Survival rate changes in children with congenital diaphragmatic hernia over the past three decades: a nationwide, population-based prospective nested case-control study.

PURPOSE: The survival rate (SR) for neonates born with congenital diaphragmatic hernia (CDH) remains high. Our aim was to investigate the change in SR in children with CDH over the past decades. METHODS: The study was a nationwide, population-based prospective nested case-control study within a cohort of newborn children who was born in Sweden during the observational period from 1st January 1982 to 31st December 2015. RESULTS: In the study period, 4654 (99.6%) control children and 684 children with CDH (70.4%, p < 0.001) were with a survival of 2 years of age. Any patients who were born with CDH had a overall 5.8 times higher chance for not surviving 2 years of age than children without CDH. The SR improved significantly in CDH in the past 3 decades. Significantly higher number of patients were prematurely born in the CDH group than in the controls (23.3 vs 6.1%, p < 0.001). The SR of premature and non-premature born CDH patients has increased significantly over the past 3 decades. CONCLUSION: The SR of CDH patients were significantly increased in the past 3 decades. The 2-year survival remains 5.8 times higher than those who were not born with CDH. These changes were mainly attributed to the improved SR of premature and non-premature born CDH patients.

Predicting neonatal mortality prior to discharge from hospital in prenatally diagnosed left congenital diaphragmatic hernia.

OBJECTIVES: To evaluate the association of standardized prenatal imaging parameters and immediate neonatal variables with mortality prior to discharge in infants with isolated left congenital diaphragmatic hernia (LCDH), and to compare the performance of ultrasound- and magnetic resonance imaging (MRI)-based severity grading for the prediction of neonatal mortality. METHODS: This was a retrospective study of infants with prenatally diagnosed isolated LCDH referred to a single tertiary center between 2008 and 2020. Fetuses with right or bilateral congenital diaphragmatic hernia, additional major structural anomaly or known genetic condition, as well as cases that underwent fetal intervention or declined postnatal intervention, were excluded. Ultrasound and MRI images were reviewed retrospectively. Univariable and multivariable analyses were performed, incorporating prenatal and immediate neonatal factors to analyze the association with neonatal mortality prior to discharge, and a prediction calculator was generated. The performance of ultrasound and that of MRI for the prediction of neonatal mortality were compared. RESULTS: Of 253 pregnancies with fetal CDH, 104 met the inclusion criteria, of whom 77 (74%) neonates survived to discharge. Seventy-five fetuses underwent both prenatal ultrasound and MRI. On multivariable analysis, observed/expected (o/e) lung-to-head ratio and o/e total fetal lung volume were associated independently with neonatal death (adjusted odds ratio, 0.89 (95% CI, 0.83-0.95) and 0.90 (95% CI, 0.84-0.97), respectively), whereas liver position was not. There was no significant difference in predictive performance between using ultrasound and MRI together (area under the receiver-operating-characteristics curve (AUC), 0.85 (95% CI, 0.76-0.93)) compared with using ultrasound alone (AUC, 0.81 (95% CI, 0.72-0.90); P = 0.19). The addition of neonatal parameters (gestational age at birth and small-for-gestational age) did not improve model performance (AUC, 0.87 (95% CI, 0.80-0.95)) compared with the combined ultrasound and MRI model (P = 0.22). There was poor agreement between severity assessment on ultrasound and MRI (Cohen's κ, 0.19). Most discrepancies were seen among cases deemed to be non-severe on ultrasound and severe on MRI, and outcomes were more consistent with MRI-based prognostication. CONCLUSIONS: In fetuses with prenatally diagnosed isolated LCDH, mortality prediction using standardized ultrasound and MRI measurements performed reasonably well. In cases classified as non-severe on ultrasound, MRI is recommended, as it may provide more accurate prognostication and assist in the determination of candidacy for fetal intervention. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Vital Dye Uptake of YO-PRO-1 and DASPEI Depends Upon Mechanoelectrical Transduction Function in Zebrafish Hair Cells.

