Microdeletion on Xq27.1 in a Chinese VACTERL-Like Family with Kidney and Anal Anomalies.

Objective: VATER/VACTERL-like association is associated with adverse pregnancy outcomes. Genetic evidence of this disorder is sporadic. In this study, we aimed to provide genetic insights to improve the diagnosis of VACTERL. Methods: We have described a Chinese family in which four members were affected by renal defects or agenesis, anal atresia, and anovaginal fistula, which is consistent with the diagnosis of a VACTERL-like association. Pedigree and genetic analyses were conducted using genome and exome sequencing. Results: Segregation analysis revealed the presence of a recessive X-linked microdeletion in two living affected individuals, harboring a 196-380 kb microdeletion on Xq27.1, which was identified by familial exome sequencing. Genome sequencing was performed on the affected male, confirming a -196 kb microdeletion in Xq27.1, which included a 28% loss of the CDR-1 gene. Four family members were included in the co-segregation analysis, and only VACTERL-like cases with microdeletions were reported in X27.1. Conclusion: These results suggest that the 196-380 kb microdeletion in Xq27.1 could be a possible cause of the VATER/VACTERL-like association. However, further genetic and functional analyses are required to confirm or rule out genetic background as the definitive cause of the VACTERL association.

Impact of preoperative respiratory distress on outcomes of slide tracheoplasty.

OBJECTIVES: Children with congenital tracheal stenosis born in the developing world face a high risk of mortality due to limited access to proper treatment. Patients who required preoperative respiratory support were suspected to have poor survival after slide tracheoplasty; however, this was not clearly demonstrated in the previous studies. This study aims to investigate the impact of preoperative respiratory conditions on outcomes of slide tracheoplasty. METHODS: From 2016 to 2022, children who underwent slide tracheoplasty were retrospectively reviewed. Patients with respiratory distress requiring emergency operations (group A) were compared with patients in stable condition who were scheduled for surgery (group B). RESULTS: Perioperative results revealed that group A (n = 43) had a longer bypass time (P < 0.001), operation time (P = 0.01), postoperative ventilation time (P < 0.001) and length of intensive care unit stay (P = 0.00125) than group B (n = 60). The early mortality rate was 7.8%, and the actuarial 5-year survival rate was 85.3%. The cumulative incidence test revealed that group A was highly significant for overall mortality [sudistribution (SHR) 4.5; 95% confidence interval (CI) 1.23-16.4; P = 0.023]. Risk factors for overall mortality were prolonged postoperative ventilation time (hazard ratio 3.86; 95% CI 1.20-12.48; P = 0.024), bronchial stenosis (hazard ratio 5.77; 95% CI 1.72-19.31; P = 0.004), and preoperative tracheal mucositis (hazard ratio 5.67; 95% CI 1.51-21.31; P = 0.01). Four patients needed reintervention during a follow-up of 28.4 months (interquartile range 15.3-47.3). CONCLUSIONS: Preoperative respiratory distress negatively affected the outcomes of patients who required slide tracheoplasty. Therefore, early detection of congenital tracheal stenosis and aggressive slide tracheoplasty are crucial and obligatory to enhance long-term survival in this lethal congenital airway disease.

Stridor and severe subglottic stenosis: emergency tracheostomy for a neonate with a pinhole trachea.

Congenital subglottic stenosis is a rare but potentially catastrophic condition. In this report, we describe the management of a term neonate who was noted to have biphasic stridor during preassessment for correction of an imperforate anus at 26 hours of life. The neonate was found to have a pinhole trachea secondary to congenital subglottic stenosis. It was impossible to pass an endotracheal tube, so the neonate underwent an emergency surgical tracheostomy with a good outcome. A high index of suspicion led to appropriate steps being taken to safely anaesthetise the neonate.

Reconstructive Surgery of the Laryngotracheal Junction. / Rekonstruktive Chirurgie des laryngo-trachealen Übergangs.

The laryngotracheal junction is an anatomical region with special pathophysiological features. This review presents clinical pictures and malformations that manifest pre-dilectively at this localisation in children and adolescents as well as in adults. The diagnostic procedure is discussed. The possibilities of surgical reconstruction are presented depending on the pathology and age of the patient.

Slide tracheoplasty for congenital tracheal stenosis with involvement of the carina and bronchi: a case report.

A female newborn presented with respiratory distress at birth and was diagnosed with congenital tracheal stenosis. The stenosis was positioned at the distal trachea and compromised the carina and the right and left bronchi. She underwent surgical treatment using circulatory life support with veno-arterial peripheral extracorporeal membrane oxygenation, and the airway was reconstructed using the slide tracheoplasty technique to build a neocarina. The patient had an excellent postoperative course, was successfully weaned from extracorporeal membrane oxygenation and invasive ventilation, and was discharged.

