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Pulmonary hypertension (PH) and lung hypoplasia are major contributors to morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). The soluble receptor for advanced glycation end products (sRAGE) is a marker of endothelial function and might be associated with disease severity in CDH newborns. In a cohort of 30 CDH newborns and 20 healthy control newborns, sRAGE concentration was measured at birth and at 6 h, 12 h, 24 h, 48 h, and 7–10 days. In healthy newborns, sRAGE was significantly higher at birth and at 48 h compared with CDH newborns (both P < 0.001). Among CDH newborns, sRAGE was significantly lower at birth ( P = 0.033) and at 7–10 days ( P = 0.035) in patients receiving extracorporeal membrane oxygenation (ECMO) compared with patients not receiving ECMO. In contrast, CDH newborns receiving ECMO had significantly higher values at 6 h ( P = 0.001), 12 h ( P = 0.004), and 48 h (0.032). Additionally, sRAGE correlated significantly with PH severity, intensity and duration of mechanical ventilation, and prenatally assessed markers of CDH severity (lung size, liver herniation). The probability to receive ECMO therapy was five times higher in CDH newborns with sRAGE concentrations below the calculated cutoff of 650 pg/ml at birth ( P = 0.002) and nine times higher in CDH newborns with sRAGE concentrations above the cutoff of 3,500 pg/ml at 6 h ( P = 0.001). These findings suggest a potential involvement of sRAGE in the pathophysiology of CDH and may act as a therapeutic target in future treatment approaches.

Funded by National Institute of General Medical Sciences of the National Institutes of Health. Grant Number: P30GM114750 Department of Pediatrics Kilguss Research Core of Women & Infants Hospital of Rhode Island

Scimitar syndrome is a variant of partial anomalous pulmonary venous connection (PAPVC), in which all or part of the right lung is drained by right pulmonary veins that anomalously connect to the inferior vena cava (IVC). The affected lung and its associated airways are often hypoplastic. In addition, aortopulmonary collateral vessels may be involved on the affected side, causing sequestration of that side; such involvement is commonly associated with cardiac defects. We report a case of infantile scimitar syndrome that involved a typical association with the right lung, but with extremely unusual associations with congenital hydrocephalus and heart blockage. The presentation of this case and the role of different diagnostic approaches and management are discussed.

Resumen: Introducción: La hipoplasia pulmonar es la anomalía congénita más frecuentemente asociada a mortalidad perinatal. Material y métodos: Se ha realizado un estudio descriptivo retrospectivo de los casos de hipoplasia pulmonar diagnosticados entre 1995 y 2014 en un hospital universitario de tercer nivel, analizando estudios prenatales, manifestaciones clínicas, pruebas diagnósticas, tratamiento, datos de seguimiento a largo plazo y supervivencia. Resultados: Se identificaron 60 casos, todos con estudio prenatal. Dieciséis recibieron intervención quirúrgica intraútero. La hernia diafragmática congénita fue la entidad más frecuentemente asociada. La manifestación clínica más habitual fue distrés respiratorio neonatal, hipoxemia grave y necesidad de soporte con ventilación mecánica. Se halló un 47% de mortalidad antes de los 60 días de vida y del 75% en las primeras 24 h de vida. Durante el seguimiento de los supervivientes se detectaron episodios de neumonías y bronquitis recidivantes, función pulmonar con patrón obstructivo y aceptable calidad de vida y tolerancia al ejercicio. Conclusiones: La elevada mortalidad neonatal y la importante morbilidad a largo plazo de la hipoplasia pulmonar requieren de un diagnóstico temprano y la intervención de un equipo multidisciplinar especializado. Abstract: Introduction: Pulmonary hypoplasia is the most frequent congenital anomaly associated with perinatal mortality. Material and methods: A retrospective and descriptive review was conducted on cases of patients diagnosed with pulmonary hypoplasia between 1995 and 2014 in a tertiary university hospital. An analysis was made of the prenatal imaging, clinical manifestations, post-natal diagnostic tests, treatment and management, long-term follow up, and survival data. Results: A total of 60 cases were identified, all of them with prenatal imaging. Sixteen patients required foetal surgery. Congenital diaphragmatic hernia was the most frequent diagnosis. Main clinical presentation was respiratory distress with severe hypoxemia and high requirements of mechanical ventilation. Mortality rate was 47% within first 60 days of life, and 75% for the first day of life. Pneumonia and recurrent bronchitis episodes were observed during follow-up. They had a lung function obstructive pattern, and their quality of life and exercise tolerance was good. Conclusions: High neonatal mortality and significant long-term morbidity associated with pulmonary hypoplasia requires an early diagnosis and a specialised multidisciplinary team management.