PURPOSE: Vital dyes allow the visualization of cells in vivo without causing tissue damage, making them a useful tool for studying lateral line and inner ear hair cells in living zebrafish and other vertebrates. FM1-43, YO-PRO-1, and DASPEI are three vital dyes commonly used for hair cell visualization. While it has been established that FM1-43 enters hair cells of zebrafish and other organisms through the mechanoelectrical transduction (MET) channel, the mechanism of entry into hair cells for YO-PRO-1 and DASPEI has not been established despite widespread use. We hypothesize that YO-PRO-1 and DASPEI entry into zebrafish hair cells is MET channel uptake dependent similar to FM1-43. METHODS: To test this hypothesis, we used both genetic and pharmacologic means to block MET channel function. Genetic based MET channel assays were conducted with two different mechanotransduction defective zebrafish lines, specifically the myo7aa-/- loss of function mutant tc320b (p.Y846X) and cdh23-/- loss of function mutant (c.570-571del). Pharmacologic assays were performed with Gadolinium(III) Chloride (Gad(III)), a compound that can temporarily block mechanotransduction activity. RESULTS: Five-day post fertilization (5dpf) myo7aa-/- and cdh23-/- larvae incubated with FM1-43, YO-PRO-1, and DASPEI all showed nearly absent uptake of each vital dye. Treatment of wildtype zebrafish larvae with Gad(III) significantly reduces uptake of FM1-43, YO-PRO-1, and DASPEI vital dyes. CONCLUSION: These results indicate that YO-PRO-1 and DASPEI entry into zebrafish hair cells is MET channel dependent similar to FM1-43. This knowledge expands the repertoire of vital dyes that can be used to assess mechanotransduction and MET channel function in zebrafish and other vertebrate models of hair cell function.

Cadherin 16 promotes sensory gating via the endocrine corpuscles of Stannius.

Sensory thresholds enable animals to regulate their behavioral responses to environmental threats. Despite the importance of sensory thresholds for animal behavior and human health, we do not yet have a full appreciation of the underlying molecular-genetic and circuit mechanisms. The larval zebrafish acoustic startle response provides a powerful system to identify molecular mechanisms underlying establishment of sensory thresholds and plasticity of thresholds through mechanisms like habituation. Using this system, we identify Cadherin 16 as a previously undescribed regulator of sensory gating. We demonstrate that Cadherin 16 regulates sensory thresholds via an endocrine organ, the corpuscle of Stannius (CS), which is essential in zebrafish for regulating Ca2+ homeostasis. We further show that Cadherin 16 regulates whole-body calcium and ultimately behavior through the hormone Stanniocalcin 1L, and the IGF-regulatory metalloprotease, Papp-aa. Finally, we demonstrate the importance of the CS through ablation experiments that reveal its role in promoting normal acoustic sensory gating. Together, our results uncover a previously undescribed brain non-autonomous pathway for the regulation of behavior and establish Ca2+ homeostasis as a critical process underlying sensory gating in vivo.

Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review.

More than 25 years ago, CDH1 pathogenic variants (PVs) were identified as the primary cause of hereditary diffuse gastric cancer (HDGC), an inherited cancer syndrome that increases the lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Since DGC is associated with a poor prognosis, a prophylactic total gastrectomy (PTG) is currently the gold standard for reducing the risk of DGC in CDH1 PV carriers. However, as germline genetic testing becomes more widespread, many CDH1 PV carriers have been identified, including in families with lower penetrance levels or without a history of gastric cancer (GC). When including these families, recent findings suggest that the cumulative lifetime risk of developing advanced DGC is much lower than previously thought and is now estimated to be 13-19%. This lower risk, combined with the fact that around one third of the CDH1 PV carriers decline PTG due to potential lifelong physical and psychological consequences, raises critical questions about the current uniformity in recommending PTG to all CDH1 PV carriers. As a result, there is a growing need to consider alternative strategies, such as endoscopic surveillance. However, despite the currently lower estimated risk of infiltrative (advanced) DGC, almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC. Therefore, the primary goal of surveillance should be to identify atypical, deeper infiltrating lesions rather than every SRC lesion. Understanding the progression from indolent to more infiltrative lesions, and recognizing their endoscopic and histological features, is crucial in deciding the most suitable management option for each individual.