Rare type of tracheal agenesis: Unexpected presentation and immediate consideration of emergent esophageal intubation in neonatal resuscitation program. Case reports and review of the literature.

BACKGROUND: Tracheal agenesis, or tracheal atresia, is a rare congenital anomaly. The presence of a tracheoesophageal fistula (TEF) can help with breathing for newborns with tracheal agenesis. In this article, we presented three unique cases and outcomes of neonates with tracheal agenesis along with a review of the literature. METHODS: This study consisted of a single center case series followed by a review of literature. Case reports were generated using both written and electronic medical records from a single hospital. We summarized three unique cases and outcomes of neonates with tracheal agenesis and performed a review of the literature. RESULTS: We identified three cases of tracheal agenesis presented with severe cyanosis without spontaneous crying upon birth. Experienced pediatricians attempted to intubate the babies but were unsuccessful. Endotracheal tubes were subsequently either accidentally or purposely placed into the esophagus, and oxygen saturation levels improved. This suggested tracheal agenesis with TEF. Two cases underwent surgical intervention after resuscitation with esophageal intubation. CONCLUSION: Esophageal intubation may be a life-sustaining ventilation support for patients with tracheal agenesis and TEF at initial resuscitation. Clinicians should suspect tracheal agenesis when a newborn presents with severe cyanosis and voiceless crying upon birth, and esophageal intubation should be immediately attempted.

VACTERL Association in Patients With Metopic Synostosis: Is There a Link?

VACTERL association is diagnosed based on the non-random co-occurrence of at least 3 out of 6 congenital malformations. The prevalence is thought to be less than 1 in 10,000 to 1 in 40,000. There is no known link between VACTERL association and metopic synostosis in the literature. There were 122 operated cases of metopic synostosis at our institution from 1999 to 2023, with a 2.3:1 male-to-female ratio. The authors describe the co-occurrence of VACTERL association and metopic synostosis in 3 female patients with no identifiable genetic variants. Given that VACTERL association is a diagnosis of exclusion, other rare syndromes were considered but ultimately excluded. This suggests that the co-occurrence of VACTERL association and metopic synostosis is a potentially rare finding, and underlying pathogenic variants are yet to be identified.

[A Uncommon Case: Kasabach-Merritt syndrome with VACTERL Association]. / Ein seltener Fall: Kasabach-Merrit-Syndrom bei VACTERL-Assoziation.

The Kasabach-Merrit syndrome is characterized as the association of a vascular tumor, typically a caposiform hemangioendothelioma and rarely a tufted hemangioma, and a severe consumptive coagulopathy with potentially life-threatening thrombocytopenia. The severe coagulopathy with increased bleeding tendency must be considered before invasive procedures and often requires repeated platelet concentrate substitutions. We present a case of a mature male neonate with Kasabach-Merritt- Syndrome as well as VACTERL association. The VACTERL association describes a group of malformations. Our patient presented with anal atresia combined with tethered cord, and left renal agenesis. The VACTERL association as well as Kasabach-Merritt syndrome were found to be independent pathologies within this patient. A common occurrence or an association with each other has not been described in the literature so far. The challenging coagulation setting due to severe thrombocytopenia complicated the surgical management so far. Finally, mTOR-inhibitor sirolimus was successful in terms of tumor reduction and especially reduction of platelet consumption.

Long- term outcomes of congenital tracheal stenosis after slide tracheoplasty.

PURPOSE: Long-term outcomes of slide tracheoplasty in patients with congenital tracheal stenosis (CTS) have rarely been reported. This study aimed to clarify the long-term outcomes of CTS after slide tracheoplasty. METHODS: The medical records of 33 patients who underwent slide tracheoplasty for CTS at our institution between January 2005 and July 2018, with a follow-up duration > 5 years, were retrospectively reviewed. Patients' characteristics, perioperative condition, operative management, postoperative course, tracheal stenosis rates and growth data, were collected from medical records. RESULTS: The median operative age, minimum tracheal diameter, length of stenosis, duration of hospital stays, and follow-up duration were 8 months, 2.4 mm, 35 mm, 39 days, and 90 months, respectively. One patient died of bleeding in the right lung at 126 months postoperatively. Among the 10 patients requiring postoperative tracheostomy, seven were successfully decannulated at a median of 65 months postoperatively. Tracheal stenosis rates improved postoperatively and were subsequently maintained. Growth impairment and psychomotor delay were observed in 9 and 16 patients, respectively with significant differences found only in cases with genetic abnormalities and not in tracheal stenosis severity. CONCLUSION: Slide tracheoplasty for CTS leads to favorable long-term outcomes. However, various associated anomalies may influence growth and psychomotor development, emphasizing the importance of adequate support.

Bovine Aortic Arch with an Aberrant Left Vertebral Artery in a 3-Year-Old Boy with VACTERL Association: A Case Report.

