scholarly journals Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia

2021 ◽  
Vol 31 (06) ◽  
pp. 472-481
Author(s):  
Charlotte Bendixen ◽  
Erwin Brosens ◽  
Wendy Kay Chung
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Genetic Diagnostics ◽  
Molecular Karyotyping ◽  
Mortality And Morbidity ◽  
Diagnostic Strategies ◽  
Counseling And Testing ◽  
Family Based

AbstractCongenital diaphragmatic hernia (CDH) is a relatively common and severe birth defect with variable clinical outcome and associated malformations in up to 60% of patients. Mortality and morbidity remain high despite advances in pre-, intra-, and postnatal management. We review the current literature and give an overview about the genetics of CDH to provide guidelines for clinicians with respect to genetic diagnostics and counseling for families. Until recently, the common practice was (molecular) karyotyping or chromosome microarray if the CDH diagnosis is made prenatally with a 10% diagnostic yield. Undiagnosed patients can be reflexed to trio exome/genome sequencing with an additional diagnostic yield of 10 to 20%. Even with a genetic diagnosis, there can be a range of clinical outcomes. All families with a child with CDH with or without additional malformations should be offered genetic counseling and testing in a family-based trio approach.

scholarly journals Perinatal stabilisation of infants born with congenital diaphragmatic hernia: a review of current concepts

2020 ◽  
Vol 105 (4) ◽  
pp. 449-454
Author(s):  
Emily J J Horn-Oudshoorn ◽  
Ronny Knol ◽  
Arjan B Te Pas ◽  
Stuart B Hooper ◽  
Suzan C M Cochius-den Otter ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Management Strategies ◽  
Fetal Surgery ◽  
Adverse Outcomes ◽  
Delivery Room ◽  
Treatment Modalities ◽  
Mortality And Morbidity ◽  
Early Predictors ◽  
Stabilisation Period

Congenital diaphragmatic hernia (CDH) is associated with high mortality rates and significant pulmonary morbidity, mainly due to disrupted lung development related to herniation of abdominal organs into the chest. Pulmonary hypertension is a major contributor to both mortality and morbidity, however, treatment modalities are limited. Novel prenatal and postnatal interventions, such as fetal surgery and medical treatments, are currently under investigation. Until now, the perinatal stabilisation period immediately after birth has been relatively overlooked, although optimising support in these early stages may be vital in improving outcomes. Moreover, physiological parameters obtained from the perinatal stabilisation period could serve as early predictors of adverse outcomes, thereby facilitating both prevention and early treatment of these conditions. In this review, we focus on the perinatal stabilisation period by discussing the current delivery room guidelines in infants born with CDH, the physiological changes occurring during the fetal-to-neonatal transition in CDH, novel delivery room strategies and early predictors of adverse outcomes. The combination of improvements in the perinatal stabilisation period and early prediction of adverse outcomes may mitigate the need for specific postnatal management strategies.

Neonatal and fetal therapy of congenital diaphragmatic hernia-related pulmonary hypertension

2021 ◽  
pp. fetalneonatal-2021-322617
Author(s):  
Felix R De Bie ◽  
Catherine M Avitabile ◽  
Luc Joyeux ◽  
Holly L Hedrick ◽  
Francesca M Russo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Future Research ◽  
Fetal Therapy ◽  
Mortality And Morbidity ◽  
Pulmonary Vasodilation ◽  
Experimental Drug ◽  
Therapeutic Mechanisms ◽  
Experimental Treatments

Congenital diaphragmatic hernia (CDH) is a complex malformation characterised by a triad of pulmonary hypoplasia, pulmonary hypertension (PH) and cardiac ventricular dysfunction. Much of the mortality and morbidity in CDH is largely accounted for by PH, especially when persistent beyond the neonatal period and refractory to available treatment. Gentle ventilation, haemodynamic optimisation and pulmonary vasodilation constitute the foundations of neonatal treatment of CDH-related PH (CDH-PH). Moreover, early prenatal diagnosis, the ability to assess severity and the developmental nature of the condition generate the perfect rationale for fetal therapy. Shortcomings of currently available clinical therapies in combination with increased understanding of CDH pathophysiology have spurred experimental drug trials, exploring new therapeutic mechanisms to tackle CDH-PH. We herein discuss clinically available neonatal and fetal therapies specifically targeting CDH-PH and review the most promising experimental treatments and future research avenues.

