Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome.

Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.

Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1.

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17-/- mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

Three-dimensional imaging of pulmonary arterial vasa vasorum using optical coherence tomography in patients after bidirectional Glenn and Fontan procedures.

AIMS: We evaluated pulmonary arterial (PA) vasa vasorum (VV) in Fontan candidate patients with a novel three-dimensional (3D) imaging technique using optical coherence tomography (OCT). METHODS AND RESULTS: This prospective study assessed the development of adventitial VV in the distal PA of 10 patients with bidirectional Glenn circulation (BDG group, 1.6 ± 0.3 years) and Fontan circulation (Fontan group, 3.3 ± 0.3 years), and in 20 children with normal PA haemodynamics and morphology (Control group, 1.5 ± 0.3 years). We assessed the PA VV with two-dimensional (2D) cross-sectional, multi-planar reconstruction (MPR), and volume rendering (VR) imaging. VV development was evaluated by the VV area/volume ratio, defined as the VV area/volume divided by the adventitial area/volume. Compared to the control group, the observed VV number and diameter on 3D images of MPR and VR were significantly higher, and curved and torturous-shaped VV were more frequently observed in the BDG and Fontan groups (P < 0.001, all). The median VV volume ratio was significantly greater in the BDG than in the control group (3.38% vs. 0.61%; P < 0.001). Although the VV volume ratio decreased significantly after the Fontan procedure (2.64%, P = 0.005 vs. BDG), the ratio remained higher than in the control group (P < 0.001 vs. control). CONCLUSION: 3D OCT imaging is a novel method that can be used to evaluate adventitial PA VV and may provide pathophysiological insight into the role of the PA VV in these patients.

Next-generation sequencing for the diagnosis of patients with congenital multiple anomalies and†/†or intellectual disabilities.

Background : In clinical practice, a large proportion of patients with multiple congenital anomalies and/or intellectual disabilities (MCA / ID) lacks a specific diagnosis. Recently, next-generation sequencing (NGS) has become an efficient strategy for genetic diagnosis of patients with MCA/ID. OBJECTIVE: To review the utility of NGS for the diagnosis of patients with MCA / ID. METHOD: Patients with MCA/ID were recruited between 2013 and 2017. Molecular diagnosis was performed using NGS-based targeted panel sequencing for 4,813 genes. Promising causative variants underwent confirmation by Sanger sequencing or chromosomal microarray. RESULTS: Eighteen patients with MCA/ID were enrolled in this study. Of them, 8 cases (44%) were diagnosed by targeted panel sequencing. Most of diagnosed patients were able to receive better counseling and more appropriate medical management. CONCLUSION: NGS-based targeted panel sequencing seems to be an effective testing strategy for diagnosis of patients with MCA/ID. J. Med. Invest. 67 : 246-249, August, 2020.

Successful treatment by stent implantation for systemic-to-pulmonary shunt obstruction due to a Staphylococcus aureus abscess: a case report.

A 13-year-old girl with a single ventricle and bilateral systemic-to-pulmonary shunts developed hypoxia due to shunt stenosis, which was caused by a methicillin-sensitive Staphylococcus aureus abscess. Stent implantation associated with appropriate antibiotic administration was crucial to dilate and maintain shunt patency.

A novel index equivalent to the myocardial performance index for right ventricular functional assessment in children and adolescent patients.

The aims of the present study were to develop and check the utility and feasibility of a novel right ventricular (RV) functional index (RV angular velocity; RVω, s-1) derived from the angular velocity in harmonic oscillator kinematics obtained from the RV pressure waveform. We hypothesized that RVω reflects the myocardial performance index (MPI), which represents global RV function. A total of 132 consecutive patients, ranging in age from 3 months to 34 years with various cardiac diseases were included in this prospective study. RVω was defined as the difference between the peak derivative of pressure (dP/dt_max - dP/dt_min) divided by the difference between the maximum and minimum pressure (Pmax - Pmin). RVω showed significant negative correlations with the pulsed-wave Doppler-derived myocardial performance index (PWD-MPI) and the tissue Doppler imaging-derived MPI (TDI-MPI) (r = -0.52 and -0.51, respectively; both p < 0.0001). RVω also showed significant positive correlations with RV fractional area change (RVFAC) and RV ejection fraction (RVEF) (r = 0.41 and 0.39, respectively; both p < 0.0001), as well as a significant negative correlation with tricuspid E/e' (r = -0.19, p = 0.0283). The clinical feasibility and utility of RVω for assessing global RV performance, incorporating both systolic and diastolic function, were demonstrated.

