Objectives/Hypothesis: To translate the Velopharyngeal Insufficiency Effects on Life Outcomes (VELO) instrument into Chinese and test its psychometric properties.Study Design: Quality of life instrument translation and validation. Methods: The original English version of the VELO instrument was translated into Mandarin, back-translated, and adapted among the Chinese population, based on the standardized guidelines for the cross-culture adaption process. Velopharyngeal insufficiency (VPI) patients were identified by a professional speech and language pathologist. Internal reliability of the VELO instrument was assessed by the Cronbach's α coefficient. Discriminant validity was tested by the Mann-Whitney U test. Construct validity was assessed by factor analysis.Results: A total of 113 patients with VPI and 72 parents of the patients were enrolled. The mean age of the VPI patients was 14.8 years. Internal reliability was excellent; Cronbach's α coefficients were 0.92 and 0.94 for VPI patients and their parents, respectively. The Chinese VELO discriminated well between the VPI group and the controls, with a mean (standard deviation) score that was significantly lower for the VPI group (74.8 [25.7]) than the control group (98.0 [15.9]) (P < .001). The total scores and scores in the emotional domain or perception domain showed differences between VPI patients and their parents. Similar to the original study, the factor loading after rotation followed hypothesized domains largely, in spite of items from several domains loaded on the same factor.Conclusions: The translated Chinese version of the VELO instrument demonstrated an acceptable reliability, discriminant validity, and construct validity. These psychometric properties suggested theoretical evidence for the further use of the VELO instrument among Chinese patients with VPI.

Chinese school-aged children with cleft lip and palate are at raised risk for social and academic difficulties. Specific pattern of behavior problems displays differently depending on gender of the patient.

Contactin-associated protein-like 4 (Cntnap4) is a member of the neurexin superfamily of transmembrane molecules that have critical functions in neuronal cell communication. Cntnap4 knockout mice display decreased presynaptic gamma-aminobutyric acid (GABA) and increased dopamine release that is associated with severe, highly penetrant, repetitive, and perseverative movements commonly found in human autism spectrum disorder patients. However, no known function of Cntnap4 has been revealed besides the nervous system. Meanwhile, secretory protein neural EGFL-like 1 (Nell-1) is known to exert potent osteogenic effects in multiple small and large animal models without the off-target effects commonly found with bone morphogenetic protein 2. In this study, while searching for a Nell-1-specific cell surface receptor during osteogenesis, we identified and validated a ligand/receptor-like interaction between Nell-1 and Cntnap4 by demonstrating: 1) Nell-1 and Cntnap4 colocalization on the surface of osteogenic-committed cells; 2) high-affinity interaction between Nell-1 and Cntnap4; 3) abrogation of Nell-1-responsive Wnt and MAPK signaling transduction, as well as osteogenic effects, via Cntnap4 knockdown; and 4) replication of calvarial cleidocranial dysplasias-like defects observed in Nell-1-deficient mice in Wnt1-Cre-mediated Cntnap4-knockout transgenic mice. In aggregate, these findings indicate that Cntnap4 plays a critical role in Nell-1-responsive osteogenesis. Further, this is the first functional annotation for Cntnap4 in the musculoskeletal system. Intriguingly, Nell-1 and Cntnap4 also colocalize on the surface of human hippocampal interneurons, implicating Nell-1 as a potential novel ligand for Cntnap4 in the nervous system. This unexpected characterization of the ligand/receptor-like interaction between Nell-1 and Cntnap4 indicates a novel biological functional axis for Nell-1 and Cntnap4 in osteogenesis and, potentially, in neural development and function. © 2018 American Society for Bone and Mineral Research.

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Skeletal class II and III malocclusions are craniofacial disorders that negatively impact people’s quality of life worldwide. Unfortunately, the growth patterns of skeletal malocclusions and their clinical correction prognoses are difficult to predict largely due to lack of knowledge of their precise etiology. Inspired by the strong inheritance pattern of a specific type of skeletal malocclusion, previous genome-wide association studies (GWAS) were reanalyzed, resulting in the identification of 19 skeletal class II malocclusion-associated and 53 skeletal class III malocclusion-associated genes. Functional enrichment of these genes created a signal pathway atlas in which most of the genes were associated with bone and cartilage growth and development, as expected, while some were characterized by functions related to skeletal muscle maturation and construction. Interestingly, several genes and enriched pathways are involved in both skeletal class II and III malocclusions, indicating the key regulatory effects of these genes and pathways in craniofacial development. There is no doubt that further investigation is necessary to validate these recognized genes’ and pathways’ specific function(s) related to maxillary and mandibular development. In summary, this systematic review provides initial insight on developing novel gene-based treatment strategies for skeletal malocclusions and paves the path for precision medicine where dental care providers can make an accurate prediction of the craniofacial growth of an individual patient based on his/her genetic profile.

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NELL‐1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1‐p15.3 deletion involving the Nell‐1 gene was recently reported in a patient with short stature and delayed fontanelle closure. Here we sought to define the role of Nell‐1 in endochondral ossification by investigating Nell‐1‐specific inactivation in Col2α1‐expressing cell lineages. Nell‐1flox/flox; Col2α1‐Cre+ (Nell‐1Col2α1KO) mice were generated for comprehensive analysis. Nell‐1Col2α1KO mice were born alive but displayed subtle femoral length shortening. At 1 and 3 months postpartum, Nell‐1 inactivation resulted in dwarfism and premature osteoporotic phenotypes. Specifically, Nell‐1Col2α1KO femurs and tibias exhibited significantly reduced length, bone mineral density (BMD), bone volume per tissue volume (BV/TV), trabecular number/thickness, cortical volume/thickness/density, and increased trabecular separation. The decreased bone formation rate revealed by dynamic histomorphometry was associated with altered numbers and/or function of osteoblasts and osteoclasts. Furthermore, longitudinal observations by in vivo micro‐CT showed delayed and reduced mineralization at secondary ossification centers in mutants. Histologically, reduced staining intensities of Safranin O, Col‐2, Col‐10, and fewer BrdU‐positive chondrocytes were observed in thinner Nell‐1Col2α1KO epiphyseal plates along with altered distribution and weaker expression level of Ihh, Patched‐1, PTHrP, and PTHrP receptor. Primary Nell‐1Col2α1KO chondrocytes also exhibited decreased proliferation and differentiation, and its downregulated expression of the Ihh‐PTHrP signaling molecules can be partially rescued by exogenous Nell‐1 protein. Moreover, intranuclear Gli‐1 protein and gene expression of the Gli‐1 downstream target genes, Hip‐1 and N‐Myc, were also significantly decreased with Nell‐1 inactivation. Notably, the rescue effects were diminished/reduced with application of Ihh signaling inhibitors, cyclopamine or GANT61. Taken together, these findings suggest that Nell‐1 is a pivotal modulator of epiphyseal homeostasis and endochondral ossification. The cumulative chondrocyte‐specific Nell‐1 inactivation significantly impedes appendicular skeletogenesis resulting in dwarfism and premature osteoporosis through inhibiting Ihh signaling and predominantly altering the Ihh‐PTHrP feedback loop. © 2018 American Society for Bone and Mineral Research.