Management and Outcomes of Patients With High-Risk (Congenital Lung Malformation Volume Ratio≥ 1.6) Congenital Lung Malformations.

INTRODUCTION: Congenital lung malformations (CLMs) have a variable natural history. Larger lesions with CLM volume ratio (CVR) ≥ 1.6 are associated with hydrops and fetal mortality. The purpose of this study is to describe the management and outcomes of high-risk (CVR ≥ 1.6) CLM patients. METHODS: A retrospective cohort study was performed for all fetuses evaluated between May 2015 and May 2022. Demographics, prenatal imaging factors, prenatal and postnatal treatment, and outcomes were collected. Descriptive statistics were used to compare the cohorts. RESULTS: Of 149 fetal CLM patients referred to our fetal center, 21/149 (14%) had CVR ≥ 1.6. One CLM patient had intrauterine fetal demise, and 2 patients were lost to follow-up. Of the remaining 18 patients, 11/18 (67%) received maternal steroids. Seven out of 18 patients (39%) underwent resection at the time of delivery with 1/7 (14%) undergoing exutero intrapartum treatment (EXIT)-to-resection, 5/7 (71%) undergoing EXIT-to-exteriorization-to-resection, and 1/7 (14%) undergoing a coordinated delivery to resection; among those undergoing resection, there were 2 fatalities (28.5%). Seven out of 18 (39%) patients required urgent neonatal open lobectomies, and the remaining 4/18 (22%) patients underwent elective thoracoscopic lobectomies with no mortality. CONCLUSIONS: The natural history and outcomes of severe CLM patients remain highly variable. The EXIT-to-exteriorization-to-resection procedure may be a safe and effective approach for a subset of CLM patients with persistent symptoms of mass effect and severe mediastinal shift due to the observed decreased operative time requiring placental support observed in our study.

Novel Clinical Algorithm for Prenatal Monitoring of Congenital Lung Malformations.

INTRODUCTION: Congenital lung malformations (CLMs) are readily identified early in pregnancy with a variable natural history. Monitoring for lesion size and mediastinal shift (MS) is recommended following diagnosis. The purpose of this study is to propose a risk-stratified clinical algorithm for prenatal monitoring of CLM. METHODS: After ethical approval, all fetuses with CLMs evaluated at our fetal center from January 2015 to June 2022 were retrospectively reviewed. Patient demographics, imaging characteristics, and fetal interventions were collected. Lesions were stratified by congenital lung malformation volume ratio (CVR) and the presence of MS. Descriptive statistics and receiver operating characteristic curves were employed in the analysis. RESULTS: We analyzed 111 patients with a mean of 23.4 wk gestational age, a median CVR of 0.5 (interquartile range, 0.3-1.2), and MS in 76 of 111(68%) patients on initial evaluation. Among low-risk patients (CVR ≤1.1), 96% remained low-risk on final evaluation. No patients transitioned from low to high risk during the growth period. Patients with CVR >1.1 often had persistent MS (P < 0.001). Hydrops (5/111, 5%) and fetal intervention (4/111, 4%) only occurred in patients with CVR >1.1 (P < 0.001, P = 0.002) and MS (P = 0.144, P = 0.214). On receiver operating characteristic curve analysis, initial CVR >1.1 had 100% sensitivity and negative predictive value for hydrops and fetal intervention. CONCLUSIONS: CLMs with initial CVR ≤1.1 are low risk for hydrops and fetal intervention. We propose a risk-stratified algorithm for the monitoring of CLM during the growth period based on CVR. While our experience suggests that patients with CLM and MS are at higher risk, the current subjective assessment of MS is not adequately predictive. Incorporating an MS grading system may further refine risk stratification in the management of CLM.

Congenital laryngo-tracheo-esophageal clefts: updates from a quaternary care pediatric airway unit.