Right Ventricular Myocardial Stiffness and Relaxation Components by Kinematic Model-Based Transtricuspid Flow Analysis in Children and Adolescents with Pulmonary Arterial Hypertension.

We hypothesized that the kinematic model-based parameters obtained from the transtricuspid E-wave would be useful for evaluating the right ventricular diastolic property in pediatric pulmonary arterial hypertension (PAH) patients. The model was parametrized by stiffness/elastic recoil k, relaxation/damping c and load x. These parameters were determined as the solution of m⋅d2x/dt2 + c⋅dx/dt + kx = 0, which is based on the theory that the E-wave contour is determined by the interplay of stiffness/restoring force, damping/relaxation force and load. The PAH group had a significantly higher k and c compared with the control group (182.5 ± 72.4 g/s vs. 135.7 ± 49.5 g/s2, p = 0.0232, and 21.9 ± 6.5 g/s vs. 10.6 ± 5.2 g/s, p <0.0001, respectively). These results indicate that in the PAH group, the right ventricle had higher stiffness/elastic recoil and inferior cross-bridge relaxation. The present findings indicate the feasibility and utility of using kinematic model parameters to assess right ventricular diastolic function.

Optical coherence tomography for observing development of pulmonary arterial vasa vasorum after bidirectional cavopulmonary connection in children.

BACKGROUND: Hypoxia and low pulmonary arterial (PA) blood flow stimulate the development of systemic-to-pulmonary collateral blood vessels, which can be an adverse factor when performing the Fontan operation. The aim of this study was to use optical coherence tomography (OCT) to elucidate the morphological changes in PA vasculature after creation of a bidirectional cavopulmonary connection (BCPC) in children. METHODS: This prospective study evaluated PA wall thickness and development of PA vasa vasorum (VV) in the distal PA of eight patients (BCPC group, 1.3 ± 0.3 years) and 20 age-matched children with normal pulmonary artery hemodynamics and morphology (Control group, 1.4 ± 0.3 years). VV development was defined by the VV area ratio, defined as the VV area divided by the adventitial area in cross-sectional images. RESULTS: There was no significant difference in PA wall thickness between the BCPC and control groups (0.12 ± 0.03 mm vs. 0.12 ± 0.02 mm, respectively). The VV area ratio was significantly greater in the BCPC group than in the Control group (14.5 ± 3.5% vs. 5.3 ± 1.6%, respectively; p<0.0001). CONCLUSION: OCT is a promising new tool for evaluating PA pathology, including the development of VV in patients after BCPC.

Development of acquired intrapulmonary venous anastomosis contributing to establishment of Fontan circulation.

Pulmonary venous (PV) obstruction is associated with a poor prognosis, as well as a high risk of recurrence, following surgical treatment. It can also interfere with the successful completion of Fontan circulation in patients with complex congenital heart disease. A case of a patient who had right isomerism (also known as asplenia syndrome), total anomalous pulmonary venous connection (TAPVC), and a single right ventricle is presented. Although bilateral total occlusion of the inferior PVs was identified postoperatively, the formation of the anastomosis and collateral vessels into the superior and middle PVs enabled successful completion of Fontan circulation. Anastomoses and collateral flow of the PVs were found largely in the interlobar pleura and not in the lung parenchyma.

Pulmonary Artery Wall Thickness Assessed by Optical Coherence Tomography Correlates With Pulmonary Hemodynamics in Children With Congenital Heart Disease.

BACKGROUND: Pulmonary arterial (PA) wall thickening evaluated by optical coherence tomography (OCT) has been reported in adults with PA hypertension. The purpose of this study was to evaluate the feasibility of OCT for preoperative assessment of the PA wall in children with congenital heart disease (CHD). Methods and Results: Participants comprised 39 patients with ventricular septal defect, atrial septal defect, or patent ductus arteriosus. Attempts were made to evaluate vessels of various diameters using OCT. Clearly observed vessels that were optimal for evaluation were selected and classified into 4 subgroups by diameter of the lumen. Optimal depiction was obtained in 80 of 156 vessels in total, and 25 (64.1%), 34 (87.1%), 17 (43.6%), and 4 vessels (10.3%) in each of the 1.0-<2.0 mm, 2.0-<3.0 mm, 3.0-<4.0 mm, and 4.0-5.0 mm subgroups, respectively. Arterial walls in the 2.0-<3.0 mm subgroup were the most frequently delineated, and wall thickness correlated significantly with mean PA pressure, pulmonary vascular resistance index, pulmonary-to-systemic flow ratio, and PA capacitance index (r=0.56, 0.52, 0.37, and -0.49, respectively). The 3-layered appearance was delineated in 29 of 80 vessels (36.2%). This feature had no significant correlation with pulmonary hemodynamics. CONCLUSIONS: OCT represents a promising tool for evaluating the PA wall in children with CHD.