Managing CDH1 Cancer Risks in a Child: Complex Decision Making in a Family With Hereditary Diffuse Gastric Cancer.

Germline pathogenic variants (PVs) in CDH1 cause hereditary diffuse gastric cancer. The management of CDH1 cases with a positive family history includes total prophylactic gastrectomy or intensive surveillance. In this study, we report a 16-year-old boy with intramucosal gastric signet ring cells in the setting of a germline CDH1 PV and a family history of early-onset gastric cancer. The approach to managing both the proband and their 9-year-old sister, who also had the CDH1 PV, presented a challenge to both clinicians and the family. Herein, we present the complexities of managing gastric cancer risk when a CDH1 PV is identified in childhood in the setting of a family history of early-onset gastric cancer.

Mediastinal Shift Index: A Novel Postnatal Measurement of Mediastinal Movement that Predicts Survival in Neonates With Congenital Diaphragmatic Hernia on Extracorporeal Membrane Oxygenation.

PURPOSE: Mediastinal position varies in neonates with congenital diaphragmatic hernia (CDH), reflecting contralateral shift due to mass effect. We aimed to create and validate a postnatal measurement of mediastinal positioning using chest radiographs in neonates with CDH who require extracorporeal membrane oxygenation. METHODS: Chart review identified neonates with CDH who required veno-arterial extracorporeal membrane oxygenation between 2017 and 2022. Mediastinal shift index (MSI) is the ratio of the distance between the venous cannula tip and the contralateral chest wall divided by the total width of the contralateral hemithorax. Three raters completed MSI measurements at designated timepoints: after cannulation, post- CDH repair, and immediately before decannulation. Intraclass correlation coefficients (ICC) assessed inter-rater agreement. Initial MSI and observed/expected lung head ratio (O/E LHR) were correlated and compared between survivors and non-survivors. Receiver operative characteristic (ROC) curve analysis evaluated the ability of MSI and O/E LHR to predict survival. RESULTS: 38 neonates were included. MSI demonstrated excellent agreement (ICC>0.98) amongst raters. Initial MSI and O/E LHR had a moderate positive correlation (Spearman correlation = 0.47, p = 0.014). Initial MSI differed significantly between survivors and non-survivors (0.52 vs. 0.33, p = 0.035) as did O/E LHR (0.36 vs. 0.26, p = 0.036). ROC analysis revealed initial MSI >0.35 was predictive of survival with 73% sensitivity and 70% specificity. CONCLUSION: Mediastinal shift index is reliable and predicted survival with a higher specificity than O/E LHR. Future studies will elucidate the role of trending MSI over a patient's course to inform interventions to optimize mediastinal position.

HEARRING group genetic marker study: genetic background of CI patients.

BACKGROUND: While cochlear implantation (CI) and electric acoustic stimulation (EAS) have a positive outcome in most cases, their effectiveness varies depending on the etiology of the hearing loss. Among the various etiologies, genetic factors are the leading cause of hearing loss and may impact CI and EAS outcomes. AIMS/OBJECTIVES: To reveal the genetic background of the hearing loss in CI/EAS patients in each ethnic population, we undertook a multi-center study involving the genetic testing of hearing loss in CI/EAS patients from 10 centers. MATERIAL AND METHODS: Saliva samples and clinical information for the patients and their family members were obtained and next-generation sequencing analysis using a panel carrying 63 deafness genes was then performed. RESULTS: Genetic testing successfully identified the causative gene variants in 54.5% (48/88) of patients with pre-lingual onset hearing loss (onset under 6 years) and in 12% (12/95) of those with late-onset hearing loss (onset at 6 years or more). CONCLUSIONS AND SIGNIFICANCE: We clearly indicated that genetic factors are the most common cause of hearing loss regardless of ethnic background. Saliva-based genetic testing is a useful tool for multi-center studies seeking to clarify the genetic causes of hearing loss in CI or EAS patients between countries separated by distance.

