Lessons learned from 40 novel PIGA patients and a review of the literature.

OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.

Morphology of the Diaphragm Muscle in Southern Tamandua (Tamandua tetradactyla) and its Importance in Cases of Traumatic Hernia.

The wall of the diaphragm can be affected by changes caused by physical trauma, allowing the passage of viscera between the abdominal cavity and thoracic cavity, thus reducing the space for pulmonary expansion, leading to the formation of hernia and possible death. Thus, we aimed to characterize, size and determine the topography of the diaphragmatic muscle in the Southern Tamandua, since clinical and surgical activities in wild animals have become a reality more and more present in veterinary medicine. We used six adult animals, x-rayed and dissected, followed by collection of fragments of muscular portions for histological analysis. Initially we observed that the animals presented 17 thoracic vertebrae, 3 lumbar vertebrae and 5 sacral vertebrae. The diaphragm was conformed by three segments: sternal, costal and right and left diaphragm pillar, with presence of tendinous centre that housed the passage of the caudal vena cava, called foramen of the caudal vena cava. Dorsally to the tendinous centre, already in the muscle portion, we located the esophageal and aortic hiatus. These findings, as well as the microscopic, were equivalent to that found in the general literature also, corroborating with descriptions already carried out in other mammals' diaphragms.

Arterial tortuosity syndrome: 40 new families and literature review.

PURPOSE: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10. METHODS: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-ß signaling with immunohistochemistry for pSMAD2 and CTGF. RESULTS: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-ß signaling. CONCLUSION: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis.

Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.

Diprosopus: Systematic review and report of two cases.

BACKGROUND: Diprosopus is a subtype of symmetric conjoined twins with one head, facial duplication and a single trunk. Diprosopus is a very rare congenital anomaly. METHODS: This is a systematic review of published cases and the presentation of two new cases born in Argentina. We estimated the prevalence of conjoined twins and diprosopus using data from the National Network of Congenital Anomalies of Argentina (RENAC). RESULTS: The prevalence of conjoined twins in RENAC was 19 per 1,000,000 births (95% confidence interval, 12-29). Diprosopus prevalence was 2 per 1,000,000 births (95% confidence interval, 0.2-6.8). In the systematic review, we identified 31 diprosopus cases. The facial structures more frequently duplicated were nose and eyes. Most frequent associated anomalies were: anencephaly, duplication of cerebral hemispheres, craniorachischisis, oral clefts, spinal abnormalities, congenital heart defects, diaphragmatic hernia, thoracic and/or abdominal visceral laterality anomalies. One of the RENAC cases and three cases from the literature had another discordant nonmalformed twin. CONCLUSION: The conjoined twins prevalence was similar to other studies. The prevalence of diprosopus was higher. The etiology is still unknown. The presence of visceral laterality anomalies may indicate the link between diprosopus and the alteration or duplication of the primitive node in the perigastrulation period (12-15 days postfertilization). Pregnancies of more than two embryos may be a risk factor for diprosopus. Given the low prevalence of this defect, it would be useful to perform studies involving several surveillance systems and international consortiums. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:993-1007, 2016. © 2016 Wiley Periodicals, Inc.

Anesthetic Challenges and Management in a case of Jarcho-Levin Syndrome with a Neural Tube Defect in a Newborn.

Jarcho-Levin syndrome (JLS) is a rare axial skeletal growth disorder characterized by the presence of multi-level costovertebral malformations, a short neck, a short trunk, and kyphoscoliosis at birth. Neural tube defects appear to be common findings in patients with JLS, and chest hypoplasia frequently leads to respiratory insufficiency and death in early childhood. There have been no previous studies in the literature on the anesthetic management of JLS with neural tube defects and hydrocephalus. Therefore, we have reported a case of JLS in a female full-term newborn, who underwent surgery for myelomeningocele repair and ventriculoperitoneal shunting, with the associated anesthetic challenges and their management.

Time-Trend Analysis of Pulmonary and Diaphragmatic Functionality in Patients with Diaphragmatic Palsy or with Chronic Diaphragmatic Hernia after Surgical Treatment.