Analysis of Right Ventricular Myocardial Stiffness and Relaxation Components in Children and Adolescents With Pulmonary Arterial Hypertension.

BACKGROUND: The rate of left ventricular pressure decrease during isovolumic relaxation is traditionally assessed algebraically via 2 empirical indices: the monoexponential and logistic time constants (τE and τL). Since the pattern of right ventricular (RV) pressure decrease is quite different from that of the left ventricular, we hypothesized that novel kinematic model parameters are more appropriate and useful to evaluate RV diastolic dysfunction. METHODS AND RESULTS: Eight patients with pulmonary arterial hypertension (age 12.5±4.8 years) and 20 normal subjects (control group; age 12.3±4.4 years) were enrolled. The kinematic model was parametrized by stiffness/restoring Ek and damping/relaxation µ. The model predicts isovolumic relaxation pressure as a function of time as the solution of d2P/dt2+(1/µ)dP/dt+EkP=0, based on the theory that the pressure decay is determined by the interplay of inertial, stiffness/restoring, and damping/relaxation forces. In the assessment of RV diastolic function, τE and τL did not show significant differences between the pulmonary arterial hypertension and control groups (46.8±15.5 ms versus 32.5±14.6 ms, and 19.6±5.9 ms versus 14.5±7.2 ms, respectively). The pulmonary arterial hypertension group had a significantly higher Ek than the control group (915.9±84.2 s-2 versus 487.0±99.6 s-2, P<0.0001) and a significantly lower µ than the control group (16.5±4.3 ms versus 41.1±10.4 ms, P<0.0001). These results show that the RV has higher stiffness/elastic recoil and lower cross-bridge relaxation in pulmonary arterial hypertension. CONCLUSIONS: The present findings indicate the feasibility and utility of kinematic model parameters for assessing RV diastolic function.

Early Diastolic Left Ventricular Relaxation in Normal Neonates is Influenced by Ventricular Stiffness and Longitudinal Systolic Function.

Tissue Doppler velocity during early diastole (e') is one of the most feasible and reproducible echocardiographic assessments to reflect active relaxation of the left ventricle. Although several reports have described the mechanisms of temporal diastolic dysfunction in the early neonatal period, factors influencing diastolic function have not been determined. The purpose of this study was to elucidate factors significantly influencing e' in the early neonatal period.A total of 179 consecutive normal neonates underwent echocardiographic studies performed at 0 days and 5-10 days after birth. The statistical relationships between e' and age, body weight, mean blood pressure, heart rate, shortening fraction of the left ventricle, peak systolic motion velocity (s'), early diastolic transmitral flow velocity over annulus velocity, Tei index, and diastolic wall strain (DWS) were analyzed.Between the 0 days and 5-10-days-after birth groups, significant differences were shown in mean blood pressure, shortening fraction of left ventricle, e', and Tei index. Age, body weight, mean blood pressure, s', and DWS showed significant correlations with e'. In multivariate regression analysis within these parameters, s' (ß = 0.6119, P < 0.0001) and DWS (ß = 0.1216, P = 0.0321) showed positive correlations with e'.Longitudinal systolic motion velocity and ventricular wall stiffness of the left ventricle influence diastolic relaxation in normal neonates. Age, body weight, and circumferential systolic function are not significant factors.

Pulmonary annular motion velocity reflects right ventricular outflow tract function in children with surgically repaired congenital heart disease.