Congenital diaphragmatic hernia and cleft lip and palate: looking for a common genetic etiology.

PURPOSE: Congenital diaphragmatic hernia (CDH) and cleft lip and/or palate (CL/P) are inborn closure defects. Genetic factors in and outcomes for patients with both anomalies (CDH+CL/P) remain unclear. We aimed to investigate associated genetic aberrations, prevalence of, and outcomes for, CDH+CL/P. METHODS: Data from Congenital Diaphragmatic Hernia Study Group (CDHSG) registry were collected. CL/P prevalence in CDH patients was determined. Genetic abnormalities and additional malformations in CDH+CL/P were explored. Patient characteristics and outcomes were compared between CDH+CL/P and isolated CDH (CDH-) using Fisher's Exact Test for categorical, and t-test or Mann-Whitney U-test for continuous, data. p < 0.05 was considered statistically significant. RESULTS: Genetic anomalies in CDH+CL/P included trisomy 13, 8p23.1 deletion, and Wolf-Hirschhorn syndrome (4p16.3 deletion). CL/P prevalence in CDH was 0.7%. CDH+CL/P had lower survival rates than CDH-, a nearly fourfold risk of death within 7 days, were less supported with extracorporeal life support (ECLS), had higher non-repair rates, and survivors had longer length of hospital stay. CONCLUSION: Genetic anomalies, e.g. trisomy 13, 8p23.1 deletion, and Wolf-Hirschhorn syndrome, are seen in patients with the combination of CDH and orofacial clefts. CL/P in CDH patients is rare and associated with poorer outcomes compared to CDH-, influenced by goals of care decision-making.

Could a Two-Staged Repair Be the Solution to the Dilemma of Repair Timing for Severe Congenital Diaphragmatic Hernia Requiring Extracorporeal Membrane Oxygenation?

PURPOSE OF REVIEW: Congenital diaphragmatic hernia (CDH) remains a significant challenge, particularly in severe cases with persistent pulmonary hypertension (PPHN) and hypoplastic lungs and heart. For patients unresponsive to conventional therapies, ECMO is required. While the surgical repair is relatively simple, determining the optimal timing for surgery in patients requiring ECMO is particularly challenging. This review explores the dilemma of surgical timing and proposes a two-staged approach: a reduction in herniated organs and the creation of a silo to relieve abdominal pressure before initiating ECMO, with defect closure following ECMO decannulation. RECENT FINDINGS: Studies support pre-, on-, and post-ECMO repair, each with its own risks and benefits. Pre-ECMO repair may enhance ECMO efficacy by relieving organ compression but poses risks due to instability. Post-ECMO repair is safer but may result in losing the chance to repair. On-ECMO repair has significant hemorrhage risks, but early repair with careful anticoagulation management is currently recommended. Recently, the author reported a successful case using a two-staged approach-reducing herniated organs and creating a silo before ECMO, followed by defect closure after ECMO decannulation-which suggests a potential alternative strategy for managing severe CDH. SUMMARY: A two-staged approach may offer a solution for severe CDH patients requiring ECMO.

Proteomics and digital subtraction angiography approaches reveal CDH18 as a potential target for therapy of moyamoya disease.

Moyamoya disease, characterized by basal cerebral artery obstruction, was studied for differential protein expression to elucidate its pathogenesis. Proteomic analysis of cerebrospinal fluid from 10 patients, categorized by postoperative angiography into good and poor prognosis groups, revealed 46 differentially expressed proteins. Notably, cadherin 18 (CDH18) was the most significantly upregulated in the good prognosis group. In addition, the expression of cadherin 18 (CDH18) and phenotypic transformation-related proteins were measured by qRT-PCR and western blot. The effects of CDH18 in vascular smooth muscle cells were detected by CCK-8, EdU, transwell and wound healing assays. The overexpression of CDH18 in vascular smooth muscle cells (VSMCs) was found to inhibit proliferation, migration, and phenotypic transformation. These findings suggest CDH18 as a potential therapeutic target in moyamoya disease.