PURPOSE: To review the operative techniques, outcomes, and complications following surgery in pediatric patients with laryngo-tracheo-esophageal clefts (LTEC). We describe a new combined approach to treat long LTECs. METHODS: Twenty-five patients underwent surgical repair for LTEC from March 2012 to July 2022 at our hospital. Every patient underwent a diagnostic endoscopy under general anesthesia and spontaneous ventilation to assess the LTEC and synchronous aero-digestive comorbidities/malformations. All patients underwent at least one surveillance endoscopy after the repair at our institution. RESULTS: The patients had multiple other malformations, specifically gastro-intestinal, synchronous airway, and cardiac. The cleft distribution according to the modified Benjamin and Inglis classification was type I (n = 5, 20%), type II (n = 6, 24%), type IIIa (n = 8, 32%), type IIIb (n = 4, 16%), and type IVa (n = 2, 8%). The median follow-up was 44.6 months. Five patients (20%) had undergone previous cleft corrective surgery(s). Seven patients (28%) had partial to complete breakdown of the repair, needing additional intervention(s), and two required a combined-open plus endoscopic repair. Preoperatively, most patients (n = 18, 72%) needed a feeding assistance. At latest follow-up, feeding assistance was weaned off in 13 out of 18 patients, which was a 72% improvement. Ten patients (40%) needed ventilation assistance before the surgery. Post-operatively, ventilatory assistance was weaned off in 6 patients, meaning a 60% improvement. CONCLUSION: LTEC are rare malformations, and their management needs precise diagnosis, appropriate surgical planning, and execution, and dedicated post-operative care. Primary and revision repair of long clefts with tracheal extension may require a combined approach.

Congenital lung malformations: a nationwide survey on management aspects by the Italian Society of Pediatric Surgery.

INTRODUCTION: Over the years, congenital lung malformations (CLM) management remains a controversial topic in pediatric thoracic surgery. The Italian Society of Pediatric Surgery performed a national survey to study the current management variability among centers, trying to define national guidelines and a standardized approach of children with congenital lung malformations. METHODS: Following a National Society approval, an electronic survey including 35 items on post-natal management was designed, focusing on surgical, anesthesiology, radiology and pneumology aspects. The survey was conducted contacting all pediatric surgical units performing thoracic surgery. RESULTS: 39 pediatric surgery units (97.5%) participated in the study. 13 centers (33.3%) were classified as high-volume (Group A), while 26 centers (66.7%) were low volume (Group B). Variances in diagnostic imaging protocols were observed, with Group A performing fewer CT scans compared to Group B (p = 0.012). Surgical indications favored operative approaches for asymptomatic CLM and pulmonary sequestrations in both groups, while a wait-and-see approach was common for congenital lobar emphysema. Surgical timing for asymptomatic CLM differed significantly, with most high-volume centers operating on patients younger than 12 months (p = 0.02). Thoracoscopy was the preferred approach for asymptomatic CLM in most of centers, while postoperative long-term follow-up was not performed in most of the centers. CONCLUSION: Thoracoscopic approach seems uniform in asymptomatic CLM patients and variable in symptomatic children. Lack of uniformity in surgical timing and preoperative imaging assessment has been identified as key areas to establish a common national pattern of care for CLM.

Dysregulation of CITED2 in abnormal lung development in the nitrofen rat model.

PURPOSE: CITED2 both modulates lung, heart and diaphragm development. The role of CITED2 in the pathogenesis of congenital diaphragmatic hernia (CDH) is unknown. We aimed to study CITED2 during abnormal lung development in the nitrofen model. METHODS: Timed-pregnant rats were given nitrofen on embryonic day (E) 9 to induce CDH. Fetal lungs were harvested on E15, 18 and 21. We performed RT-qPCR, RNAscope™ in situ hybridization and immunofluorescence staining for CITED2. RESULTS: We observed no difference in RT-qPCR (control: 1.09 ± 0.22 and nitrofen: 0.95 ± 0.18, p = 0.64) and in situ hybridization (1.03 ± 0.03; 1.04 ± 0.03, p = 0.97) for CITED2 expression in E15 nitrofen and control pups. At E18, CITED2 expression was reduced in in situ hybridization of nitrofen lungs (1.47 ± 0.05; 1.14 ± 0.07, p = 0.0006), but not altered in RT-qPCR (1.04 ± 0.16; 0.81 ± 0.13, p = 0.33). In E21 nitrofen lungs, CITED2 RNA expression was increased in RT-qPCR (1.04 ± 0.11; 1.52 ± 0.17, p = 0.03) and in situ hybridization (1.08 ± 0.07, 1.29 ± 0.04, p = 0.02). CITED2 protein abundance was higher in immunofluorescence staining of E21 nitrofen lungs (2.96 × 109 ± 0.13 × 109; 4.82 × 109 ± 0.25 × 109, p < 0.0001). CONCLUSION: Our data suggest that dysregulation of CITED2 contributes to abnormal lung development of CDH, as demonstrated by the distinct spatial-temporal distribution in nitrofen-induced lungs.