Right ventricular (RV) dysfunction is generally evaluated using analyses of tricuspid annular motion. However, it represents only one aspect of RV performance. Whether measuring pulmonary annular motion velocity could serve as a novel way to evaluate global RV and/or RV outflow tract (RVOT) performance in pediatric congenital heart disease (CHD) patients with surgically repaired RVOT was evaluated. In this prospective study, tissue Doppler-derived pulmonary annular motion velocity was measured in children (aged 2-5 years) with RVOT reconstruction (RVOTR group, n = 48) and age-matched healthy children (Control, n = 60). The types of RVOTR procedures were as follows: pulmonary valve-sparing procedure (PVS, n = 7); transannular patch with monocusp valve reconstruction (TAP, n = 29); and RV-to-PA conduit reconstruction using a pericardial valve with expanded polytetrafluoroethylene conduit (Rastelli, n = 12). Pulmonary annular motion velocity waveforms comprised systolic bimodal (s1' and s2') and diastolic e' and a' waves in all participants. The peak velocities of s1', s2', e', and a' were significantly lower in the RVOTR group than in the control group (all p < 0.0001). Furthermore, these parameters depended significantly on the type of surgical procedure. The peak velocities of s1', s2', and e' had significant correlations with RVOT ejection fraction (RVOT-EF) (r = 0.56, 0.49, and 0.34, respectively), and RVOT fractional shortening (RVOT-FS) (r = 0.72, 0.55, and 0.41, respectively), although there were no significant correlations between pulmonary annular motion and global RV function, including RV ejection fraction (RVEF) and RV fractional area change (RVFAC) in the assessment of all RVOTR group patients. The pulmonary annular motion parameters in the PVS group had significant correlations with both global RV and RVOT performance. The TAP group showed significant correlations between RVOT function and pulmonary annular motion. The Rastelli group showed almost no significant correlations between RV/RVOT function and tissue Doppler parameters. Pulmonary annular motion velocity is a simple, rapid, reproducible, and useful method of assessing RVOT function in children with surgically repaired CHD.

Assessment of pulmonary arterial compliance evaluated using harmonic oscillator kinematics.

We hypothesized that KPA, a harmonic oscillator kinematics-derived spring constant parameter of the pulmonary artery pressure (PAP) profile, reflects PA compliance in pediatric patients. In this prospective study of 33 children (age range = 0.5-20 years) with various cardiac diseases, we assessed the novel parameter designated as KPA calculated using the pressure phase plane and the equation KPA = (dP/dt_max)2/([Pmax - Pmin])/2)2, where dP/dt_max is the peak derivative of PAP, and Pmax - Pmin is the difference between the minimum and maximum PAP. PA compliance was also calculated using two conventional methods: systolic PA compliance (sPAC) was expressed as the stroke volume/Pmax - Pmin; and diastolic PA compliance (dPAC) was determined according to a two-element Windkessel model of PA diastolic pressure decay. In addition, data were recorded during abdominal compression to determine the influence of preload on KPA. A significant correlation was observed between KPA and sPAC (r = 0.52, P = 0.0018), but not dPAC. Significant correlations were also seen with the time constant (τ) of diastolic PAP (r = -0.51, P = 0.0026) and the pulmonary vascular resistance index (r = -0.39, P = 0.0242). No significant difference in KPA was seen between before and after abdominal compression. KPA had a higher intraclass correlation coefficient than other compliance and resistance parameters for both intra-observer and inter-observer variability (0.998 and 0.997, respectively). These results suggest that KPA can provide insight into the underlying mechanisms and facilitate the quantification of PA compliance.

Temporal Sequential Pattern of Right Ventricular Free Wall Contraction in Normal Children.

BACKGROUND: The temporal sequence of right ventricular (RV) deformation is related to RV dysfunction. The sequence of RV free wall contraction was investigated.Methods and Results:In this prospective study, strain profiles using speckle-tracking echocardiography and tissue Doppler-derived pulmonary and tricuspid annular motion were assessed in 60 normal children. Circumferential RV free wall strain of 3 individual segments (anterior, lateral, and inferior) was evaluated. Longitudinal strain was assessed in 3 individual segments (RV outflow tract [RVOT], apical, and RV inflow tract [RVIT]). The isovolumetric contraction time (ICT) and the time interval between the onset of the QRS wave to the peak s' wave were measured for pulmonary and tricuspid annular motion velocities. The time to peak circumferential strain was significantly lower in the anterior than in the lateral and inferior segments (339.1±19.5, 358.3±21.8, and 366.6±22.4 ms, respectively; P<0.0001). Longitudinal deformation of the RVOT segment occurred before the apical and RVIT segments (351.8±23.1, 366.3±20.1, and 369.2±21.3 ms, respectively; P<0.0001). The ICT and the time to peak s' were significantly shorter in pulmonary than in tricuspid annular motion (49.4±10.1 vs 58.0±13.2 ms; and 104.7±12.2 vs. 160.5±27.1 ms; P<0.0001 for each). CONCLUSIONS: Longitudinal deformation of RVOT precedes RVIT. Circumferential deformation occurs in the anterior segment before the lateral and posterior segments. The presence of mechanical time heterogeneity appears important for RV performance.