Endoscopic screening for identification of signet ring cell gastric cancer foci in carriers of germline pathogenic variants in CDH1.

To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.

CDH3 Is an Effective Serum Biomarker of Colorectal Cancer Distant Metastasis Patients.

Few robust biomarkers are available for distant metastatic colorectal cancer (CRC) patients. Aberrant high expression of CDH3 has been reported in advanced CRC patients, but the value of CDH3 as a biomarker for the diagnosis and prognosis of distant metastatic CRC patients remains to be evaluated. In this study, we explored the serum levels of CDH3 in different stages of CRC patients and sought to determine whether serum CDH3 serves as an independent biomarker for distant metastatic CRC patients. We analyzed the serum CDH3 levels by ELISA in a cohort of CRCs (n=96) and normal controls (n=28). We compared the serum CDH3 levels between normal controls and different stages of CRCs. As a potential diagnostic marker of distant metastatic CRC, the specificity and sensitivity of serum CDH3 were evaluated. Multivariate analysis was also performed to determine whether serum CDH3 was an independent risk factor. Moreover, the changes of serum CDH3 levels were monitored and analyzed before and after palliative chemotherapy. Serum levels of CDH3, CA24-2, CA19-9, CA72-4, and CEA were significantly elevated in distant metastatic CRCs. CA24-2 (r=0.24, P=0.01), CA19-9 (r=0.20, P=0.03), CA72-4 (r=0.64, P<0.0001), and CEA (r=0.31, P=0.0012) all had a certain correlation with CDH3. After three cycles of palliative chemotherapy, levels of CDH3, CA24-2, CA19-9, CA72-4, and CEA of partial response CRCs were reduced to 38.8% (95% confidence interval [CI]: 30.95%-53.77%), 57.73% (95% CI: 2.085%-73.83%), 50.33% (95% CI: 9.935%-79.42%), 74.74% (95% CI: 25.21%-88.00%), and 59.16% (95% CI: 12.65%-83.56%) of baseline, respectively. The areas under the receiver operating characteristic curves of CDH3, CA24-2, CA19-9, CA72-4, and CEA with chemotherapy response were 0.900, 0.597, 0.635, 0.608, and 0.507, respectively. Serum CDH3 is an effective serum biomarker for the diagnosis of distant metastatic CRCs and monitoring response to palliative chemotherapy in distant metastatic CRCs.

A Systematic Review of Surgical and Pathological Outcomes in Patients With a CDH1 Mutation Undergoing Total Gastrectomy.

BACKGROUND: CDH1 (E-cadherin) genetic mutations are associated with a 30%-70% increased lifetime risk of hereditary diffuse gastric cancer (HDGC). Although prophylactic total gastrectomy (PTG) reduces long-term risk of gastric cancer, the associated morbidity and mortality remain unclear. This systematic review aims to characterise postoperative surgical outcomes in patients undergoing total gastrectomy. METHODS: A systematic literature search was performed for studies reporting endoscopic surveillance, surgical and pathological outcomes for patients with CDH1 mutation undergoing a total gastrectomy. RESULTS: Thirty-nine studies included 1849 patients, of which 96% had a CDH1 (n = 1777) or CTNNA1 (n = 3) mutation. Endoscopy outcomes were reported for 1640 patients. Cancer foci were identified in 32% (n = 523/1640) and 71% of these patients went on to have a total gastrectomy (n = 369/523). The remaining 78% of patients did not have cancer foci detected on endoscopy (n = 1117/1640). Of these patients, 62% underwent a total gastrectomy (n = 688/1117) and 81% were found to have cancer on surgical histology (n = 556/688). Pathological staging was reported for 790 patients undergoing surgery, of which 68% had pT1 disease (n = 537). Postoperative complications were reported for 430 patients across 23 studies, with the most common complications being anastomotic strictures (25%), anastomotic leaks (13%), wound infections (12%) and pulmonary complications (11%). Only one postoperative death was reported within 30 days. CONCLUSION: Rates of early cancers are high in CDH1 patients undergoing PTG, highlighting the need for improvement in reliable endoscopic surveillance. Although postoperative mortality in this surgical cohort remains low, high rates of postoperative complications warrant careful patient counselling.