Background The aim of this study was to assess long-term pulmonary and diaphragmatic function in two cohorts of patients: the first one affected by diaphragmatic palsy (DP) who underwent plication reinforced by rib-fixed mesh and the second one affected by chronic diaphragmatic hernia (TDH) who underwent surgical reduction and direct suture. Materials and Methods From 1996 to 2011, 10 patients with unilateral DP and 6 patients with TDH underwent elective surgery. Preoperative and long-term (12 months) follow-up assessments were completed in all patients, including pulmonary function tests (PFTs) with diffusion of the lung for carbon monoxide (DLCO), measure of maximum inspiratory pressure (MIP) assessed both in standing and in supine positions, blood gas analysis, chest computed tomographic (CT) scan, and dyspnea score. The Pearson chi-square test, Fisher exact test, and Student t-test were applied when indicated. Results At long-term (12 months) postoperative follow-up, patients operated for DP showed a significant improvement in terms of forced expiratory volume in 1 second (FEV1%) (+ 18.2%, p < 0.001), forced vital capacity (FVC%) (+ 12.8%, p < 0.001), DLCO% (+ 8.3%, p = 0.04), and Po 2 (+ 9.86 mm Hg, p < 0.001) when compared with baseline values. Conversely, when considering the TDH group, only the levels of Po 2 were found to be significantly higher in the postoperative assessment (+ 8.3 mm Hg, p = 0.04). Although MIP increased in both the groups after surgery, a persistent and significant decrease of MIP was detected in TDH group when comparing the levels assessed in supine position with those measured in the standing position (p < 0.001). Medical Research Council dyspnea scale improved in the DP group by a factor of 0.80 (p < 0.001) and in the TDH group by a factor of 0.33 (p = 0.175). Conclusion In patients who underwent surgery for DP, good long-term results may be predicted in terms of pulmonary flows, volumes, and DLCO. Conversely, in patients who underwent elective surgery for chronic TDH, a persistent overall restrictive pattern, lower MIP values in supine position, and paradoxical motion could be expected.

Thoracoscopic Approach for Repair of Diaphragmatic Hernia Occurring After Pediatric Liver Transplant.

Diaphragmatic hernias (DH) occurring after pediatric liver transplantation (LT) are rare. However, such complications have been previously reported in the literature and treatment has always been surgical repair via laparotomy. We report our experience of minimally invasive thoracoscopic approach for repair of DH occurring after LT in pediatric recipients.From April 2010 to December 2014, 7 cases of DH were identified in pediatric LT recipient in Samsung Medical Center. Thoracoscopic repair was attempted in 3 patients. Patients' medical records were retrospectively reviewed.Case 1 was a 12-month-old boy, having received deceased donor LT for biliary atresia (BA) 5 months ago. He presented with dyspnea and left-sided DH was detected. Thoracoscopic repair was successfully done and the boy was discharged at postoperative day 7. Case 2 was a 13-month-old boy, having received deceased donor LT for BA 2 months ago. He presented with vomiting and right-sided DH was detected. Thoracoscopic repair was done along with primary repair of herniated small bowel that was perforated while attempting reduction into the peritoneal cavity. The boy recovered from the surgery without complications and was discharged on the 10th postoperative day. Case 3 was a 43-month-old girl, having received deceased donor LT for Alagille syndrome 28 months ago. She was diagnosed with right-sided DH during steroid pulse therapy for acute rejection. Thoracoscopic repair was attempted but a segment of necrotic bowel was noticed along with bile colored pleural effusion and severe adhesion in the thoracic cavity. She received DH repair with small bowel resection and anastomosis via laparotomy.Thoracoscopic repair was attempted in 3 cases of DH occurring after LT in pediatric recipients. With experience and expertise in pediatric minimally invasive surgery, thoracoscopic approach is feasible in this rare population of patients.

Ventilation causes pulmonary vascular dilation and modulates the NOS and VEGF pathway on newborn rats with CDH.