Congenital Diaphragmatic Hernia: More than Just a Lung Problem

2021 ◽  
Vol 8 (4) ◽  
Author(s):  
Emam D ◽  
◽  
Van der Veeken L ◽  
El Badry A ◽  
Elattar A ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Lung Hypoplasia ◽  
Short Term ◽  
Mortality And Morbidity ◽  
Abdominal Organs ◽  
Increased Risk ◽  
Prenatal Intervention ◽  
The Cost ◽  
Neurodevelopmental Problems

Congenital Diaphragmatic Hernia (CDH) is a rare congenital anomaly characterized by a defect in the diaphragm, which permits abdominal organs to herniate into the thorax. This causes lung hypoplasia and at birth, children with CDH experience respiratory distress and pulmonary hypertension. Despite optimal neonatal treatment, CDH is still associated with a high mortality and morbidity. In severe cases, Fetal Intervention (FETO) may alter the natural course of this disease. Herein we describe the rationale, action mechanism and technique to perform this intervention. Despite hope giving results, this technique remains investigational for left sided CDH. However, an increased survival may come at the cost of increased morbidity. Children born with CDH are at increased risk for long and short-term morbidity, including neurodevelopmental problems. Until now, there are still uncertainties about the severity and prevalence of neurologic morbidity. Furthermore, it remains uncertain if these problems are already present prenatally and if a prenatal intervention influence this.

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

2019 ◽  
Vol 29 (04) ◽  
pp. 317-327
Author(s):  
Lina Antounians ◽  
Rebeca Lopes Figueira ◽  
Lourenço Sbragia ◽  
Augusto Zani
Keyword(s):  
Pulmonary Hypertension ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Vascular Remodeling ◽  
Pulmonary Hypoplasia ◽  
Genetic Alterations ◽  
Diaphragmatic Defect ◽  
Morbidity Rate ◽  
Lung Growth ◽  
Mortality And Morbidity

AbstractCongenital diaphragmatic hernia (CDH) is a devastating disease that still carries a high mortality and morbidity rate. Poor outcomes for fetuses and infants with CDH are mainly related to pulmonary hypoplasia (PH) and pulmonary vascular remodeling that leads to pulmonary hypertension (PHTN). Over the last five decades, research efforts have focused on modeling CDH not only to study the pathophysiology of the diaphragmatic defect, pulmonary hypoplasia, and pulmonary hypertension, but also to identify therapies that would promote lung growth and maturation, and correct vascular remodeling. As CDH is a multifactorial condition whose etiology remains unknown, there is not a single model of CDH, rather several ones that replicate different aspects of this disease. While small animals like the mouse and the rat have mainly been used to uncover biological pathways underlying the diaphragmatic defect and poor lung growth, larger animals like the lamb and the rabbit models have been instrumental for pursuing medical and surgical interventions. Overall, the use of animal models has indeed advanced our knowledge on CDH and helped us test innovative therapeutic options. For example, the lamb model of CDH has been the paradigm for testing fetal surgical procedures, including tracheal occlusion, which has been translated to clinical use. In this review, we outline the induction protocols of CDH in animals with the use of chemicals, dietary changes, genetic alterations, and surgical maneuvers, and we describe the studies that have translated experimental results to the bedside.

scholarly journals Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

2021 ◽  
Vol 22 (12) ◽  
pp. 6353
Author(s):  
Giulia Cannata ◽  
Chiara Caporilli ◽  
Federica Grassi ◽  
Serafina Perrone ◽  
Susanna Esposito
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
De Novo ◽  
Current Knowledge ◽  
Lung Hypoplasia ◽  
Cellular Mechanisms ◽  
Major Life ◽  
Mortality And Morbidity ◽  
Functional Studies ◽  
Life Threatening