BACKGROUND The VACTEREL association is an acronym that includes vertebral malformations (V), anal atresia (A), cardiac defects (C), tracheoesophageal fistula (TE), renal defects (R), and limb malformations (L). The aortic arch is the section between the ascending aorta and the descending aorta, where some variants have been described, such as the right aortic arch and bovine aortic arch, among others. A rare presentation in the Natsis classification is the "type X" where a bovine aortic arch and anomalous origin of the left vertebral artery are present. Several structural cardiac malformations have been described in the VACTEREL association. Still, there is no bovine arch or an anomalous left vertebral artery. CASE REPORT Our patient was a 3-year-old boy with a diagnosis of VACTEREL association (type III esophageal atresia, congenital hip dislocation, scoliosis, bilateral clubfoot, and grade IV biliary ureteral reflux). Echocardiographic findings showed changes in the aortic arch, and angiotomography and magnetic resonance angiography showed a bovine aortic arch and an anomalous left vertebral artery. At the time of diagnosis, there were no clinical manifestations or complications due to the anomalous origin of the left vertebral artery. CONCLUSIONS This is the first description of a bovine type X arch according to the Natsis classification in a VACTEREL association. In general, knowledge of the anatomical variants of the aortic arch and the origin and course of the vertebral arteries is of great clinical and interventional importance, mainly because of the risk of cerebral ischemia.

Tracheal agenesis versus tracheal atresia: anatomical conditions, pathomechanisms and causes with a possible link to a novel MAPK11 variant in one case.

BACKGROUND: In this study we aimed to describe the morphological and pathogenetic differences between tracheal agenesis and tracheal atresia, which are not clearly distinguished from each other in the literature, and to contribute thereby to the understanding and management of these conditions. Both tracheal agenesis and tracheal atresia represent rare disorders of still unknown aetiology that cannot be detected by prenatal ultrasound. If the affected foetuses survive until birth these conditions result in respiratory failure and in futile attempts to rescue the infant's life. RESULTS: Autopsies and genetic analyses, including singleton or trio exome sequencing, were performed on five neonates/foetuses with tracheal agenesis and three foetuses with tracheal atresia. Tracheal agenesis was characterized by absence of the sublaryngeal trachea and presence of a bronchooesophageal fistula and by pulmonary isomerism and occurred as an isolated malformation complex or as part of a VACTERL association. Special findings were an additional so-called 'pig bronchus' and a first case of tracheal agenesis with sirenomelia. Tracheal atresia presenting with partial obliteration of its lumen and persistence of a fibromuscular streak resulted in CHAOS. This condition was associated with normal lung lobulation and single, non-VACTERL type malformations. Trio ES revealed a novel variant of MAPK11 in one tracheal agenesis case. Its involvement in tracheooesophageal malformation is herein discussed, but remains hypothetical. CONCLUSION: Tracheal agenesis and tracheal atresia represent different disease entities in terms of morphology, pathogenesis and accompanying anomalies due to a primary developmental and secondary disruptive possibly vascular disturbance, respectively.

SALL4 deletion and kidney and cardiac defects associated with VACTERL association.

Congenital anomalies of the kidney and urinary tract (CAKUT) can be a part of the VACTERL association, which represents the non-random combination of the following congenital anomalies: vertebral anomalies, anal anomalies, cardiac anomalies, tracheal-esophageal anomalies, kidney anomalies, and limb anomalies. VACTERL association is generally considered to be a non-genetic condition. Exceptions include a patient with a heterozygous nonsense SALL4 variant and anal stenosis, tetralogy of Fallot, sacro-vertebral fusion, and radial and thumb anomalies. SALL4 encodes a transcription factor that plays a critical role in kidney morphogenesis. Here, we report a patient with VACTERL association and a heterozygous 128-kb deletion spanning SALL4 who presented with renal hypoplasia, radial and atrio-septal defects, and patent ductus arteriosus. The present report of SALL4 deletion, in addition to a previously reported patient with VACTERL association phenotype and SALL4 nonsense mutation, further supports the notion that SALL4 haploinsufficiency can lead to VACTERL association.

Tracheobronchial abnormalities on computed tomography angiography in children with congenital heart disease.