[Chronic cough in adult patients-evidence-based approach]. / Chronischer Husten bei erwachsenen Patienten ­ evidenzbasiertes Vorgehen.

Approximately 10% of the population suffer from a cough lasting longer than 8 weeks. Compared to acute cough, which usually occurs in the context of banal respiratory tract infections, the differential diagnoses of chronic cough require an increased use of diagnostic tests and thus a structured, evidence-based approach according to current international guidelines. A targeted history (smoking status, medication, previous diseases) and ENT status are always followed by chest x­ray and pulmonary function tests before extended diagnostics. In the case of angiotensin-converting enzyme (ACE) inhibitor use and unremarkable physical examination, a drug discontinuation test can be carried out first. In case of inconspicuous findings, a disease entity that can be treated empirically such as upper airway cough syndrome is most likely. If the cough remains unexplained, cough suppression techniques, physiotherapy or speech therapy should be sought before off-label-use of medication.

Congenital Pulmonary Airway Malformations With a Reconsideration and Current Perspective on the Stocker Classification.

Congenital cystic pulmonary lesions (CCPLs) are represented by the following entities: congenital pulmonary airway malformation (CPAM), formerly congenital cystic adenomatoid malformation, extra- and intralobar sequestration (EIS), congenital lobar emphysema (overexpansion), and bronchogenic cyst. The developmental model of CPAM histogenesis by Stocker proposed perturbations designated as CPAM type 0 to type 4 without known or specific pathogenetic mechanisms along the airway from the bronchus to the alveolus. This review highlights mutational events either at the somatic level in KRAS (CPAM types 1 and possibly 3) or germline variants in congenital acinar dysplasia, formerly CPAM type 0, and pleuropulmonary blastoma (PPB), type I, formerly CPAM type 4. The potential for overt malignant progression exists in the case of PPB type I and CPAM type 1 in some cases to well-differentiated mucinous adenocarcinoma. On the other hand, CPAM type 2 is an acquired lesion resulting from interruption in lung development secondary to bronchial atresia. The latter is also regarded as the etiology of EIS whose pathologic features are similar, if not identical, to CPAM type 2. These observations have provided important insights into the pathogenetic mechanisms in the development of the CPAMs since the Stocker classification.

The Proteomic Profile of Interstitial Lung Abnormalities.

Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 × 10-67), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 × 10-40), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 × 10-36) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.

Associations of Monocyte Count and Other Immune Cell Types with Interstitial Lung Abnormalities.

