AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.

Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the ß-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.

Adults with osteogenesis imperfecta: Clinical characteristics of 151 patients with a focus on bisphosphonate use and bone density measurements.

An expert center for adults with Osteogenesis Imperfecta (OI) has been founded at the Isala Hospital in Zwolle, the Netherlands to achieve optimal care for adults with OI. Clinical data such as patient history, Dual Energy X-ray Absorptiometry measurements and laboratory findings are collected with patient consent. This study provides an overview of clinical characteristics of the patients who visited the clinic during its first 5 years, a total of 151 patients. In this study, we focus on bisphosphonate use and bone density measurements at time of presentation at the expert center. As such, insight into the natural history of OI in adults will be increased. Analysing the data of a large group of adults with this rare disorder within a national expert center will allow detailed exploration of the course of OI over time.

Efficacy and Safety of Bisphosphonate Therapy in Children with Osteogenesis Imperfecta: A Systematic Review.

BACKGROUND/AIMS: To systematically assess contemporary knowledge regarding the effectiveness and safety of bisphosphonates (BPs) in children with osteogenesis imperfecta (OI). METHODS: PubMed/MEDLINE, Embase, and Cochrane were searched for eligible articles up to June 2014. Studies eligible for inclusion were (randomized) controlled trials assessing the effects of BPs in children with OI. Methodological quality was assessed independently by 4 reviewers using the Cochrane Collaboration's tool for risk of bias. RESULTS: Ten studies (519 children) were included. Four studies (40%) showed a low risk of bias. All studies investigating lumbar spine areal bone mineral density indicated a significant increase as a result of BP treatment. Most studies observed a significant decrease in fracture incidence. The most frequently reported adverse events were gastrointestinal complaints, fever, and muscle soreness. A significant decrease in (bone) pain due to BP treatment was observed in more than half of the studies. Most studies measuring urinary markers of bone resorption reported a significant decrease. The majority of studies with intravenous treatment showed a significant increase in lumbar projection area, whereas studies with oral treatment did not. CONCLUSIONS: Treatment with oral or intravenous BPs in children with OI results in an increase in bone mineral density and seems to be safe and well tolerated.

Evaluating NIR vascular imaging to support intravenous cannulation in awake children difficult to cannulate; a randomized clinical trial.

BACKGROUND: Recently, various near-infrared vascular imaging devices aimed at facilitating peripheral intravenous cannulation (PIC) were introduced, all claiming to increase success rate of PIC. We evaluated the clinical utility of a near-infrared vascular imaging device (VascuLuminator(®)) in pediatric patients who were referred to the anesthesiologist because of difficult cannulation. METHODS: There were 226 consecutive children referred to pediatric anesthesiologists by the treating pediatrician of the in- and outpatient clinic, because of difficulties with intravenous cannulation, were included in this cluster randomized clinical trial. The presence and use of the near-infrared vascular imaging device for PIC was randomized in clusters of 1 week. Success at first attempt (Fisher exact test) and time to successful cannulation (Log-rank test) were assessed to evaluate differences between groups. RESULTS: Success at first attempt in the group with the VascuLuminator(®) (59%) was not significantly different from the control group (54%, P = 0.41), neither was the median time to successful cannulation: 246 s and 300 s, respectively (P = 0.54). CONCLUSIONS: Visualization of blood vessels with near-infrared light and with near-infrared vascular imaging device did not improve success of PIC in pediatric patients who are known difficult to cannulate.

Predictive factors for difficult intravenous cannulation in pediatric patients at a tertiary pediatric hospital.

BACKGROUND: It is generally believed that certain patient characteristics (e.g., Body Mass Index and age) predict difficulty of intravenous cannulation in children, but there is not much literature evaluating these risk factors. In this study, we investigated predictive factors for success rate at first attempt and time needed for intravenous cannulation. METHODS/MATERIALS: In a prospective cohort study, we observed characteristics of intravenous cannulations in pediatric patients at the operating room (n = 1083) and the outpatient care unit (n = 178) of a tertiary referral pediatric hospital. Time to successful intravenous cannulation, success at first attempt, and potential predictors for difficult cannulation (age, gender, skin color, BMI or weight-to-age z-score, the child being awake or anesthetized, operator profession and surgical specialty) were recorded. Regression models were constructed to find significant predictors. RESULTS: Success at first attempt was 73% and 81%, respectively. In the operating room age, operator and surgical specialty were predictive for a successful first attempt and time to successful cannulation. No significant predictive factors were found for the outpatient care unit. BMI or weight-to-age was not related to difficult intravenous cannulation. CONCLUSIONS: This study shows that in one-fifth to one-third of the patients, intravenous cannulation required more than one attempt. It is difficult to predict with accuracy the difficulty of intravenous cannulation solely with easily obtainable patient characteristics.