Notch1 signaling pathway promotes growth and metastasis of gastric cancer via modulating CDH5.

OBJECTIVE: To explore the underlying molecular mechanism of Notch1/cadherin 5 (CDH5) pathway in modulating in cell malignant behaviors of gastric cancer (GC). METHODS: We performed bioinformatic analyses to screen the potential target genes of Notch1 from cadherins in GC. Western blot and RT-PCR were conducted to detect CDH5 expression in GC tissues and cells. We utilized chromatin immunoprecipitation (CHIP) assays to assess the interaction of Notch1 with CDH5 gene. The effects of Notch1/CDH5 axis on the proliferation, invasion, migration and vasculogenic mimicry in GC cells were evaluated by EdU, wound healing, transwell, and tubule formation assays. RESULTS: Significantly increased CDH5 expression was found in GC tissues compared with paracancerous tissues and associated to clinical stage and poor overall survival (OS) in patients with GC. Notch1 positively regulate the expression of CDH5 in GC cells. CHIP assays validated that CDH5 was a direct target of Notch1. In addition, Notch1 upregulation enhanced the proliferation, migration, invasion and vasculogenic mimicry capacity of GC cells, which could be attenuated by CDH5 silencing. CONCLUSIONS: These results indicated Notch1 upregulation enhanced GC malignant behaviors by triggering CDH5, suggesting that targeting Notch1/CDH5 axis could be a potential therapeutic strategy for GC progression.

Beyond Bronchopulmonary Dysplasia: A Comprehensive Review of Chronic Lung Diseases in Neonates.

In neonates, pulmonary diseases such as bronchopulmonary dysplasia and other chronic lung diseases (CLDs) pose significant challenges due to their complexity and high degree of morbidity and mortality. This review discusses the etiology, pathophysiology, clinical presentation, and diagnostic criteria for these conditions, as well as current management strategies. The review also highlights recent advancements in understanding the pathophysiology of these diseases and evolving strategies for their management, including gene therapy and stem cell treatments. We emphasize how supportive care is useful in managing these diseases and underscore the importance of a multidisciplinary approach. Notably, we discuss the emerging role of personalized medicine, enabled by advances in genomics and precision therapeutics, in tailoring therapy according to an individual's genetic, biochemical, and lifestyle factors. We conclude with a discussion on future directions in research and treatment, emphasizing the importance of furthering our understanding of these conditions, improving diagnostic criteria, and exploring targeted treatment modalities. The review underscores the need for multicentric and longitudinal studies to improve preventative strategies and better understand long-term outcomes. Ultimately, a comprehensive, innovative, and patient-centered approach can enhance the quality of care and outcomes for neonates with CLDs.

MED12 Loss-of-Function Variants as a Cause of Congenital Diaphragmatic Hernia in Females With Hardikar Syndrome and Nonspecific Intellectual Disability.

Mediator complex subunit 12 (MED12) is required for the assembly of the kinase module of Mediator, a regulatory complex that controls the formation of the RNA polymerase II-mediated preinitiation complex. MED12-related disorders display unique gender-specific genotype-phenotype associations and include X-linked recessive Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, and nonspecific intellectual disability in males predominantly carrying missense variants, and X-linked dominant Hardikar syndrome and nonspecific intellectual disability in females known to predominantly carry de novo nonsense/frameshift and nonsense/missense variants, respectively. MED12 was previously identified as a low-penetrance candidate gene for non-isolated congenital diaphragmatic hernia (CDH+). At the time, however, there was insufficient evidence to confirm this association. In a clinical database search, we identified 18 individuals who were molecularly diagnosed with MED12-related disorders by exome or genome sequencing, including eight missense, four frameshift, two nonsense, and one splice variant. Nine of these variants have not been previously reported. Two females with nonspecific intellectual disability were found to carry a de novo frameshift variant, indicating that potentially truncating variants causing nonspecific intellectual disability are not limited to nonsense variants. Notably, CDH was reported in three out of seven females with Hardikar syndrome or nonspecific intellectual disability but was not reported in males with MED12-related disorders. These results suggest that pathogenic MED12 variants are a cause of CDH+ in females with Hardikar syndrome and nonspecific intellectual disability.

