Complex Congenital Defects Research Articles

Choledochal malformations: global research, scientific advances and key controversies.

Choledochal malformations (CMs) represent a spectrum of relatively rare and complex congenital anomalies, characterized by abnormal dilatation of the biliary tract in the absence of any acute obstruction. Today, almost 20% of CMs can be detected in-utero using maternal ultrasonography. Formal scientometric analysis was used to identify where modern CM research is taking place and perhaps where our attention should be directed in the future. Thus, this article offers a comprehensive review of recent scientific advances relating to CMs including the current understanding of etiology and classification, whilst also discussing key controversies such as risk of malignant transformation and the role of newer modalities of surgical treatment. Although laparoscopic excision of CMs and biliary reconstruction is nowadays feasible and safe, care should be taken before dispensing with standard open techniques, which have minimal complication rates and proven long-term benefit.

Oculo-auriculo-vertebral spectrum with complete absence of the right condyle and ramus - Case report

Oculo-auriculo-vertebral spectrum (OAVS), formerly known as Goldenhar syndrome is a complex congenital anomaly arising from mal-development of first and second branchial arches, mainly affecting the face, eyes and ears. Majority of patients diagnosed with OAVS have some degree of facial asymmetry, featured with unilateral facial hypoplasia, prominent forehead, hypoplasia of the zygomatic area, maxilla and mandible. Herewith, we report a case of OAVS in a 13-year-old male who presented with Kaban type III TMJ deformity, in addition to facial and skeletal dysmorphology.

Three-Dimensional Printing of a Complex Aortic Anomaly

Complex congenital aortic anomalies include diverse types of malformations that may be clinically asymptomatic or present with respiratory or esophageal symptoms. These anomalies may be associated with other congenital heart diseases. It is hard to identify the accurate anatomic vessel location from two-dimensional imaging data, such as computed tomography. As an additive manufacturing method, three-dimensional (3-D) printing can covert the acquired imaging data into 3-D physical models. This protocol describes the procedure for modeling the volumetric DICOM imaging into 3-D data and printing it as an anatomically realistic 3-D model. Using this model, surgeons can identify the vessel location of complex aortic anomalies, which is helpful for pre-operative planning and intra-operative guidance.

Safeguarding the Anomalous Vertebral Artery While Dissecting, Drilling, and Instrumentation of C1-2 Joint for Congenital Atlantoaxial Dislocation: 2-Dimensional Operative Video.

The pathology in congenital atlantoaxial instability is usually in C1-2 joints. Addressing the joints appears to be the most rationale approach. The joints are usually approached posteriorly, manipulated, and fused. Understanding the normal and abnormal anatomy is important. Normally, the third segment of the vertebral artery courses lateral to the C1-2 joint. However, in about 20% of the cases with complex congenital craniovertberal junction anomalies the artery crosses the joint posteriorly. The artery in such cases may be injured while joint manipulation and instrumentation with disastrous consequences. Alternatively, occipital squama can be fused to the cervical spine. However, this requires fusion of multiple segments affecting the neck movements significantly. An anomalous vertebral artery can be dissected, mobilized, and safeguarded while dissecting, manipulating, and fusing the C1-2 joint. In this operative video, authors have highlighted the technique to safeguard the anomalous vertebral artery during joint manipulation. Proper informed consent was obtained from the patient.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.

Complex congenital cardiac anomalies in the setting of right isomerism in a 31-month-old infant: a case report

BackgroundCongenital cardiac defects are not rare among neonates. Prompt assessment for life-threatening anomalies is essential for rapid management decisions and positive outcomes. Extracardiac anomalies can occur in congenital heart defects, and their presence increases morbidity and mortality in these neonates.Case presentationWe report a case of a 31- month-old infant black girl in Tanzania who presented with an on-and-off history of difficulty in breathing, easy fatigability, facial and lower-limb swelling, recurrent respiratory tract infections, and failure to thrive.ConclusionsManagement of patients with heterotaxy syndrome is complex and largely depends on specific anatomy of both cardiac and noncardiac lesions. Cardiac and noncardiac management must be tailored to individual anatomy, including prophylaxis against encapsulated organisms for asplenic patients.