In severe cases of congenital diaphragmatic hernia (CDH), extracorporeal membrane oxygenation (ECMO) therapy improves survival. Later on, lung morbidity mainly defines development. The purpose of this study was to investigate whether 2-year-old children who need ECMO therapy after delivery have reduced perfusion MRI values as a sign of more severe lung hypoplasia than do children who do not need ECMO.After CDH repair, 38 children underwent dynamic contrast-enhanced MRI with a 3D time-resolved angiography with stochastic trajectories sequence. Fifteen (39%) of the children had received ECMO therapy in the neonatal period. Pulmonary blood flow (PBF), pulmonary blood volume (PBV), and mean transit time were calculated for both lungs. In addition, the ratio of ipsilateral to contralateral lung was calculated for all parameters.In all children, those with and those without ECMO requirement, PBF and PBV were significantly reduced on the ipsilateral side (p0.05). Children who had received ECMO therapy had significantly reduced PBF and PBV values on the ipsilateral side (p0.05) compared with children who had not needed ECMO therapy. The ratios of ipsilateral to contralateral lung for PBF and PBV were also significantly reduced after ECMO.Two-year-old children undergoing CDH repair who had needed neonatal ECMO had significantly reduced perfusion MRI values in the ipsilateral lung in comparison with children who had not needed ECMO. Perfusion MRI measurements are associated with the severity of lung hypoplasia and may therefore be helpful in follow-up investigations.

International audience; Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Scimitar syndrome is a rare congenital heart defect characterized by the combination of vascular, bronchial, and parenchymal malformations. This syndrome includes anomalous right pulmonary venous drainage to the inferior caval vein, hypoplastic right pulmonary artery, right lung hypoplasia and the presence of aortopulmonary collaterals to the right lung. In this study, we evaluate the different surgical approaches of 3 cases with Scimitar syndrome who was corrected successfully.

Rationale: Unilateral hypoplasia of the lung is a rare congenital condition, the mechanism of which is poorly understood. Primary pulmonary hypoplasia occurring in an adult is extremely rare and we present what is probably the first case of a link to a tuberculous pleural effusion in a young woman after childbirth. Patient concerns: Herein, we describe a 31-year-old woman with left lung hypoplasia, and she not only survived to adulthood without problems, but was able to deliver a baby in natural labor. Diagnoses: Left lung hypoplasia, right tuberculous pleural effusion. Interventions: We initiated an anti-tuberculosis treatment for this patient with dose adjustments to her weight of isoniazid (0.3 g/day), rifampicin (0.45 g/day), pyrazinamide (1.5 g/day), and ethambutol (0.75 g/day) for 2 months then isoniazid and rifampicin for another 4 months. Outcomes: Ten days later after beginning therapy, she became afebrile and the pleural effusion resolved. No recurrence was observed during a 6-month follow-up period. Lessons: In clinical practice, if one sees a chest x-ray revealing complete or incomplete opacification of a hemithorax with volume loss and history of repeated respiratory infections, one should consider the possibility of unilateral pulmonary hypoplasia. In such cases, regular close follow-up is important to minimize infections and to prevent development of cor pulmonale or respiratory failure.

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 ( E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH.