Rationale: Higher blood monocyte counts are associated with worse survival in adults with clinically diagnosed pulmonary fibrosis. Their association with the development and progression of interstitial lung abnormalities (ILA) in humans is unknown. Objectives: We evaluated the associations of blood monocyte count, and other immune cell types, with ILA, high-attenuation areas, and FVC in four independent cohorts. Methods: We included participants with measured monocyte counts and computed tomographic (CT) imaging enrolled in MESA (Multi-Ethnic Study of Atherosclerosis, n = 484), AGES-Reykjavik (Age/Gene Environment Susceptibility Study, n = 3,547), COPDGene (Genetic Epidemiology of COPD, n = 2,719), and the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points, n = 646). Measurements and Main Results: After adjustment for covariates, a 1-SD increment in blood monocyte count was associated with ILA in MESA (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.8), AGES-Reykjavik (OR, 1.2; 95% CI, 1.1-1.3), COPDGene (OR, 1.3; 95% CI, 1.2-1.4), and ECLIPSE (OR, 1.2; 95% CI, 1.0-1.4). A higher monocyte count was associated with ILA progression over 5 years in AGES-Reykjavik (OR, 1.2; 95% CI, 1.0-1.3). Compared with participants without ILA, there was a higher percentage of activated monocytes among those with ILA in MESA. Higher monocyte count was associated with greater high-attenuation areas in MESA and lower FVC in MESA and COPDGene. Associations of other immune cell types were less consistent. Conclusions: Higher blood monocyte counts were associated with the presence and progression of interstitial lung abnormalities and lower FVC.

Reticulation Is a Risk Factor of Progressive Subpleural Nonfibrotic Interstitial Lung Abnormalities.

Rationale: Interstitial lung abnormalities (ILAs) are being increasingly identified in clinical practice. In particular, for subpleural nonfibrotic ILAs, the risk of progression over time and the risk factors for progressive behavior are still largely unknown. Objectives: To determine the age band prevalence of ILAs and the risk of radiological progression of subpleural nonfibrotic ILAs over time in a large health checkup population and to identify how reticulation contributes to the risk of radiological progression. Methods: On the basis of the ILAs definition by the Fleischner Society, low-dose chest computed tomography images from the community-dwelling population who have undergone health checkups were evaluated for ILAs. Multivariable logistic regression was used to assess the risk of radiological progression. Measurements and Main Results: Among 155,539 individuals, 3,300 (2.1%) were confirmed to have ILAs: the vast majority (81.7%) were defined as subpleural nonfibrotic ILAs. The prevalence of ILAs increased linearly with age (P for trend < 0.0001). Of 454 individuals with subpleural nonfibrotic ILAs, 198 (43.6%) had radiological progression over 4 years. The presence of reticulation on initial imaging was an independent predictor of radiological progression (odds ratio, 1.9; 95% confidence interval, 1.2-3.0; P = 0.0040). No difference in radiological progression was identified between subpleural nonfibrotic ILAs with extensive reticulation and subpleural fibrotic ILAs (73.0% vs. 68.8%; P = 0.7626). Conclusions: The prevalence of ILAs increases linearly with age. Nearly half of subpleural nonfibrotic ILAs progress radiologically over 4 years. The presence of reticulation is a risk factor for radiological progression. Subpleural nonfibrotic ILAs with extensive reticulation are likely to be a feature of subpleural fibrotic ILAs.

Autophagy Is Impaired in Fetal Hypoplastic Lungs and Rescued by Administration of Amniotic Fluid Stem Cell Extracellular Vesicles.

Rationale: Pulmonary hypoplasia secondary to congenital diaphragmatic hernia is characterized by reduced branching morphogenesis, which is responsible for poor clinical outcomes. Administration of amniotic fluid stem cell extracellular vesicles (AFSC-EVs) rescues branching morphogenesis in rodent fetal models of pulmonary hypoplasia. Herein, we hypothesized that AFSC-EVs exert their regenerative potential by affecting autophagy, a process required for normal lung development. Objectives: To evaluate autophagy in hypoplastic lungs throughout gestation and establish whether AFSC-EV administration improves branching morphogenesis through autophagy-mediated mechanisms. Methods: EVs were isolated from c-kit+ AFSC-conditioned medium by ultracentrifugation and characterized for size, morphology, and EV markers. Branching morphogenesis was inhibited in rat fetuses by nitrofen administration to dams and in human fetal lung explants by blocking RAC1 activity with NSC23766. The expression of autophagy activators (BECN1 and ATG5) and adaptor (SQSTM1/p62) was analyzed in vitro (rat and human fetal lung explants) and in vivo (rat fetal lungs). Mechanistic studies on rat fetal primary lung epithelial cells were conducted using inhibitors for microRNA-17 and -20a contained in the AFSC-EV cargo and known to regulate autophagy. Measurements and Main Results: Rat and human models of fetal pulmonary hypoplasia showed reduced autophagy mainly at pseudoglandular and canalicular stages. AFSC-EV administration restored autophagy in both pulmonary hypoplasia models by transferring miR-17∼92 cluster members contained in the EV cargo. Conclusions: AFSC-EV treatment rescues branching morphogenesis partly by restoring autophagy through microRNA cargo transfer. This study enhances our understanding of pulmonary hypoplasia pathogenesis and creates new opportunities for fetal therapeutic intervention in congenital diaphragmatic hernia babies.

