A novel HRAS c.466C>T p.(Phe156Leu) variant in two patients with attenuated features of Costello syndrome.

Costello syndrome (CS) is caused by heterozygous HRAS germline mutations. Most patients share the HRAS variant p.Gly12Ser that is associated with a typical, homogeneous phenotype. Rarer pathogenic HRAS variants (e.g., p.Thr56Ile) were identified in individuals with attenuated CS phenotypes. The obvious phenotypical variability reflects different dysfunctional consequences of distinct HRAS variants. We report on two boys with the novel de novo HRAS variant c.466 C > T p.(Phe156Leu). Both had severe feeding difficulties, airway obstruction and developmental delay, which are typical findings in CS. They showed subtle facial and dermatologic features consistent with attenuated CS. They significantly differed in their musculoskeletal, cardiovascular and endocrinologic manifestations underscoring the clinical variability of individuals with identical, in particular rarer pathogenic HRAS variants. Functional studies revealed enhanced effector-binding, increased downstream signaling activation and impaired growth factor-induced signaling dynamics in cells expressing HRASPhe156Leu. Our data further illustrate the molecular and phenotypic variability of CS.

Genomic testing for children with interstitial and diffuse lung disease (chILD): parent satisfaction, understanding and health-related quality of life.

OBJECTIVE: Research is needed to determine best practice for genomic testing in the context of child interstitial or diffuse lung disease (chILD). We explored parent's and child's health-related quality of life (HRQoL), parents' perceived understanding of a genomic testing study, satisfaction with information and the study and decisional regret to undertake genomic testing. METHODS: Parents of children with diagnosed or suspected chILD who were enrolled in a genomic sequencing study were invited to complete questionnaires pretesting (T1) and after receiving the result (T2). RESULTS: Parents' (T1, n=19; T2, n=17) HRQoL was lower than population norms. Study satisfaction (T1) and perceived understanding (T2) were positively correlated (rs=0.68, p=0.014). Satisfaction with information (T1 and T2) and decisional regret (T2) were negatively correlated (T1 rs=-0.71, p=0.01; T2 rs=-0.56, p=0.03). Parents reported wanting more frequent communication with staff throughout the genomic sequencing study, and greater information about the confidentiality of test results. CONCLUSIONS: Understanding of genomic testing, satisfaction with information and participation and decisional regret are inter-related. Pretest consultations are important and can allow researchers to explain confidentiality of data and the variable turnaround times for receiving a test result. Staff can also update parents when there will be delays to receiving a result.

Review of the radiation exposure during screening of surgically implanted central venous access devices.

PURPOSE: Ionizing radiation is used for the insertion of surgically implanted venous access devices (SIVADs) with children at the highest risk of cumulative radiation effects from these procedures. This study examines the radiation dose in a pediatric population during intraoperative radiological screening. METHODS: A retrospective study looked at all pediatric patients in a tertiary hospital between January 2008 and January 2014 who had a surgically implanted venous access device inserted using intraoperative fluoroscopy. Patient demographics, reason for SIVAD insertion, the type and method of insertion, fluoroscopy time and radiation dose area product were determined. RESULTS: A total of 505 patients had 682 SIVADs inserted, with 123 patients receiving multiple SIVAD over the six year period. There were two types of SIVAD inserted, 492 were totally implanted venous access devices (TIVAD) and 190 were tunneled central venous catheters (cuffed central line). Five hundred seven of the SIVAD inserted recorded the dose area product and fluoroscopy time. The median time for screening was 5seconds (range 1 to 275seconds) and the median dose area product was 0.00352mGym(2) (range 0.000001mGym(2) to 0.28mGym(2)). Of the 507 SIVAD that recorded the radiation data, 479 were open surgical cut-down insertion and 27 were percutaneous insertion. Percutaneously inserted surgically implanted venous access devices (mean 0.0060mGym(2)) had a longer dose area product than open insertion (mean 0.0034mGym(2); p=0.05). CONCLUSION: Screening of SIVAD involves low levels of radiation exposure and is comparable to a chest x-ray or a transatlantic flight. The excess lifetime cancer risk to patients is estimated to be very low and is considered to be outweighed by the benefits of insertion. Open surgical cut-down insertion has a significantly reduced radiation exposure compared to percutaneous techniques. Although radiation dose is higher with percutaneous procedures, the clinical effects are considered minimal, and the resultant radiation risk is estimated to be very low. Radiation dose should not determine technique of insertion of SIVAD.

Regional differences in susceptibiity of bronchial epithelium to mesenchymal transition and inhibition by the macrolide antibiotic azithromycin.

OBJECTIVE: Dysregulated repair following epithelial injury is a key forerunner of disease in many organs, and the acquisition of a mesenchymal phenotype by the injured epithelial cells (epithelial to mesenchymal transition, EMT) may serve as a source of fibrosis. The macrolide antibiotic azithromycin and the DNA synthesis inhibitor mycophenolate are in clinical use but their mechanism of action remains unknown in post-transplant bronchiolitis obliterans syndrome (BOS). Here we determined if regional variation in the EMT response to TGFß1 underlies the bronchiolocentric fibrosis leading to BOS and whether EMT could be inhibited by azithromycin or mycophenolate. METHODS/RESULTS: We found that small and large airway epithelial cells from stable lung transplant patients underwent EMT when stimulated with TGFß1, however mesenchymal protein expression was higher and loss of epithelial protein expression more complete in small airway epithelial cells. This regional difference was not mediated by changes in expression of the TGFßRII or Smad3 activation. Azithromycin potentially inhibited EMT in both small and large airway epithelial cells by inhibiting Smad3 expression, but not activation. CONCLUSION: Collectively, these observations provide a biologic basis for a previously unexplained but widely observed clinical phenomena, and a platform for the development of new approaches to fibrotic diseases.