BACKGROUND/PURPOSE: Congenital diaphragmatic hernia (CDH) is a defect that presents high mortality because of pulmonary hypoplasia and hypertension. Mechanical ventilation changes signaling pathways, such as nitric oxide and VEGF in the pulmonary arterioles. We investigated the production of NOS2 and NOS3 and expression of VEGF and its receptors after ventilation in rat fetuses with CDH. METHODS: CDH was induced by Nitrofen. The fetuses were divided into 6 groups: 1) control (C); 2) control ventilated (CV); 3) exposed to nitrofen (N-); 4) exposed to nitrofen ventilated (N-V), 5) CDH and 6) CDH ventilated (CDHV). Fetuses were harvested and ventilated. We assessed body weight (BW), total lung weight (TLW), TLW/BW ratio, the median pulmonary arteriolar wall thickness (MWT). We analyzed the expression of NOS2, NOS3, VEGF and its receptors by immunohistochemistry and Western blotting. RESULTS: BW, TLW, and TLW/BW ratio were greater on C than on N- and CDH (p<0.05). The MWT was higher in CDH than in CDHV (p<0.001). CDHV showed increased expression of NOS3 (p<0.05) and VEGFR1 (p<0.05), but decreased expression of NOS2 (p<0.05) and VEGFR2 (p<0.001) compared to CDH. CONCLUSION: Ventilation caused pulmonary vasodilation and changed the expression of NOS and VEGF receptors.

Airway and vascular maturation stimulated by tracheal occlusion do not correlate in the rabbit model of diaphragmatic hernia.

BACKGROUND: In animal models of congenital diaphragmatic hernia (CDH), tracheal occlusion (TO) has induced maturation of both airway spaces and vascular structures. Airway and vascular response to TO are assumed to occur in parallel. This study aims to describe and measure the relationship between airway and vascular maturation induced by TO. METHODS: A rabbit model of CDH on gestational day (GD) 23 and TO on GD 28 (term = GD 31) has been used. Two study groups have been defined: DH (diaphragmatic hernia) and TO (DH treated with TO). Animals were collected on GD 30 and blood flow data of the pulmonary artery (pulsatility index (PI) and fractional moving blood volume) were ultrasonographically measured. Lung morphometry consisted of measurements of radial alveolar count (RAC) and arterial muscular thickness. RESULTS: Animals in the DH group (n = 9) had the worst hemodynamic parameters; their lungs were hypoplastic and had the thickest arterial muscular layer. Animals in the TO group (n = 10) had all these effects reversed. There were no correlations among hemodynamic, airway, and vascular parameters, except for RAC and PI (r = -0.528, P = 0.043). CONCLUSION: Airway and vascular maturation after TO appear to be uncorrelated effects. TO could trigger several pathways that separately regulate airway and vascular responses.

Exercise capacity, daily activity, and severity of fatigue in term born young adults after neonatal respiratory failure.

Little is known about long-term effects of neonatal intensive care on exercise capacity, physical activity, and fatigue in term borns. We determined these outcomes in 57 young adults, treated for neonatal respiratory failure; 27 of them had congenital diaphragmatic hernia with lung hypoplasia (group 1) and 30 had normal lung development (group 2). Patients in group 2 were age-matched, with similar gestational age and birth weight, and similar neonatal intensive care treatment as patients in group 1. All patients were born before the era of extracorporeal membrane oxygenation, nitric oxide administration, and high frequency ventilation. Exercise capacity was measured by cycle ergometry, daily physical activity with an accelerometry-based activity monitor, and fatigue by the fatigue severity scale. Median (range) VO2peak in mL/kg/min was 35.4 (19.6-55.0) in group 1 and 37.6 (15.7-52.7) in group 2. There was a between-group P-value of 0.65 for exercise capacity. Daily activity and fatigue were also similar in both groups. So, residual lung hypoplasia did not play an important role in this cohort. There were no significant associations between exercise capacity and perinatal characteristics. Future studies need to elucidate whether exercise capacity is impaired in patients with more severe lung hypoplasia who nowadays survive.

Right ventricular diastolic function measured by tissue Doppler imaging predicts early outcome in congenital diaphragmatic hernia.