Short-term outcomes of thoracoscopic versus open lobectomy for congenital lung malformations.

PURPOSE: Thoracoscopic and open approaches for the management of congenital lung malformations (CLM) has been debated. The aim of this study is to compare 30-day outcomes for non-emergent lobectomies in children. METHODS: The National Surgical Quality Improvement Program-Pediatric database was queried for patients undergoing CLM resection from 2013 to 2020. Outcomes were compared by operative technique in an intention-to-treat model and then propensity matched. RESULTS: 2157 patients met inclusion criteria and underwent non-emergent pulmonary lobectomy for CLM. The intended operative approach was thoracoscopic in 57.7% of patients. Patients in the open group compared to the thoracoscopic were more likely to be born premature, have chronic lung disease, require preoperative oxygen support, and be ventilator dependent. After propensity matching, there was no statistically significant difference in 30-day mortality, unplanned readmission, and other complications between the thoracoscopic and open groups. Thoracoscopic approach was associated with a shorter length of stay. The proportion of cases approached via thoracoscopy increased over time from 48.8% in 2013 to 69.9% in 2020. CONCLUSIONS: This large multicenter retrospective matched analysis demonstrates thoracoscopic lobectomy in children has similar favorable 30-day outcomes and shorter length of stay for the non-emergent management of CLM, compared to open thoracotomy. LEVEL OF EVIDENCE: Level III.

A Case Report on Lateral Proboscis: A Rare Congenital Anomaly.

Lateral proboscis is a rare congenital condition characterized by a cylindrical protuberance on the nasofrontal region accompanied by abnormal nasal development on the affected side. We aimed to describe the management of the lateral proboscis in staged repair. A 7-year-old girl came with a tube-like projection on the left medial canthal region and nasal agenesis on the ipsilateral side. She was diagnosed with lateral proboscis, left microphthalmia, lower eye lid coloboma, and asymmetry in the orbital region. The patient has undergone 3 major surgeries at our institution. The first surgery involved the deconstruction of the tube to form the left nasal body and nostril. The second operation involved trimming of the new nose form and the excision of the bony protrusion directly beneath the base of the pedicle through bifrontal craniotomy. The remaining bone defect was closed using a pericranial flap. The orbital floor was reconstructed using titanium mesh. The third operation involved nasal reconstruction using a costal cartilage graft to create a dorsal nasal and alar framework. The patient healed with no complications, had become less reserved and her grades improved significantly after the operation. Further appointments are being scheduled to evaluate growth distortion and the resulting facial asymmetry. Surgical correction will be planned thereafter to further reconstruct the facial features. Evaluation of patient is necessary to explore possible clinical outcomes and corresponding treatment options. Multidisciplinary management is highly recommended, involving plastic surgeons, neurosurgeons, ophthalmologists, pediatricians, and pediatric psychiatrists in order to improve patient's quality of life.

A Single Stage Composite Cleft Septorhinoplasty for Correction of the Mature Unilateral Cleft Nose Deformity - The Gujrat Technique.