Sirenomelia, also known as “mermaid syndrome”, is a rare congenital deformity of uncertain etiology. Sirenomelia is characterized by complete or partial fusion of lower limbs, giving the appearance of the tail of a ‘mermaid’. This syndrome is almost always lethal due to associated congenital visceral abnormalities such as severe lung hypoplasia, and abnormalities of the kidneys, large intestines, and genitalia. We hereby, report a case of sirenomeila due to rarity of this condition and term live birth. Keywords: Caudal regression syndrome, Mermaid syndrome, Newborn, Potter’s facies, Sirenomelia

Unilateral absence of pulmonary artery or pulmonary artery agenesis (UAPA) is a rare congenital malformation that can present as an isolated lesion or in association with other cardiac anomalies. Though congenital, presentation in adults are also reported. Most common presentation in adults is of exercise intolerance. The developing lung on the affected side is hypoplastic. Diagnosis of UAPA is established by imaging methods like CT and MRI . There is no specific treatment for this condition. Treatment depends on patients symptomatology, presence of pulmonary hypertension and collateral circulation. Presence of pulmonary hypertension carries a bad prognosis. We present two adult patients with isolated left sided unilateral pulmonary artery agenesis with ipsilateral lung hypoplasia. The diagnosis was confirmed by CT chest and perfusion scan.

Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality.

Congenital diaphragmatic hernia (CDH) is associated with high mortality due to lung hypoplasia, pulmonary hypertension and co-existent anomalies. This paper highlights recent progress in the perinatal management of CDH and addresses long term outcome issues for survivors indicating the need for multidisciplinary follow up.

The triad of deficient abdominal wall musculature, undescended testes and urinary tract anomalies characterizes the Prune Belly Syndrome (PBS). PBS can be associated with other comorbid urological and non urological conditions. But the full pathogenesis and best treatment is still a matter of debate. A term newborn with a classical PBS (Woodhouse Group 2, Smith and Woodard Group 2) plus lung hypoplasia and funnel chest deformity, a megapenis with a tight phimosis and an obturated anterior urethra is presented. Unfortunately, the baby died in urosepsis and renal failure in his 3rd week of life, despite urine drainage surgery and peritoneal dialysis undertaken. According to the best of our knowledge, this is an unique combination of rare anomalies in PBS patients.

Epub ahead of print, We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH).Background:Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR-200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy.Methods:We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model.Results:We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR-200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-β signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH.Conclusions:Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH., Objective: We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH). Background: Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR-200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy. Methods: We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model. Results: We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR-200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-β signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH. Conclusions: Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH, CCHCSP -Manitoba Lung Association(undefined), info:eu-repo/semantics/acceptedVersion

We explored the possibility of using postmortem MRI for the diagnostics of lung hypoplasia associated with innate diaphragmatic hernia in neonates. The main experimental group consisted of 17 newborns with innate diaphragmatic hernia including 10 non-operated newborns and 7 newborns died after surgery for innate diaphragmatic hernia. It was demonstrated that postmortem MRI allows objective quantitative assessment of the absolute and relative dimensions of the lungs in the thoracic cavity and thereby reveals their hypoplasia, which contributes to the determination of tanatogenesis. Surgery for congenital diaphragmatic hernia leads to an increase in the mass and volume of the lungs, but does not always eliminate their hypoplasia.

Lung hypoplasia, pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia (CDH). This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling, promotes branching, and improves alveolarization in experimental nitrofeninduced CDH.Nitrofen (100 mg) was gavage-fed to pregnant rats at post conception day (PCD) 9 to induce CDH. The rats were randomized to 5 groups: 1) control; 2) nitrofen; 3) nitrofen+sildenafil 100 mg/kg per day at PCD 16-20; 4) nitrofen+bosentan 30 mg/kg per day, at PCD 16-20, and 5) nitrofen+bosentan+sildenafil, same doses and administration days. After cesarean delivery, the offsprings were sacrificed. The diaphragmatic defect and pulmonary hypoplasia were identified, and the lungs were dissected. Arterial wall thickness, bronchiolar density and alveolarization were assessed.The offsprings with CDH were characterized by severe pulmonary hypoplasia (lung weight-to-body weight ratio: 0.0263 [95% confidence interval (CI) 0.0242-0.0278)] in the nitrofen group versus 0.0385 (95% CI 0.0355-0.0424) in the control group (P=0.0001). Pulmonary arterial wall thickness was decreased to 3.0 (95% CI 2.8-3.7) μm in the nitrofen+sildenafil group versus 5.0 (95% CI 4.1-4.9) μm in the nitrofen group (P=0.02). Terminal bronchioles increased to 13.7 (95% CI 10.7-15.2) μm in the nitrofen+bosentan group in contrast to 8.7 (95% CI 7.2-9.4) μm in the nitrofen group (P=0.002). More significant differences (P=0.0001) were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group [14.0 (95% CI 12.5-15.4) μm versus 8.5 (95% CI 7.1-9.3) μm]. Pulmonary arterial wall thickness was also decreased in the former group.In this rat model, antenatal treatment with sildenafil attenuates vascular remodeling. Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.

