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American Journal of Human Genetics Oct 2023Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We...
Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.
Topics: Adult; Humans; Male; Animals; Mice; Hernias, Diaphragmatic, Congenital; Actins; Mutation, Missense; Osteoporosis
PubMed: 37751738
DOI: 10.1016/j.ajhg.2023.09.002 -
Ultrasound in Obstetrics & Gynecology :... Sep 2023To develop a core set of prenatal and neonatal outcomes for clinical studies evaluating perinatal interventions for congenital diaphragmatic hernia, using a validated... (Review)
Review
OBJECTIVE
To develop a core set of prenatal and neonatal outcomes for clinical studies evaluating perinatal interventions for congenital diaphragmatic hernia, using a validated consensus-building method.
METHODS
An international steering group comprising 13 leading maternal-fetal medicine specialists, neonatologists, pediatric surgeons, patient representatives, researchers and methodologists guided the development of this core outcome set. Potential outcomes were collected through a systematic review of the literature and entered into a two-round online Delphi survey. A call was made for stakeholders with experience of congenital diaphragmatic hernia to review the list and score outcomes based on their perceived relevance. Outcomes that fulfilled the consensus criteria defined a priori were discussed subsequently in online breakout meetings. Results were reviewed in a consensus meeting, during which the core outcome set was defined. Finally, the definitions, measurement methods and aspirational outcomes were defined in online and in-person definition meetings by a selection of 45 stakeholders.
RESULTS
Overall, 221 stakeholders participated in the Delphi survey and 198 completed both rounds. Fifty outcomes met the consensus criteria and were discussed and rescored by 78 stakeholders in the breakout meetings. During the consensus meeting, 93 stakeholders agreed eventually on eight outcomes, which constituted the core outcome set. Maternal and obstetric outcomes included maternal morbidity related to the intervention and gestational age at delivery. Fetal outcomes included intrauterine demise, interval between intervention and delivery and change in lung size in utero around the time of the intervention. Neonatal outcomes included neonatal mortality, pulmonary hypertension and use of extracorporeal membrane oxygenation. Definitions and measurement methods were formulated by 45 stakeholders, who also added three aspirational outcomes: duration of invasive ventilation, duration of oxygen supplementation and use of pulmonary vasodilators at discharge.
CONCLUSIONS
We developed with relevant stakeholders a core outcome set for studies evaluating perinatal interventions in congenital diaphragmatic hernia. Its implementation should facilitate the comparison and combination of trial results, enabling future research to better guide clinical practice. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Pregnancy; Female; Infant, Newborn; Child; Humans; Hernias, Diaphragmatic, Congenital; Research Design; Prenatal Care; Obstetrics; Outcome Assessment, Health Care; Delphi Technique; Treatment Outcome
PubMed: 37099763
DOI: 10.1002/uog.26235 -
NeoReviews Nov 2023Congenital diaphragmatic hernia (CDH) results in abdominal contents entering the thoracic cavity, affecting both cardiac and pulmonary development. Maldevelopment of the...
Congenital diaphragmatic hernia (CDH) results in abdominal contents entering the thoracic cavity, affecting both cardiac and pulmonary development. Maldevelopment of the pulmonary vasculature occurs within both the ipsilateral lung and the contralateral lung. The resultant bilateral pulmonary hypoplasia and associated pulmonary hypertension are important components of the pathophysiology of this disease that affect outcomes. Despite prenatal referral to specialized high-volume centers, advanced ventilation strategies, pulmonary hypertension management, and the option of extracorporeal membrane oxygenation, overall CDH mortality remains between 25% and 30%. With increasing recognition that cardiac dysfunction plays a large role in morbidity and mortality in patients with CDH, it becomes imperative to understand the different clinical phenotypes, thus allowing for individual patient-directed therapies. Further research into therapeutic interventions that address the cardiopulmonary interactions in patients with CDH may lead to improved morbidity and mortality outcomes.
Topics: Pregnancy; Female; Humans; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Lung
PubMed: 37907403
DOI: 10.1542/neo.24-11-e720 -
The Veterinary Clinics of North... Jul 2024Hiatal hernias result from a widening of the esophageal hiatus that leads to the displacement of the lower esophageal sphincter and stomach into the thoracic cavity.... (Review)
Review
Hiatal hernias result from a widening of the esophageal hiatus that leads to the displacement of the lower esophageal sphincter and stomach into the thoracic cavity. Clinical signs of regurgitation, gastroesophageal reflux, and esophagitis are managed medically, but surgery is considered in those that fail to respond to medical management. Surgical treatment of hiatal hernia can be performed laparoscopically. Treatment involves plication of the esophageal hiatus, as well as a pexy of the esophagus to the diaphragm and a left sided gastropexy. Outcomes with laparoscopic treatment are comparable to those performed via laparotomy.
Topics: Hernia, Hiatal; Laparoscopy; Animals; Dog Diseases; Dogs; Cats; Cat Diseases
PubMed: 38503597
DOI: 10.1016/j.cvsm.2024.02.009 -
BJOG : An International Journal of... Oct 2023To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging...
OBJECTIVES
To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival.