OBJECTIVES: To evaluate the assortment of tracheobronchial abnormalities on computed tomography angiography (CTA) in children with congenital heart disease (CHD). METHODS: In this study approved by the Institute ethics committee, CTA studies of 182 children (age range: 2 days-8 years) with CHD, performed from July 2021 to March 2023 were analyzed. Two pediatric radiologists independently assessed the tracheobronchial airways (from the trachea to lobar bronchi) for developmental and branching anomalies and airway compromise (narrowing). In cases which demonstrated airway compromise, the extent and the cause of airway narrowing were evaluated, and the etiology were divided into extrinsic and intrinsic causes. Interobserver agreement between the two radiologists was calculated using kappa statistics. RESULTS: One hundred children demonstrated normal airway anatomy and no luminal narrowing. Airway narrowing was observed in 63 (34.6%) children (κ: 0.954), and developmental airway anomalies were seen in 32 (17.5%) children (κ: 0.935). Of the 63 children with airway narrowing, 47 (25.8%) children had extrinsic cause for narrowing, 11 (6%) children had intrinsic causes for narrowing, and 5 (2.7%) children had both intrinsic and extrinsic causes attributing to airway compromise. Significant airway narrowing (>50% reduction) was seen in 35 (19.2%) children (κ: 0.945). CONCLUSION: Tracheobronchial airway abnormalities are frequently associated in children with CHD and need to be appraised preoperatively. Cross-sectional imaging with CTA provides excellent information on tracheobronchial airway anatomy and caliber as well as delineates the possible etiology of airway narrowing, thus accurately diagnosing airway anomalies.

Laryngotracheoesophageal Cleft Type IV in a Preterm Neonate. A Case Report and Literature Review.

We present a case of a preterm neonate with a type IV laryngo-tracheo-oesophageal cleft, an uncommon congenital malformation, resulting from the failure of separation of the trachea and the oesophagus during fetal development, often associated with other deformities as well. Data in the literature shows that the long-term morbidity from the entity has declined over the last decades, even though prognosis remains unfavourable for types III and IV. This report emphasizes the complex issues neonatologists are faced with, when treating neonates with this rare disorder in the first days of life, what will raise suspicion of this rare medical entity, and that direct laryngoscopy/bronchoscopy finally depicts the exact extension of the medical condition. At the same time extensive evaluation for coexisting congenital anomalies should be performed. For all the above reasons, these neonates should be treated in specialized tertiary pediatric centers for multidisciplinary prompt management, which may improve, the outcome.

TBX5 pathogenic variant in a patient with congenital heart defect and tracheal stenosis.

Congenital tracheal stenosis is a rare life-threatening disorder caused by narrow O-shaped tracheal ring without smooth muscle. Its underlying genetic cause has not been elucidated. We performed whole exome sequencing in a patient with congenital tracheal stenosis and congenital heart defect, and identified a de novo pathogenic TBX5 variant (NM_181486.4:c.680T>C, p.(Ile227Thr)). The Ile227Thr-TBX5 protein was predicted to have a decreased stability by in silico protein structural analyses, and was shown to have a significantly reduced activity for the NPPA promoter by luciferase assay. The results, together with the expression of mouse Tbx5 in the lung and trachea and the development of tracheal cartilage dysplasia in the lung-specific Tbx5 null mice, imply the relevance of TBX5 pathogenic variants to congenital tracheal stenosis.

Survival and factors associated with mortality among infants with anorectal malformation: a population-based study from a middle-income country.

Limited data on the survival of anorectal malformation (ARM) patients from lower- and middle-income countries is available. This retrospective population-based study from the State of Johor, Malaysia, determines the incidence, mortality rate, and survival of ARM patients and factors associated with mortality. Kaplan-Meier survival analysis was used to estimate the survival of ARM patients at 1, 5, and 10 years. In addition, multivariate Cox regression analysis was used to analyze mortality-related factors. There were 175 ARM patients among 803,850 live births, giving an overall ARM incidence of 2.2 (95% confidence interval [CI], 1.9 to 2.5) per 10,000 live births. The male-to-female ratio was 1.5:1. There were 122 (69%) non-isolated ARM, of which 41 were Trisomy-21 and 34 had VACTERL association. Seventy-three (42%) had congenital heart disease (CHD), with 38 severe and 35 non-severe CHD. Overall, 33 (19%) patients died, with a median age of death of 5.7 months (interquartile range (IQR) 25 days to 11.2 months). The overall estimated 1-, 5-, and 10-year survival rate for ARM patients was 82% (95% CI, 76-89%), 77% (95% CI, 70-84%), and 77% (95% CI, 70-84%), respectively. Univariate analysis shows that non-isolated ARM, VACTERL association, and severe CHD were associated with mortality. However, only severe CHD is the independent factor associated with mortality, with a hazard ratio of 4.0 (95% CI, 1.9-8.4).  Conclusion: CHD is common among ARM patients, and one in five ARM patients had a severe cardiac defect, significantly affecting their survival. What is Known: • VACTERL association and congenital heart disease are common in patient with anorectal malformation. • Low birth weight and prematurity are associated with a lower rate of survival. What is New: • Congenital heart disease is common in ARM patients in a middle-income country. • Severe congenital heart disease plays a significant role in the survival of patients with an anorectal malformation in lower- and middle-income countries.