Antecedentes: La hernia diafragmática congénita es una malformación congénita que afecta a 1 de cada 2 200 recién nacidos. Está asociada a elevada morbimortalidad, principalmente por hipoplasia pulmonar e hipertensión. En la última década la medicina perinatal ha concentrado su interés en la investigación de marcadores prenatales para evaluar la gravedad de la hipoplasia pulmonar, principalmente la relación pulmón cabeza (RPC; LHR, por sus siglas en inglés). Objetivos: Evaluar la RPC y la presencia de hígado en saco herniario en el tórax como predictores de resultados perinatales adversos en fetos con hernia diafragmática aislada. Diseño: Estudio retrospectivo, observacional, analítico, correlacional. Institución: Unidad de Vigilancia Fetal, Hospital Nacional Edgardo Rebagliati Martins, EsSalud, Lima, Perú. Participantes: Gestantes y sus fetos. Intervenciones: Se evaluó todos los casos de pacientes con diagnóstico de hernia diafragmática congénita de sus fetos, entre enero 2005 y diciembre 2011, y que contaran con medición ecográfica del índice pulmón-cabeza (RPC). En caso la paciente tuviera más de una medición del RPC, se consideró la medida tomada con menor edad gestacional. Se precisó la posición del hígado respecto al tórax fetal y si existía o no herniación del hígado en el tórax. En todos los casos, y con consentimiento, se realizó un estudio anatómico detallado y cariotipo fetal. Se consideró la variable supervivencia neonatal a los tres meses de edad y la relación entre la RPC y la presencia del hígado en el tórax fetal con respecto a la supervivencia neonatal. Basado en estudios previos, las pacientes fueron estratificados en dos grupos, en función del valor de la RPC: menor de 1,2 y más de 1,2. Se evaluó las diferencias entre los dos grupos mediante las pruebas chi-cuadrado y t de Student. Principales medidas de resultados: Supervivencia a los tres meses con relación a los marcadores ecográficos. Resultados: Durante el periodo de estudio se encontró 23 casos de hernia diafragmática congénita. Se excluyó 8 casos por presentar otras anormalidades. Solo 15 casos cumplieron los criterios de inclusión. La edad media materna fue 30,2 años. El promedio de edad gestacional en el último estudio ecográfico previo al término de embarazo fue 35 1,2 semanas. Todos los casos tuvieron más de 32 semanas al nacer. La media de edad gestacional al término de embarazo fue 35,7 semanas. Todos los casos terminaron vía cesárea, de acuerdo al protocolo institucional; nueve casos fueron cesárea de urgencia por causas fetales. En cinco casos (33,3%) se detectó herniación intratorácica del hígado y fueron informados como ‘hígado arriba’, de acuerdo al protocolo de la unidad. De ellos, ningún caso sobrevivió al nacer. Ocho casos presentaron RPC >1,2: de ellos sobrevivieron siete (87,5%). Siete otros casos presentaron RPC 1,2 fue mejor indicador de supervivencia neonatal que el ‘hígado abajo’. Conclusiones: La hernia diafragmática congénita con RPC 1.2, and seven survived (87.5%). Seven other cases presented LHR 1.2 was better predictor of neonatal survival than ‘liver down’. Conclusions: Congenital diaphragmatic hernia with LHR