OBJECTIVE: To evaluate the results of a single stage composite cleft septorhinoplasty procedure ("The Gujrat Technique") to correct the exaggerated cleft nose deformity after completion of nasal growth in an adult patient cohort. METHODS: Adult patients with a residual unilateral cleft nasal deformity were deemed eligible for the proposed "Gujrat Technique". Over a 10-year period (2007-2017), 96 adult patients underwent this composite cleft septorhinoplasty as a single stage operation. Post-operative nasal symmetry evaluation was undertaken using the validated computer program 'SymNose'. Functional outcome and patient satisfaction were assessed using Nasal Obstruction Symptom Evaluation scale and Rhinoplasty Outcome Evaluation (ROE) questionnaires respectively. Various statistical analysis methods were used to validate the obtained results. RESULTS: Due to poor compliance with follow-up, post-operative assessments were undertaken in only 32 patients. The single group study design using the non-parametric matching pairs Wilcoxon Sign test (p < 0.001) showed overall good to excellent functional and aesthetic outcomes and higher scores of the digital SymNose grading system. There was a significant improvement in ROE scores (from 26.4 ± 2.9 to 85.9 ± 4.7, p < 0.001). There were no major complications or revisions needed in our series. CONCLUSION: The individual components of "The Gujrat Technique" are not novel but their combination in this adult unilateral cleft rhinoplasty cohort has demonstrated a high patient satisfaction with its aesthetic appeal and functional versatility. In the background of limited resources and unpredictable patient follow up, the simplicity, reproducibility and cost effectiveness of this technique make it a practical reconstructive option.

Proboscis Lateralis With Basal Encephalocele: A Report of Clinical Management and Reconstructive Approach.

Proboscis lateralis is a rare craniofacial anomaly in which a rudimentary nasal appendage arises at the medial canthal area. The severity depends on organ involvement, including eyes, nose, cleft lip/palate, and/or concomitant intracranial anomalies. Here, we present a child with proboscis lateralis and associated trans-ethmoidal encephalocele. We suggest doing the preoperative CT and/or MRI to rule out associated intracranial anomalies and reliably preoperative planning tools. Moreover, we proposed an alternative nasal reconstructive technique using a composite graft from the proboscis mass at the same time as encephalocele repair with promising results.

Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic SNV in a lung-specific enhancer in trans to the frameshifting TBX4 variant.

Variants involving TBX4 are associated with a wide variety of disorders, including pulmonary arterial hypertension, ischiocoxopodopatellar syndrome (ICPPS)/small patella syndrome (SPS), lethal lung developmental disorders (LLDDs) in neonates, heart defects, and prenatally lethal posterior amelia with pelvic and pulmonary hypoplasia syndrome. The objective of our study was to elucidate the wide variable phenotypic expressivity and incomplete penetrance in a three-generation family with a truncating variant in TBX4. In addition to exome and genome sequencing analyses, a candidate noncoding regulatory single nucleotide variant (SNV) within the lung-specific TBX4 enhancer was functionally tested using an in vitro luciferase reporter assay. A heterozygous frameshift variant c.1112dup (p.Pro372Serfs*14) in TBX4 was identified in patients with mild interstitial lung disease (1), bronchiolitis obliterans (1), recurrent pneumothorax (1), ICPPS/SPS (1), LLDD (2), and in unaffected individuals (4). In two deceased neonates with LLDD, we identified a noncoding SNV rs62069651-C located in trans to the mutated TBX4 allele that reduced the TBX4 promoter activity by 63% in the reporter assay. Our findings provide a functional evidence for the recently reported model of complex compound inheritance in which both TBX4 coding and in trans noncoding hypomorphic variants in the lung-specific enhancer of TBX4 contribute to LLDD.

Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients.

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.

Maternal Steroids in High-Risk Congenital Lung Malformations.