OBJECTIVE: To investigate the relationship between early right ventricular function measured by tissue Doppler imaging and early outcome measures in newborn infants with congenital diaphragmatic hernia. DESIGN: Retrospective cohort study. SETTING: Surgical neonatal ICU within a regional pediatric center. PATIENTS: Twenty newborn infants with congenital diaphragmatic hernia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analysis of serial echocardiograms in a cohort of 20 infants with congenital diaphragmatic hernia was done. Tissue Doppler early diastolic and systolic myocardial velocities were measured to assess diastolic and systolic function, respectively, in the basal right ventricle. Pulmonary:systemic peak pressure ratio was estimated using velocity of tricuspid regurgitation. Physiologic, treatment, and early outcome data (duration of respiratory support and length of stay) were recorded. For analysis, duration of respiratory support was selected as the main outcome measure, and infants were divided into two groups based on median duration of respiratory support of 21 days: duration of respiratory support more than 21 days and duration of respiratory support less than 21 days. In 16 surviving infants, mean right ventricular early diastolic myocardial velocity on days 1 and 2 of life correlated with length of stay and duration of respiratory support (r = -0.75, p = 0.002 and r = -0.84, p = 0.0001, respectively). Mean pulmonary:systemic peak pressure ratio on days 1 and 2 of life did not significantly correlate with outcome measures. At receiver-operating characteristics analysis, averaged right ventricular early diastolic myocardial velocity on days 1 and 2 of life of less than 4.6 cm/s predicted duration of respiratory support more than 21 days, with 100% sensitivity and 88% specificity (area under the curve = 0.96, p = 0.002). Right ventricular early diastolic myocardial velocity was significantly lower in the first week of life in the duration of respiratory support more than 21-day group on days 1 and 2 and days 7 and 8. After surgery, right ventricular early diastolic myocardial velocity decreased in the duration of respiratory support more than 21-day group and was significantly lower at days 3 and 4 postoperative. CONCLUSIONS: Tissue Doppler imaging mean right ventricular early diastolic myocardial velocity on days 1 and 2 of life predicted early outcome in surviving infants with congenital diaphragmatic hernia. Right ventricular diastolic dysfunction is associated with disease severity in congenital diaphragmatic hernia. Right ventricular function may be optimized by delaying surgical repair in infants with severe congenital diaphragmatic hernia.

Diagnosis and treatment of pulmonary hypertension in infancy.

Normal pulmonary vascular development in infancy requires maintenance of low pulmonary vascular resistance after birth, and is necessary for normal lung function and growth. The developing lung is subject to multiple genetic, pathological and/or environmental influences that can adversely affect lung adaptation, development, and growth, leading to pulmonary hypertension. New classifications of pulmonary hypertension are beginning to account for these diverse phenotypes, and or pulmonary hypertension in infants due to PPHN, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). The most effective pharmacotherapeutic strategies for infants with PPHN are directed at selective reduction of PVR, and take advantage of a rapidly advancing understanding of the altered signaling pathways in the remodeled vasculature.

Pulmonary artery endothelial cell dysfunction and decreased populations of highly proliferative endothelial cells in experimental congenital diaphragmatic hernia.

Decreased lung vascular growth and pulmonary hypertension contribute to poor outcomes in congenital diaphragmatic hernia (CDH). Mechanisms that impair angiogenesis in CDH are poorly understood. We hypothesize that decreased vessel growth in CDH is caused by pulmonary artery endothelial cell (PAEC) dysfunction with loss of a highly proliferative population of PAECs (HP-PAEC). PAECs were harvested from near-term fetal sheep that underwent surgical disruption of the diaphragm at 60-70 days gestational age. Highly proliferative potential was measured via single cell assay. PAEC function was assessed by assays of growth and tube formation and response to known proangiogenic stimuli, vascular endothelial growth factor (VEGF), and nitric oxide (NO). Western blot analysis was used to measure content of angiogenic proteins, and superoxide production was assessed. By single cell assay, the proportion of HP-PAEC with growth of >1,000 cells was markedly reduced in the CDH PAEC, from 29% (controls) to 1% (CDH) (P < 0.0001). Compared with controls, CDH PAEC growth and tube formation were decreased by 31% (P = 0.012) and 54% (P < 0.001), respectively. VEGF and NO treatments increased CDH PAEC growth and tube formation. VEGF and VEGF-R2 proteins were increased in CDH PAEC; however, eNOS and extracellular superoxide dismutase proteins were decreased by 29 and 88%, respectively. We conclude that surgically induced CDH in fetal sheep causes endothelial dysfunction and marked reduction of the HP-PAEC population. We speculate that this CDH PAEC phenotype contributes to impaired vascular growth in CDH.