Congenital Diaphragmatic hernia (CDH) is a condition characterized by a defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity interfering with normal development of the lungs. The defect may range from a small aperture in the posterior muscle rim to complete absence of diaphragm. The pathophysiology of CDH is a combination of lung hypoplasia and immaturity associated with persistent pulmonary hypertension of newborn (PPHN) and cardiac dysfunction. Prenatal assessment of lung to head ratio (LHR) and position of the liver by ultrasound are used to diagnose and predict outcomes. Delivery of infants with CDH is recommended close to term gestation. Immediate management at birth includes bowel decompression, avoidance of mask ventilation and endotracheal tube placement if required. The main focus of management includes gentle ventilation, hemodynamic monitoring and treatment of pulmonary hypertension followed by surgery. Although inhaled nitric oxide is not approved by FDA for the treatment of PPHN induced by CDH, it is commonly used. Extracorporeal membrane oxygenation (ECMO) is typically considered after failure of conventional medical management for infants ≥ 34weeks' gestation or with weight >2kg with CDH and no associated major lethal anomalies. Multiple factors such as prematurity, associated abnormalities, severity of PPHN, type of repair and need for ECMO can affect the survival of an infant with CDH. With advances in the management of CDH, the overall survival has improved and has been reported to be 70-90% in non-ECMO infants and up to 50% in infants who undergo ECMO.

Scimitar syndrome is a rare congenital heart defect characterized by anomalous venous drainage of part or all of the right lung to the inferior vena cava, variable systemic blood supply to part of the right lung, dextroposition of the heart, and variable right lung hypoplasia with abnormal right bronchial distribution. A majority of patients with scimitar syndrome presented in association other congenital heart malformations, which contribute to characterize the complex anatomical features of this rare syndrome.

Scimitar syndrome (SS) is a rare congenital heart defect (CHD) characterized by anomalous venous drainage of part or all of the right lung to the inferior vena cava, variable right lung hypoplasia, and variable systemic blood supply to part of the right lung.

Sudden unexpected deaths in neonates usually result from underlying natural disease. We report a case of death in a full term apparently healthy female neonate delivered normally at the -M.I.M.E.R. Medical College hospital, Talegaon, Pune, India, who cried after birth, developed cyanosis and died in a few minutes. The foetus was received in the Dept. of Anatomy, M.I.M.E.R. Medical College for embalming and dissection. Detailed examination and dissection revealed congenital diaphragmatic hernia (CDH) with bilateral lung hypoplasia in the newborn. With the advent of better antenatal diagnosis and neonatal care, the chances of survival in CDH have improved. However, there still remains a significant risk of death and complications in infants with CDH, primarily due to the associated lung hypoplasia. The insult to the lungs is now thought to be an independent, associated finding, due to a common genetic pathway involved in the development of the diaphragm and the lungs, rather than a cause-effect relationship. Keywords - Sudden death, neonate, congenital diaphragmatic hernia, lung hypoplasia, genetic pathway

Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm. It allows abdominal viscera to herniate into the chest and leads to lung hypoplasia. Congenital diaphragmatic hernia is one of the most severe birth defects, with extremely high neonatal mortality. This paper presents a review of the available literature on prenatal diagnosis, management and treatment options for CDH. In selected cases, a prenatal procedure to improve neonatal survival is possible. The authors of this manuscript believe their work might contribute to a better understanding of congenital diaphragmatic hernia and patient selection for the FETO (fetal endoscopic tracheal occlusion) surgery or expectant management.