INTRODUCTION: The purpose of the present study is to evaluate our institutional management of high-risk congenital lung malformations (CLM) with particular consideration of the use of multiple maternal steroid courses and maternal steroids in CLMs with pathologies other than congenital pulmonary airway malformation (CPAM). METHODS: A single-center retrospective review was performed for all fetuses evaluated for CLM who received maternal steroids and/or had a CLM volume ratio (CVR) ≥ 1.6 (2015-2020). Fetuses were categorized as receiving no steroids, single steroid, or multiple steroid courses. Outcomes evaluated included CVR growth rate, resolution of early hydrops, and resolution of hydrops. Results are reported with a descriptive analysis. RESULTS: Nineteen patients were identified who had CVR ≥ 1.6 (single steroid course 9/19, multiple steroid courses 6/19, and no steroids 4/19). A majority (n = 13, 68%) of all lesions had a reduction or no change in CVR between initial and final measurements (single steroid course 7/9, 78%; multiple steroid courses 4/6, 67%). When evaluating by pathology, ≥ 50% of each classification had reduction or no growth of CVR (CPAM 7/11, bronchial atresia 2/4, sequestration 3/3, congenital lobar emphysema 1/1). Seventy five percent (3/4) of lesions with early hydrops had resolution following steroid treatment (single steroid course 1, multiple steroid courses 2). Of the four lesions that had hydrops, only one had resolution after receiving multiple steroid courses. CONCLUSIONS: Our institutional experience reports the majority of CLM (including pathologies other than CPAM) who received steroids had reduction or no change in CVR. Given the low risk-benefit ratio of maternal steroids, physicians could consider use of multiple steroid courses for CLM refractory to a single course.

Fetal lung regeneration using stem cell-derived extracellular vesicles: A new frontier for pulmonary hypoplasia secondary to congenital diaphragmatic hernia.

The poor outcomes of babies with congenital diaphragmatic hernia (CDH) are directly related to pulmonary hypoplasia, a condition characterized by impaired lung development. Although the pathogenesis of pulmonary hypoplasia is not fully elucidated, there is now evidence that CDH patients have missing or dysregulated microRNAs (miRNAs) that regulate lung development. A prenatal therapy that supplements these missing/dysregulated miRNAs could be a strategy to rescue normal lung development. Extracellular vesicles (EVs), also known as exosomes when of small dimensions, are lipid-bound nanoparticles that can transfer their heterogeneous cargo (proteins, lipids, small RNAs) to target cells to induce biological responses. Herein, we review all studies that show evidence for stem cell-derived EVs as a regenerative therapy to rescue normal development in CDH fetal lungs. Particularly, we report studies showing that administration of EVs derived from amniotic fluid stem cells (AFSC-EVs) to models of pulmonary hypoplasia promotes fetal lung growth and maturation via transfer of miRNAs that are known to regulate lung developmental processes. We also describe that stem cell-derived EVs exert effects on vascular remodeling, thus possibly preventing postnatal pulmonary hypertension. Finally, we discuss future perspectives and challenges to translate this promising stem cell EV-based therapy to clinical practice.

Impact of fetal endoscopic tracheal occlusion in fetuses with congenital diaphragmatic hernia and moderate lung hypoplasia.

OBJECTIVE: To assess the effect of Fetal Endoscopic Tracheal Occlusion (FETO) on neonatal survival in fetuses with left congenital diaphragmatic hernia (CDH) and moderate lung hypoplasia. STUDY DESIGN: CDH fetuses with moderate pulmonary hypoplasia (observed/expected lung area to head ratio between 26% and 35%, or between 36% and 45% with liver herniation) were prospectively recruited. Included patients were matched to a control group who were ineligible for FETO. Primary outcomes were survival at 28 days, at discharge, and at 6 months of age, respectively. RESULTS: 58 cases were recruited, 29 treated with FETO and 29 matched controls. Median gestational age (GA) at balloon placement and removal were 29.6 and 33.6 weeks, respectively. FETO group showed significantly lower GA at delivery (35.2 vs. 37.1 weeks, respectively, p < 0.01), higher survival at 28 days (51.7 vs. 24.1%, respectively, p = 0.03), at discharge (48.3 vs. 24.1%, respectively, p = 0.06), and at six months of age (41.4 vs. 24.1%, respectively, p = 0.16), and significantly lower length of ventilatory support (17.8 vs. 32.3 days, p = 0.01) and NICU stay (34.2 vs. 58.3 days, p = <0.01) compared to controls. CONCLUSION: FETO was associated with a non-significant increase in survival and significantly lower neonatal respiratory morbidity among CDH fetuses with moderate lung hypoplasia.