Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 ...are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway ...is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.
A common form of chondrodysplasia punctata has been defined by characteristic clinical and radiologic features in 23 patients seen in Melbourne. The patients presented during infancy because of ...failure to thrive, apparent mental retardation, and/or unusual appearance. The typical facies is almost diagnostic, and the diagnosis is completed by finding punctate calcification in the calcaneum in lateral radiographs of the feet, and sometimes in other sites. Growth and developmental progress improved during childhood and the final outcome seems likely to comprise low normal height and intelligence with persistence of typical facies. Mild cases probably pass unrecognized at present. Seventeen patients were male. Paternal age was significantly increased; however, family data did not support a genetic cause. Illnesses during pregnancy were unusually frequent, and anticonvulsants taken during pregnancy may have had an etiologic role in some patients.
The radiological findings in 13 patients with total aganglionosis coli were reviewed. There was a male to female ratio of 7:6. Fifty-four percent of patients presented in the first week of life, but ...a significant number (31%) did not present until after 1 month of age. All patients had plain film evidence of bowel obstruction when referred for a barium enema. There were no pathognomonic barium enema findings, and barium enema results covered the entire spectrum of findings which can be encountered in the neonate and young infant with bowel obstruction. Seventy-seven percent had normal calibre colon, 23% had micro colon, 23% had a shortened colon, 46% had colonic wall irregularity, 33% had significant ileal reflux. Delayed evacuation of barium from colon occurred in the two patients who had delayed films. Total colonic aganglionosis should be considered in any infant or young child with plain film evidence of bowel obstruction, whatever the barium enema findings. Hirschsprung's disease and the level of transition can only be definitively diagnosed by biopsy.
Patient portals may improve communication between families of children with asthma and their primary care providers and improve outcomes. However, the feasibility of using portals to collect ...patient-reported outcomes from families and the barriers and facilitators of portal implementation across diverse pediatric primary care settings have not been established.
We evaluated the feasibility of using a patient portal for pediatric asthma in primary care, its impact on management, and barriers and facilitators of implementation success.
We conducted a mixed-methods implementation study in 20 practices (11 states). Using the portal, parents of children with asthma aged 6-12 years completed monthly surveys to communicate treatment concerns, treatment goals, symptom control, medication use, and side effects. We used logistic regression to evaluate the association of portal use with child characteristics and changes to asthma management. Ten clinician focus groups and 22 semistructured parent interviews explored barriers and facilitators of use in the context of an evidence-based implementation framework.
We invited 9133 families to enroll and 237 (2.59%) used the portal (range by practice, 0.6%-13.6%). Children of parents or guardians who used the portal were significantly more likely than nonusers to be aged 6-9 years (vs 10-12, P=.02), have mild or moderate/severe persistent asthma (P=.009 and P=.04), have a prescription of a controller medication (P<.001), and have private insurance (P=.002). Portal users with uncontrolled asthma had significantly more medication changes and primary care asthma visits after using the portal relative to the year earlier (increases of 14% and 16%, respectively). Qualitative results revealed the importance of practice organization (coordinated workflows) as well as family (asthma severity) and innovation (facilitated communication and ease of use) characteristics for implementation success.
Although use was associated with higher treatment engagement, our results suggest that achieving widespread portal adoption is unlikely in the short term. Implementation efforts should include workflow redesign and prioritize enrollment of symptomatic children.
Clinicaltrials.gov NCT01966068; https://clinicaltrials.gov/ct2/show/NCT01966068 (Archived by WebCite at http://www.webcitation.org/6i9iSQkm3).
Feasible, valid, and reliable tools are needed to assess dietary quality among preschoolers. We aimed to test construct-/criterion-related validity and reliability of a dietary quality index ...generated from a liking survey and novel dietary patterns for characterizing food hedonism and parental feeding practices.
Participants included 416 economically disadvantaged, diverse preschoolers (41% overweight/obese) from educational centers and their parents. Parents completed liking and frequency surveys; the liking survey took half as long to complete. Preschoolers' skin carotenoid status (measured by Resonance Raman spectroscopy) and BMI percentile (measured weight/height) were assessed. The Healthy Eating Preference Index (HEPI) was constructed from weighted averages of liking scores for food groups and healthy variety score and Healthy Eating Index 2010 (HEI) from nutrient analysis of the frequency survey.
The HEPI was normally distributed and showed construct validity and adequate internal reliability. In hierarchical regression analyses, the HEPI explained carotenoid status and adiposity as alternative or value-added predictors to HEI, supporting criterion-related validity of HEPI. Parental reporting of children's liking of high-fat/sweet/salty foods in excess of pleasurable activities (food hedonism) predicted heavier preschoolers, as did discord between HEI and HEPI (potential parental pressure toward healthy eating). HEPI alone or with HEI explained variability in carotenoid status and adiposity in path models with adequate to good fits.
With simple collection and processing, the liking survey can generate a valid/reliable dietary quality index in child care settings to identify preschoolers at risk for lower nutritional status. Using liking and frequency-based screeners could improve understanding of parental feeding behaviors and precision of predicting nutritional status.
Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast ...cell activation syndromes.
This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community’s efforts to improve diagnosis, management, therapy, and patients’ quality of life by addressing unmet needs.
In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs.
Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research.
Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders.
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