Congenital diaphragmatic hernia (CDH) is a relatively common major life-threatening birth defect that results in significant mortality and morbidity depending primarily on lung hypoplasia, persistent pulmonary hypertension, and cardiac dysfunction. Despite its clinical relevance, CDH multifactorial etiology is still not completely understood. We reviewed current knowledge on normal diaphragm development and summarized genetic mutations and related pathways as well as cellular mechanisms involved in CDH. Our literature analysis showed that the discovery of harmful de novo variants in the fetus could constitute an important tool for the medical team during pregnancy, counselling, and childbirth. A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

2007 ◽  
Vol 293 (4) ◽  
pp. L1079-L1087 ◽  
Author(s):  
B. Rhiannon Noble ◽  
Randal P. Babiuk ◽  
Robin D. Clugston ◽  
T. Michael Underhill ◽  
Hui Sun ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Acid Synthesis ◽  
Mortality And Morbidity ◽  
Retinoid Signaling ◽  
Cell Assays ◽  
Series Of Experiments ◽  
Oxidative Effects ◽  
Rate Limiting

Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported.

scholarly journals A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia

2012 ◽  
Vol 158A (12) ◽  
pp. 3137-3147 ◽  
Author(s):  
Cammon B. Arrington ◽  
Steven B. Bleyl ◽  
Nori Matsunami ◽  
Neil E. Bowles ◽  
Tami I. Leppert ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Family Based

scholarly journals NeoAPACHE II. Relationship Between Radiographic Pulmonary Area and Pulmonary Hypertension, Mortality, and Hernia Recurrence in Newborns With CDH

2021 ◽  
Vol 9 ◽  
Author(s):  
Ilaria Amodeo ◽  
Nicola Pesenti ◽  
Genny Raffaeli ◽  
Francesco Macchini ◽  
Valentina Condò ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Secondary Analysis ◽  
Recurrence Risk ◽  
Hernia Recurrence ◽  
Systolic Pulmonary Artery Pressure ◽  
Clinical Trial Registration ◽  
Mortality And Morbidity ◽  
Lung Area

Congenital diaphragmatic hernia is a rare disease with high mortality and morbidity due to pulmonary hypoplasia and pulmonary hypertension. The aim of the study is to investigate the relationship between radiographic lung area and systolic pulmonary artery pressure (sPAP) on the first day of life, mortality, and hernia recurrence during the first year of life in infants with a congenital diaphragmatic hernia (CDH). A retrospective data collection was performed on 77 CDH newborns. Echocardiographic sPAP value, deaths, and recurrence cases were recorded. Lung area was calculated by tracing the lung's perimeter, excluding mediastinal structures, and herniated organs, on the preoperative chest X-ray performed within 24 h after birth. Logistic and linear regression analyses were performed. Deceased infants showed lower areas and higher sPAP values. One square centimeter of rising in the total, ipsilateral, and contralateral area was associated with a 22, 43, and 24% reduction in mortality risk. sPAP values showed a decreasing trend after birth, with a maximum of 1.84 mmHg reduction per unitary increment in the ipsilateral area at birth. Recurrence patients showed lower areas, with recurrence risk decreasing by 14 and 29% per unit increment of the total and ipsilateral area. In CDH patients, low lung area at birth reflects impaired lung development and defect size, being associated with increased sPAP values, mortality, and recurrence risk.Clinical Trial Registration: The manuscript is an exploratory secondary analysis of the trial registered at ClinicalTrials.gov with identifier NCT04396028.

scholarly journals Strategies in Rapid Genetic Diagnostics of Critically Ill Children: Experiences From a Dutch University Hospital