Insights into E-Cadherin Impairment in CDH1-Unaltered Invasive Lobular Carcinoma: A Comprehensive Bioinformatic Study.

Invasive lobular carcinoma exhibits unique morphological features frequently associated with alterations in CDH1. Although some studies have identified abnormalities in adhesion factors other than E-cadherin, the molecular mechanisms underlying E-cadherin abnormalities in CDH1-unaltered invasive lobular carcinoma remain poorly understood. In this study, we investigated the molecular underpinnings of E-cadherin dysregulation in invasive lobular carcinoma in the absence of CDH1 gene alterations, using comprehensive bioinformatic analyses. We conducted a comparative study of CDH1-mutated and non-mutated invasive lobular carcinoma and evaluated the differences in mRNA levels, reverse-phase protein array, methylation, and miRNAs. We observed that invasive lobular carcinoma cases without CDH1 alterations exhibited a significantly higher incidence of the Claudin-low subtype (p < 0.01). The results of the reverse-phase protein array indicate no significant difference in E-cadherin expression between CDH1-mutated and non-mutated cases. Therefore, abnormalities in E-cadherin production also exist in CDH1 non-mutated invasive lobular carcinoma. Considering that there are no differences in mRNA levels and methylation status, post-translational modifications are the most plausible explanation for the same. Hence, future studies should focus on elucidating the mechanism underlying E-cadherin inactivation via post-translational modifications in CDH1 non-mutated invasive lobular carcinoma.

Right-Sided Congenital Diaphragmatic Hernia With Gut Malrotation: A Rare Case Report.

Congenital diaphragmatic hernia (CDH) is a rare surgical cause of respiratory distress in neonates. CDH is caused by the protrusion of the abdominal contents into the thoracic cavity due to the failure of the pleuroperitoneal canal to close by eight weeks of gestation. We present the case of a full-term, female child, weighing 2.85 kg at birth, born by normal vaginal delivery to a 21-year-old primigravida admitted at our level III neonatal intensive care unit (NICU). Antenatal obstetric ultrasonography suggested duodenal atresia. After birth, the child was found to have right-sided CDH with gut malrotation. Intraoperative laparotomy revealed a right Bochdalek posterolateral defect with herniation of small bowel loops and a portion of the right lobe of the liver into the chest cavity and minimally malrotated cecum in the right iliac fossa (RIF). This case highlights the critical need for early detection and multidisciplinary management of congenital anomalies. Effective management requires a multidisciplinary approach, including prenatal counseling, careful surgical intervention, and intensive neonatal care to optimize respiratory and cardiovascular outcomes for affected infants.

E-cadherin staining in the diagnosis of lobular versus ductal neoplasms of the breast: the emperor has no clothes.

Categorizing breast neoplasia as ductal or lobular is a daily exercise that relies on a combination of histologic and immunohistochemical tools. The historically robust link between loss of the E-cadherin molecule and lobular neoplasia has rendered staining for E-cadherin by immunohistochemistry a staple of this diagnostic process. Unfortunately, discordances between E-cadherin expression and histomorphology, and variations in E-cadherin staining patterns and intensities abound in clinical practice, but are often neglected in favour of a binary interpretation of the E-cadherin result. In this article, we highlight the complexities of E-cadherin expression through a review of the E-cadherin protein and its associated gene (CDH1), the mechanisms leading to aberrant/absent E-cadherin expression, and the implications of these factors on the reliability of the E-cadherin immunohistochemical stain in the classification of ductal versus lobular mammary neoplasia.