Kongenitalna dijafragmalna hernija (KDH) razvojni je poremećaj dijafragme u sklopu kojeg dolazi do prolapsa trbušnih organa u prsnu šupljinu. Defekt nastaje zbog poremećaja u razdvajanju prsne i trbušne šupljine tijekom 8. do 10. tjedna gestacije, u isto vrijeme kada se dešavaju ključna zbivanja u razvoju pluća i plućnih krvnih žila. Prolaps trbušnih organa sprječava normalan razvoj pluća i plućnih krvnih žila s posljedičnom parenhimnom i vaskularnom plućnom hipoplazijom. Klinička slika odraz je hipoplazije pluća, malpozicije srca, malrotacije crijeva i otvorenog duktusa Botalli. Defekt se češće nalazi na lijevoj strani i u većini je slučajeva ograničen na posterolateralni dio dijafragme. Incidencija iznosi oko 1 na 2500 živorođenih. Etiologija je nepoznata, ali novija istraživanja ukazuju na postojanje poremećaja retinoičkih signalnih puteva tijekom organogeneze. U 50-60% slučajeva KDH se javlja kao izolirana anomalija. Trećina bolesnika ima pridružene kardiovaskularne anomalije, a manji dio anomalije drugih organa i organskih sustava. KDH se može javiti u sklopu monogenskih bolesti ili kromosomskih aberacija kao što su Turnerov sindrom, trisomija 13, trisomija 18 i Fryns sindrom. Anomalija se u većini slučajeva dijagnosticira prenatalno. U slučajevima izražene plućne hipoplazije moguće je prenatalno liječenje reverzibilnom opstrukcijom fetalne traheje. Postnatalna terapija sastoji se od protektivne mehaničke ventilacije, agresivnog liječenja plućne hipertenzije te kirurškog zatvaranja dijafragmalnog defekta nakon kliničke stabilizacije bolesnika. Iako se preživljenje bolesnika kreće i do 80%, prema epidemiološkim studijama ono iznosi svega 30-40%., Congenital diaphragmatic hernia (CDH) is a developmental defect in the formation of the diaphragm, which allows abdominal organs to herniate into the chest cavity. The defect is caused by a disturbed separation of thoracic and abdominal compartments between weeks 8 and 10 of gestation, in the critical period of bronchial and pulmonary artery branching. Herniated abdominal organs cause impaired lung growth and development, resulting in pulmonary parenchymal and vascular hypoplasia. Most common pathological findings are pulmonary hypoplasia, displacement of the heart, intestinal malrotation and patent ductus arteriosus. A defect occurs more often on the left side and in most cases it is limited to the posterolateral area. CDH occurs with an incidence of ∼ 1 case per 2500 live births. The etiology is unknown although new studies point to disturbance in the retinoid-signaling pathway during organogenesis. In 50-60% of cases, CDH occurs as an isolated finding. About one third of cases have cardiovascular malformations and lesser proportions have other defects. CDH may be associated with single gene disorders or chromosomal aberrations, as in Turner syndrome, trisomy 13, trisomy 18 and Fryns syndrome. Most cases are diagnosed antenatally. Reversible fetoscopic tracheal obstruction may be indicated in cases with severe lung hypoplasia and poor prognosis. The postnatal management consists of „gentle“ ventilation, aggressive treatment of pulmonary hypertension and surgical closure of the diaphragmatic defect when medical stability is achieved. The best hospital centres report 80% survival but it remains around 30-40% in population-based studies.

INTRODUCTION. Congenital diaphragmatic hernia (CDH) combines a congenital malformation of the diaphragm with lung hypoplasia, leading to severe respiratory distress and intractable pulmonary hypertension of the newborn. Despite advances in prenatal diagnosis and neonatal intensive care, CDH is associated with high mortality and devastating morbidities. In the absence of curative treatment, numerous prenatal therapies have been used experimentally with varying success. So far, only fetal tracheal occlusion has been tested in clinical trials, but the consequences for the human lung are poorly known. AIMS. To further characterize the rabbit model of CDH, which was subsequently used to assess the effects of prenatal therapies on airway and pulmonary vascular development, including tracheal occlusion, and two novel approaches, perfluorooctylbromide and an activator of soluble guanylate cyclase (BAY 41–2272), which were given through tracheal instillation.METHODS. After a diaphragmatic incision during the pseudoglandular stage, fetal rabbits were randomized against placebo/sham operation during the saccular stage for tracheal occlusion, perfluorocarbon or BAY 41–2272. At term operated fetuses and controls were subject to evaluation of lung mechanics and/or hemodynamics as well as postmortem lung analyses. Human fetal and neonatal lung tissue, including controls and CDH with tracheal occlusion or expectant management, was analyzed histologically and biochemically.RESULTS. The rabbit model of CDH was characterized by reduced lung volumes and impaired compliance, disorders of elastin deposition within alveolar walls, and downregulation of elastogenesis-related genes. Moreover, this model reproduced features of pulmonary hypertension, including high right ventricular pressure and level of N-terminal-pro-B type natriuretic peptide, remodeling of pulmonary arterioles, decreased alveolar capillary density, and downregulation of vasodilation-related genes. In the rabbit model, lung distension caused by tracheal occlusion improved alveolar formation and elastogenesis, yet without correction of lung mechanical parameters. Tracheal occlusion increased also the expression of other extracellular matrix components, which reflected myofibroblast activity, and reduced the transcription of surfactant-associated proteins. Human neonatal lungs exposed to fetal tracheal occlusion displayed alveolar deposits of collagen and myofibroblasts. In human CDH as well as in the rabbit model of CDH, tracheal occlusion enhanced the pulmonary expression of transforming growth factor-β (TGFβ) and Rho kinase−associated proteins to the detriment of activation of SMAD2/3, which is normally detected in human lungs with advancing gestation. As an alternative to tracheal occlusion, pulmonary distension by perfluorocarbon in the fetal rabbit model of CDH improved lung mechanics and alveolar elastogenesis without transcriptional changes in extracellular matrix, surfactant protein genes or TGFβ. Finally, intratracheal instillation of BAY 41–2272 in the rabbit fetuses with CDH improved hemodynamics, reduced medial hypertrophy of pulmonary arterioles, and increased capillary bed formation by stimulating endothelial cell proliferation.CONCLUSIONS. In the fetal rabbit model of CDH, poor lung function after tracheal occlusion is compatible with activation of TGFβ and imbalance in extracellular matrix and epithelial homeostasis. In human CDH newborns treated by fetal tracheal occlusion, changes in the pulmonary interstitium and impaired TGFβ signaling raise the question of disturbances of postnatal lung development induced by tracheal occlusion. As potential alternatives to tracheal occlusion, prenatal perfluorocarbon improves lung hypoplasia, whereas prenatal BAY 41–2272 attenuates pulmonary hypertension., Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