2021 ◽  
Vol 9 ◽  
Author(s):  
Miriam E. Imafidon ◽  
Birgit Sikkema-Raddatz ◽  
Kristin M. Abbott ◽  
Martine T. Meems-Veldhuis ◽  
Morris A. Swertz ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Diagnostic Yield ◽  
Snp Array ◽  
Genetic Diagnosis ◽  
Gene Panel ◽  
University Hospital ◽  
Genetic Diagnostics ◽  
High Yield ◽  
Critically Ill Children ◽  
Genetic Consultation

Background: Genetic disorders are a substantial cause of infant morbidity and mortality and are frequently suspected in neonatal intensive care units. Non-specific clinical presentation or limitations to physical examination can result in a plethora of genetic testing techniques, without clear strategies on test ordering. Here, we review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations.Methods: We retrospectively included all patients admitted to the NICU who received clinical genetic consultation and genetic testing in our University hospital. We documented reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested and their outcomes, as well as the consequences of each (rapid) genetic diagnostic approach. We calculated diagnostic yield and turnaround times (TATs).Results: Of 171 included infants that received genetic consultation 140 underwent genetic testing. As a result of testing as first tier, 13/14 patients received a genetic diagnosis from QF-PCR; 14/115 from SNP-array; 12/89 from NGS testing, of whom 4/46 were diagnosed with a small gene panel and 8/43 with a large OMIM-morbid based gene panel. Subsequent secondary or tertiary analysis and/or additional testing resulted in five more diagnoses. TATs ranged from 1 day (QF-PCR) to a median of 14 for NGS and SNP-array testing, with increasing TAT in particular when many consecutive tests were performed. Incidental findings were detected in 5/140 tested patients (3.6%).Conclusion: We recommend implementing a broad NGS gene panel in combination with CNV calling as the first tier of genetic testing for NICU patients given the often unspecific phenotypes of ill infants and the high yield of this large panel.

scholarly journals Study of Mortality and Morbidity in Neonates with Congenital Diaphragmatic Hernia

2021 ◽  
pp. 277-282
Author(s):  
Zainab Elahi ◽  
Seyyed Abolfazl Afje ◽  
Mohammad Kazemian ◽  
Maryam Shariati ◽  
Naeeme Taslimi Taleghani ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Analytical Study ◽  
Place Of Birth ◽  
Cross Sectional ◽  
Mortality And Morbidity ◽  
Relationship Of ◽  
The Relationship ◽  
Type Of Delivery

Introduction: Congenital diaphragmatic hernia may either lead to death or cause several complications such as increased pulmonary artery pressure. Objective: The present study aimed to compare mortality and morbidity, vasopressor intake, and visceral hernia of CDH neonates with pulmonary hypertension and without pulmonary hypertension in Mahdieh and Mofid hospitals in Tehran. Methods: This cross-sectional analytical study included 56 neonates with congenital diaphragmatic hernia who were admitted to Mofid and Mahdieh Children's Hospitals from 2014 to 2018. The sample size included 56 people selected based on census method. We compared the pulmonary hypertension and non-pulmonary hypertension groups in variables, such as gender, gestational age, birth weight, place of birth, and type of delivery and we examined relationship between pulmonary hypertension and mortality and morbidity and relationship between mortality and vasopressor intake. Results: The OR value was calculated to be 1.106, which is significant at the level of 0.004 (p < 0.01). This finding indicated that the chance of death in the group of infants with severe pulmonary hypertension was increased by 1.106. Also, the relationship of visceral hernia (stomach, intestine, liver, kidney, and spleen) to thorax was examined by logistic regression. Only the OR value of liver hernia (9.42) was significant (p < 0.001), indicating that the chance of death was higher in infants with liver hernias. It also the OR value of dopamine, dobutamine, and milrinone was significant (p < 0.01). Conclusion: In general, the results obtained in our study indicated that the mortality rate in the group of infants with pulmonary hypertension was significantly higher than the group without pulmonary hypertension. Also, liver hernia to thorax was associated with the severity of pulmonary hypertension, and the patients needed medication had a higher chance of death.

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