdeletion 22q11.2

We report on three unrelated patients with the 22q11.2 microdeletion syndrome (del22q11) who have phenotypic anomalies compatible with oculo‐auriculo‐vertebral spectrum (OAVS). Hemifacial microsomia, unilateral microtia, hearing loss, congenital heart/aortic arch arteries defects, and feeding difficulties were present in all three patients. Additional anomalies occasionally diagnosed included coloboma of the upper eyelid, microphthalmia, cerebral malformation, palatal anomalies, neonatal hypocalcemia, developmental delay, and laryngomalacia. Several clinical features characteristic of OAVS have been described in patients with del22q11 from the literature, including ear anomalies, hearing loss, cervical vertebral malformations, conotruncal cardiac defects, renal malformations, feeding and respiratory difficulties. Atretic ear with facial asymmetry has been previously described in one patient. Thus, clinical expression of hemifacial microsomia and microtia resembling OAVS should now be included within the wide phenotypic expression of del22q11. The occurrence of this manifestation in del22q11 is currently low. Nevertheless, patients with hemifacial microsomia and microtia associated with clinical features typically associated with del22q11 should now have for specific cytogenetic testing.

Evaluation of the infant with an abnormal skull shape.

Purpose of review Atypical skull shapes occur in as many as 20% of infants. The purpose of this review is to discuss the clinical approach to the evaluation of a child with an abnormal head shape. Readers will learn how to identify the head shapes caused by environmental deformation and craniosynostosis. We also review recent findings with regard to the genetics of single-suture craniosynostosis. Recent findings Healthcare providers can use key aspects of the examination of a child with a head shape abnormality to differentiate positional deformity from craniosynostosis. Overlap between the genetic causes of isolated single-suture craniosynostosis and syndromic forms is discussed. Summary Pediatricians can identify the causes of the majority of head shape abnormalities by combining their understanding of normal calvarial growth with a careful physical examination. Molecular genetics is playing an increasing role in the evaluation of children with single-suture fusion.

Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis?

Epidermal nevus syndrome (ENS) is a rare, sporadic, congenital disorder of unknown etiology featuring a complex and highly variable phenotype that can include focal or generalized skeletal disease. We describe a young man with ENS manifesting right‐sided linear skin lesions, generalized weakness, diffuse osteopenia associated with hypophosphatemic rickets, and distinctive focal bone lesions ipsilateral to the skin findings. Review of the literature concerning ENS–associated skeletal disease suggested such focal bone defects are fibrous dysplasia, but our patient did not have the typical radiographic or histopathologic findings of fibrous dysplasia. Nevertheless, his circulating fibroblast growth factor 23 (FGF‐23) level was elevated, likely functioning as a “phosphatonin,” yet no activating mutations in GNAS previously reported in fibrous dysplasia or McCune–Albright syndrome were detected in his leukocytes or affected skin. We postulate that the focal skeletal disease, although different than fibrous dysplasia, may be a source of FGF‐23 in ENS.

Making the Diagnosis: Metopic Ridge Versus Metopic Craniosynostosis

Introduction The metopic suture is the only calvarial suture which normally closes during infancy. Upon closure, a palpable and visible ridge often forms which can be confused with metopic craniosynostosis. Metopic ridging (MR) is treated nonsurgically while metopic craniosynostosis (MCS) is treated surgically. Differentiating between the two is paramount; however, consensus is lacking about where a clear diagnostic threshold lies. The goal of this study is to describe the physical examination and CT scan characteristics which may help to differentiate between physiological closure of the metopic suture with ridging (MR) and MCS. Methods A retrospective chart review of all patients seen at Seattle Children’s Hospital between 2004 and 2009 with the diagnosis of either MCS or MR (n = 282) was performed. Physical examination characteristics described by diagnosing practitioners were analyzed. Clinical photos were assessed by 3 expert raters to determine the importance of these characteristics. CT scan findings were abstracted and compared between the two diagnoses. Results The “classic” triad of narrow forehead, biparietal widening, and hypotelorism was present in only 14% of patients with MCS. Ninety-eight percent of patients in both groups had a palpable metopic ridge. The photographic finding of narrow forehead and pterional constriction was present in all patients with MCS, but only in 11.2% and 2.8% of patients with MR. On CT scan, the presence of 3 or more MCS findings was diagnostic of MCS in 96% of patients. Patients with MCS were more likely to present before 6 months of age (66% vs. 32%). Conclusions Patients with MCS tend to present earlier than those with MR. Upon physical examination, the relationship between the lateral frontal bone and the lateral orbit is important in distinguishing between the two diagnoses. A CT scan can be helpful in making the diagnosis not to confirm a closed suture but to identify 3 or more MCS characteristics.

A phenotypic assessment tool for craniofacial microsomia.

Background: Craniofacial microsomia is one of the most common conditions treated by craniofacial teams. However, research regarding the cause of this condition or the surgical outcomes of treatment is scant. This is attributable to the lack of diagnostic criteria and the wide phenotypic spectrum. Standardized description of the craniofacial malformations associated with craniofacial microsomia is a necessary first step for multicenter, interdisciplinary research into this complex condition. Methods: The authors used the previously published pictorial Orbit, Mandible, Ear, Nerve, and Soft tissue–Plus classification scheme to assign a phenotypic severity score to patients with craniofacial microsomia treated at the Craniofacial Center at Seattle Childrens Hospital. The authors modified the tool based on feedback from multidisciplinary focus groups. The authors also developed a standardized photographic protocol to facilitate assessment of patients using two-dimensional images. Results: Feedback from focus groups was synthesized to create a phenotypic assessment tool for craniofacial microsomia based on the pictorial Orbit, Mandible, Ear, Nerve, and Soft tissue–Plus classification system. This tool allows for more comprehensive description of the phenotype of craniofacial microsomia and is found to be effective for clinical use within a multidisciplinary craniofacial team. In addition, the photographic protocol for patients with craniofacial microsomia allows for classification from a two-dimensional photographic database, thereby facilitating research using archived photographs. Conclusions: The phenotypic assessment tool for craniofacial microsomia protocol provides a simple and standardized method for practitioners and researchers to classify patients with craniofacial microsomia. We anticipate that this tool can be used in multicenter investigational studies to evaluate the cause of this condition, its natural history, and comparative effectiveness research.