Skeletal dysplasias are a heterogeneous group of conditions associated with various abnormalities of the skeleton. Some of them are perinatally lethal and can be diagnosed at birth. Lethality is usually due to thoracic underdevelopment and lung hypoplasia. A correct diagnosis and typing of the skeletal disorder is essential for the prognosis as is genetic counseling of the family. A retrospective review of 12 cases of clinico-radiologic diagnosis of skeletal dysplasia, leading to thoracic insufficiency, was conducted. We aimed to make differential diagnosis with special emphasis on radiological findings, and to emphasize the importance of parental counseling.

Congenital diaphragmatic hernia (CDH) is a birth anomaly where there is a defect in the diaphragm. Bochdalek hernia, which involves a posterolateral defect with herniation of the abdominal organs into the thoracic cavity, and a varying degree of lung hypoplasia, accounts for more than 95% of CDH. Non posterolateral hernias are classified into three groups: (a) retrosternal or parasternal (Morgagni-Larrey); (b) other anterior hernias that extend into the anterior portion of the central tendon and are associated with other anomalies; and (c) central hernias, where the defect primarily involves the non-muscular central tendinous part of the diaphragm (1). HISTORY (2-4)

Congenital diaphragmatic hernia (CDH) is a frequent occurring cause of neonatal respiratory distress and occurs 1 in every 3,000 liveborns. Ventilatory support and pharmaceutical treatment of the co-occurring lung hypoplasia and pulmonary hypertension are insufficient in, respectively, 20% of isolated cases and 60% of complex ones leading to early perinatal death. The exact cause of CDH remains to be identified in the majority of human CDH patients and prognostic factors predicting treatment refraction are largely unknown. Their identification is hampered by the multifactorial and heterogenic nature of this congenital anomaly. However, application of high-resolution molecular cytogenetic techniques to patients' DNA now enables detection of chromosomal aberrations in 30% of the patients. Furthermore, recent insights in rodent embryogenesis pointed to a specific disruption of the early mesenchymal structures in the primordial diaphragm of CDH-induced offspring. Together, these data allowed for the introduction of new hypotheses on CDH pathogenesis, although many issues remain to be resolved. In this review, we have combined these new insights and remaining questions on diaphragm pathogenesis with a concise overview of the clinical, embryological, and genetic data available. Pediatr Pulmonol. 2012; 47:534–545. © 2012 Wiley Periodicals, Inc.

Eine 32-jahrige Frau stellt sich in der 30. Schwangerschaftswoche mit Anhydramnion seit der 27. SSW vor. Bei der gezielten sonographischen Fehlbildungsdiagnostik wurden die Verdachtsdiagnosen fetale Nierenagenesie rechts, hypoplastisch-dyplastischen Niere links und Lungenhypoplasie gestellt. Die pranatale Diagnose konnte postpartal von neonatologischer Seite bestatigt werden. Das weibliche Neugeborene war dialyse- und initial auch beatmungspflichtig.