Noninvasive assessment of pulmonary arterial capacitance by pulmonary annular motion velocity in children with ventricular septal defect.

BACKGROUND: We hypothesized that longitudinal pulmonary arterial deformation during the cardiac cycle reflects pulmonary arterial capacitance. To examine this hypothesis, we assessed whether tissue Doppler-derived pulmonary annular motion could serve as a novel way to evaluate pulmonary arterial capacitance in pediatric patients with ventricular septal defect (VSD). METHODS: In this prospective study, pulmonary annular velocity was measured in children (age, 6 months-5 years) with a preoperative VSD (VSD group, n = 35) and age-matched healthy children (Control group, n = 23). Pulmonary artery capacitance was calculated by two methods. Systolic pulmonary arterial capacitance (sPAC) was expressed as the stroke volume/pulmonary arterial pulse pressure. Diastolic pulmonary arterial capacitance (dPAC) was determined according to a two-element windkessel model of the pulmonary arterial diastolic pressure profile. RESULTS: Pulmonary annular velocity waveforms comprised systolic bimodal (s1' and s2') and diastolic e' and a' waves in all participants. The peak velocities of s1', s2', and e' were significantly lower in the VSD group than in the Control group. On multiple regression analysis, sPAC was an independent variable affecting the peak velocities of the s1', s2', and e' waves (ß = 0.41, 0.62, and 0.35, respectively). The dPAC affected the s1' wave peak velocity (ß = 0.34). The time durations of the s1' and e' waves were independently determined by the sPAC (ß = 0.49 and 0.27). CONCLUSION: Pulmonary annular motion velocity evaluated using tissue Doppler is a promising method of assessing pulmonary arterial capacitance in children with VSD.

Ultrasound follow-up in a patient with intestinal obstruction due to post-traumatic intramural duodenal hematoma.

We report the case of a 7-year-old girl with intestinal obstruction due to post-traumatic intramural duodenal hematoma. She had fallen from the monkey bars the day before presenting to our hospital, and was admitted with signs of abdominal pain, vomiting, and nausea. Abdominal ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) demonstrated a heterogeneous solid mass located within the duodenal wall, compressing the descending part of the duodenum. The inferior vena cava was also compressed by the mass lesion, although no associated symptoms were evident. Based on these findings, the mass lesion was considered to represent intramural hematoma causing intestinal obstruction. She was managed conservatively with total parenteral nutrition. Although CT and MRI are useful for differentiating hematoma from other intestinal tumors, ultrasonography is minimally invasive and easier to perform repeatedly. In case of duodenal hematoma, ultrasonography may be quite helpful for diagnosis and follow-up by monitoring tumor size and characteristics, and the degree of duodenal compression during conservative treatment.

Diverse muscle architecture adaptations in a rabbit tibial lengthening model.

BACKGROUND: during limb lengthening, muscles are thought to increase the number of sarcomeres. However, this adaptation may differ among muscles with diverse architecture. PURPOSE: this study wish to clarify the differences in muscle adaptation in a rabbit model of tibial lengthening. METHODS: twelve rabbits underwent tibial lengthening (0.7 mm/day for 4 weeks), with the contralateral limb serving as a control, and were euthanized after either the lengthening or the consolidation period. Six muscles around the tibia were investigated in terms of muscle belly length, muscle weight, sarcomere length and serial sarcomere number. RESULTS: muscle belly length increased in all the lengthened muscles. No increases in muscle mass were noted. Sarcomere length increased in the ankle plantar-flexors and was kept longer than the optimal sarcomere length after the consolidation period. Nevertheless, significant increases in sarcomere number were observed in two ankle plantar-flexors. CONCLUSION: this study demonstrated that muscle belly length largely adapted to the lengthening. The increase in sarcomere number did not match the increase in muscle belly length. We estimated that elongation of the intramuscular aponeuroses is another mechanism of the adaptation in addition to the increase in sarcomere number.