DESIGN
Retrospective cohort study.
SETTING
Multicentre study in large referral centres.
POPULATION
Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020.
METHODS
Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung-to-head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV).
MAIN OUTCOME MEASURE
Survival to discharge.
RESULTS
We included 53 infants born at 30 (interquartile range 29 -31 ) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left-sided CDH and 33% (2/6) in right-sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left-sided CDH and 25% (2/8) in right-sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07-1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88-1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13).
CONCLUSIONS
In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Hernias, Diaphragmatic, Congenital; Infant, Premature; Retrospective Studies; Ultrasonography, Prenatal; Survival Analysis; Gestational Age; Treatment Outcome; Male
PubMed: 37069727
DOI: 10.1111/1471-0528.17497 -
The Journal of Pediatrics Aug 2023To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic...
OBJECTIVE
To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH).
STUDY DESIGN
A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores.
RESULTS
Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded.
CONCLUSIONS
In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.
Topics: Humans; Antihypertensive Agents; Epoprostenol; Male; Female; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Retrospective Studies; Infant, Newborn; Natriuretic Peptide, Brain; Treatment Outcome
PubMed: 37059388
DOI: 10.1016/j.jpeds.2023.113420 -
Thoracic Surgery Clinics May 2024The diaphragm is a musculoaponeurotic structure separating the thoracic and abdominal cavities. It plays important roles in both respiration and maintaining...
The diaphragm is a musculoaponeurotic structure separating the thoracic and abdominal cavities. It plays important roles in both respiration and maintaining gastrointestinal function. A careful consideration of anatomy should be taken during surgical procedures to minimize injury to this crucial organ.
Topics: Humans; Diaphragm
PubMed: 38705658
DOI: 10.1016/j.thorsurg.2024.01.002 -
Clinics in Perinatology Mar 2024This review provides a comprehensive summary of the current understanding of pulmonary hypertension (PH) in congenital diaphragmatic hernia, outlining the underlying... (Review)
Review
This review provides a comprehensive summary of the current understanding of pulmonary hypertension (PH) in congenital diaphragmatic hernia, outlining the underlying pathophysiologic mechanisms, methods for assessing PH severity, optimal management strategies, and prognostic implications.
Topics: Humans; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Lung; Prognosis; Severity of Illness Index
PubMed: 38325939
DOI: 10.1016/j.clp.2023.10.001 -
Thoracic Surgery Clinics May 2024The diaphragm is a critical musculotendinous structure that contributes to respiratory function. Disorders of the diaphragm are rare and diagnostically challenging.... (Review)
Review
The diaphragm is a critical musculotendinous structure that contributes to respiratory function. Disorders of the diaphragm are rare and diagnostically challenging. Herein, the author reviews the radiologic options for the assessment of the diaphragm.
Topics: Humans; Diaphragm; Magnetic Resonance Imaging; Tomography, X-Ray Computed; Hernia, Diaphragmatic
PubMed: 38705659
DOI: 10.1016/j.thorsurg.2024.02.002 -
The Journal of Trauma and Acute Care... Dec 2023Costal margin rupture (CMR) injuries are under-diagnosed and inconsistently managed, while carrying significant symptomatic burden. We hypothesized that the Sheffield...
BACKGROUND
Costal margin rupture (CMR) injuries are under-diagnosed and inconsistently managed, while carrying significant symptomatic burden. We hypothesized that the Sheffield Classification system of CMR injuries would relate to injury patterns and management options.
METHODS
Data were collected prospectively between 2006 and 2023 at a major trauma center in the United Kingdom. Computed tomography scans were interrogated and injuries were categorized according to the Sheffield Classification. Clinical, radiologic, management and outcome variables were assessed.
RESULTS
Fifty-four patients were included in the study. Intercostal hernia (IH) was present in 30 patients and associated with delayed presentation ( p = 0.004), expulsive mechanism of injury (i.e. such as occurs with coughing, sneezing, or retching), higher body mass index ( p < 0.001), and surgical management ( p = 0.02). There was a bimodal distribution of the level of the costal margin rupture, with IH Present and expulsive mechanism injuries occurring predominantly at the ninth costal cartilage, and IH Absent cases and other mechanisms at the seventh costal cartilage ( p < 0.001). There were correlations between the costal cartilage being thin at the site of the CMR and the presence of IH and expulsive etiology ( p < 0.001). Management was conservative in 23 and surgical in 31 cases. Extrathoracic mesh IH repairs were performed in 3, Double Layer Mesh Repairs in 8, Suture IH repairs in 5, CMR plating in 8, CMR sutures in 2, and associated Surgical Stabilization of Rib Fractures in 11 patients. There was one postoperative death. There were seven repeat surgical procedures in five patients.
CONCLUSION
The Sheffield Classification is associated statistically with presentation, related chest wall injury patterns, and type of definitive management. Further collaborative data collection is required to determine the optimal management strategies.
LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Topics: Humans; Rib Cage; Hernia; Hernia, Hiatal; Hernias, Diaphragmatic, Congenital; Herniorrhaphy; Rupture
PubMed: 37533145
DOI: 10.1097/TA.0000000000004068