[The long-term follow-up of patients with a congenital diaphragmatic hernia: review of the literature]. / Hernie de coupole diaphragmatique: devenir à long terme.

The increased survival rate reached in infants with congenital diaphragmatic hernia (CDH) has shown a concomitant increase in late morbidity. Many complications including pulmonary damage, cardiovascular disease, gastro-intestinal disease, failure to thrive, neurocognitive defects and musculoskeletal abnormalities have been described. Long-term pulmonary morbidity in CDH consists of obstructive and restrictive lung function impairments due to altered lung structure and prolonged ventilatory support. Long-term consequences of pulmonary hypertension are unknown. Gastro-esophageal reflux disease (GERD) is also an important contributor to overall morbidity. Failure to thrive may be caused by GERD, insufficient intake due to oral aversion and increased caloric requirements due to pulmonary morbidity. Neurological outcome is determined by an increased risk of perinatal and neonatal hypoxemia in the first days of life of CDH patients. Many studies have addressed the substantial impact of the health problems described above, on the overall well-being of CDH patients, but only a few studies focus on the health-related quality of life. Considering the scattered data indicating substantial morbidity in long-term survivors of CDH, follow-up studies that systematically assess long-term sequelae are needed. Based on such studies, a more focused approach for routine multidisciplinary follow-up programs could be established. It is the goal of the French Collaborative Network to promote exchange of knowledge, future research and development of treatment protocols.

[Surgery of the diaphragm in the planned thoracic surgery].

122 patients with different diseases of the diaphragm were operated on during 1963-2011 yy. The majority of patients - 76 (62.3%) - had hernias of the weak phrenic zones. 14 (11.5%) and 17 (14.0%) patients had posttraumatic hernia and phrenic relaxation, respectively. The majority of patients had no complaints and the disease was diagnosed on the X-ray examination. Rarely, the compression syndrome, caused by the translocation of the bowel into the thoracic cavity, was registered. That clinically emerged as short breath, heaviness sensation and cardiac rhythm disorders. The worked out reconstructive operations allow to cure such patients with minimal risk.

Functional residual capacity (FRC) and lung clearance index (LCI) in mechanically ventilated infants: application in the newborn with congenital diaphragmatic hernia (CDH).

INTRODUCTION: Functional residual capacity (FRC) and lung clearance index (LCI) are sensitive parameters for early detection of airway disease in infancy. The closed helium dilution method has been applied to assess lung volume and ventilation inhomogeneity (VI) in spontaneously breathing infants. AIMS: The aims of this study were as follows: (1) to assess applicability of the helium gas dilution technique in mechanically ventilated infants with high-risk congenital diaphragmatic hernia (CDH) and to evaluate changes in breathing patterns, lung volume, and VI during the first days of life before and after surgery, and (2) to analyze the possible correlation between changes in lung volume, cerebral hemodynamics, and oxygenation before and after surgical correction of CDH through near-infrared spectroscopy (NIRS) monitoring. METHODS: Lung function tests were performed by multibreath washout traces with an ultrasonic flowmeter and helium gas dilution technique. For all babies, three acceptable FRC and LCI measurements were collected for each test (mean and SD of three measurements were calculated) before surgery (T0), 24 h after surgery (T1) during mechanical ventilation, and within 24 h after extubation in spontaneous breathing (T2). Cerebral and splanchnic hemodynamics were continuously monitored by NIRS during mechanical ventilation to evaluate relationships between changes in lung volume and capillary-venous oxyhemoglobin saturation in tissues. Fraction of inspired oxygen delivered was adjusted to keep oxygen saturation between 90% and 95%. RESULTS: Thirteen CDH infants were studied; median GA = 38 weeks (range 35-41) and median BW = 3000 g (range 1850-3670). FRC and LCI significantly improved after extubation when compared with pre-surgical values. No differences were found in tidal volume (Vt) and NIRS monitoring before and after surgery and after extubation. Neither LCI nor FRC was correlated with NIRS values. CONCLUSIONS: Helium gas dilution technique is an applicable and reliable technique to measure lung volumes and ventilation inhomogeneity also in ventilated infants. NIRS is a non-invasive technique to monitor tissue oxygenation during surgery and mechanical ventilation. In CDH newborns these preliminary data show an improvement in both FRC and LCI after extubation.