Mutant COMP shapes growth and development of skull and facial structures in mice and humans.

BACKGROUND: Cartilage oligomeric matrix protein (COMP) is an important extracellular matrix protein primarily functioning in the musculoskeletal tissues and especially endochondral bone growth. Mutations in COMP cause the skeletal dysplasia pseudoachondroplasia (PSACH) that is characterized by short limbs and fingers, joint laxity, and abnormalities but a striking lack of skull and facial abnormalities. METHODS: This study examined both mice and humans to determine how mutant-COMP affects face and skull growth. RESULTS: Mutant COMP (MT-COMP) mice were phenotypically distinct. Snout length and skull height were diminished in MT-COMP mouse and the face more closely resembled younger controls. Three-dimensional facial measurements of PSACH faces showed widely spaced eyes, reduced lower facial height, and decreased nasal protrusion, which correlated with a more juvenile appearing face. Neither MT-COMP mice nor PSACH individuals show midface hypoplasia usually associated with abnormal endochondral bone growth. MT-COMP mice do show delayed endochondral and membranous skull ossification that normalizes with age. CONCLUSION: Therefore, mutant-COMP affects both endochondral and intramembranous bones of the skull resulting in a reduction of the nose and lower facial height in mice and humans, in addition to its well-defined role in the growth plate chondrocytes.

Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.

AGORA, a data- and biobank for birth defects and childhood cancer.

BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.

Secondary cleft rhinoplasty: impact on self-esteem and quality of life.

BACKGROUND: Rhinoplasty is one of the most challenging facial plastic procedures. Although patient satisfaction is the real outcome parameter in rhinoplasty, most authors have studied objective outcomes evaluated by professionals. The purpose of this study was to determine patient satisfaction after rhinoplasty in patients born with a cleft lip compared with outcome assessment by professionals, and to assess the impact of the procedure on appearance-related distress and generic quality of life. METHODS: Patient evaluation of the nose was performed before and 1 year after secondary cleft rhinoplasty (n = 33) using a visual analogue scale for nasal function and shape, and the Rhinoplasty Outcome Evaluation. General sinonasal complaints were evaluated using the Sino-Nasal Outcome Test. Appearance-related psychological distress was measured using the Derriford Appearance Scale. The Sheehan Disability Scale evaluated quality of life. Aesthetic outcome was evaluated by scoring of preoperative and postoperative photographs by two independent surgeons. RESULTS: One year postoperatively, patients showed significantly higher visual analogue scale scores for nasal shape (p < 0.0001) and function (p = 0.005) and higher Rhinoplasty Outcome Evaluation (p < 0.0001) scores. Correspondingly, Sino-Nasal Outcome Test scores were lower (p = 0.006). The appearance-related psychological distress was lower (p < 0.0001), and the generic quality of life was increased after rhinoplasty (p = 0.01). No correlation was found between patient outcome evaluation and surgeons' scores. CONCLUSION: There is high patient satisfaction at 12 months after secondary cleft rhinoplasty, resulting in a significant improvement of self-esteem and generic quality of life.