The advances of genetics research on Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a rare and complex congenital disorder characterized by the absence of the enteric neurons in lower digestive tract with an incidence of 1/5 000. Affected infant usually suffer from severe constipation with megacolon and distended abdomen, and face long‐term complications even after surgery. In the last 2 decades, great efforts and progresses have been made in understanding the genetics and molecular biological mechanisms that underlie HSCR. However, only a small fraction of the genetic risk can be explained by the identified mutations in the previously established genes. To search novel genetic alterations, new study designs with advanced technologies such as genome/exome‐wide association studies (GWASs/EWASs) and next generation sequencing (NGS) on target genes or whole genome/exome, were applied to HSCR. In this review, we summaries the current development of the genetics researches on HSCR based on GWASs/EWASs and NGS, focusing on the newly discovered variants and genes, and their potential roles in HSCR pathogenesis.

Whole-genome sequencing in a pair of monozygotic twins with discordant cleft lip and palate subtypes.

Orofacial clefts (OFCs) are common and etiologically complex birth defects. This study explored potential genetic differences in a pair of Japanese monozygotic (MZ) twins with different forms of OFC using whole-genome sequencing. One co-twin (MZ-1) presented with nonsyndromic bilateral cleft lip and palate; the other co-twin (MZ-2) had nonsyndromic bilateral cleft lip and unilateral left-sided cleft alveolus. Neither parent had an OFC. Craniofacial morphologic features and potential genetic differences were compared using standard cephalometry and whole-genome sequencing, respectively. Morphologically, MZ-1 had a smaller vertical mandibular height, compared to MZ-2. However, no discordant genetic differences were detected. Moreover, both twins and their parents harbored rare candidate gene variants (GRHL3; TPM1) considered to be associated with OFCs. The observed differences between MZ-1 and MZ-2 in craniofacial morphology assessed by cephalograms might be directly attributable to the effects of the OFC on growth and/or differences in surgical history, given the lack of any differences in genetic background. However, comparisons of discordant MZ twins should continue to identify novel candidates that might control OFC or that might partly explain the missing heritability for this common birth defect, in addition to understanding craniofacial growth and development.

A multidisciplinary management approach for patients with Klippel-Trenaunay syndrome and multifetal gestation with successful outcomes

Abstract Background Klippel-Trenaunay syndrome (KTS) is a complex congenital disorder characterized by the classic triad of capillary malformation, venous and lymphatic malformations and limb overgrowth. The incidence of pregnancies affected by KTS is unknown. There is a paucity of literature regarding management and outcomes of affected pregnancies, particularly in multifetal gestations. Case We present two cases of pregnancies affected by KTS and multiple gestations. A multidisciplinary approach with hematology, radiology and anesthesia resulted in two successful pregnancies with no adverse neonatal outcomes. Conclusion Management of pregnancies affected by KTS and multiple gestations should be personalized with a multi-disciplinary approach to avoid morbidity and improve maternal and neonatal outcomes.

Complex Vascular Ring Diagnosed on Cardiovascular MR in a 3-Day-Old Infant.

Prenatal ultrasonography in the early third trimester showed an unusual branching pattern of the right aortic arch. Echocardiography performed 4 h after birth showed the right aortic arch with mirror-image branching, patent ductus arteriosus, and patent foramen ovale. Because the location of the ductus arteriosus was unclear on echocardiography, cardiovascular magnetic resonance imaging was performed 3 days after birth. Advanced techniques including contrast-enhanced time-resolved magnetic resonance angiography and 3D time-of-flight magnetic resonance angiography allowed accurate diagnosis of a vascular ring comprising ascending and descending aorta, right aortic arch with mirror-image branching, and diverticulum of Kommerell giving rise to a left ligamentum arteriosum. The infant had hiccups, but no other symptoms. The esophagram was negative for obstruction. The infant was closely monitored; however, she developed esophageal obstruction at 7 months of age because of the vascular ring. She underwent lysis of the left ligamentum arteriosum followed by aortopexy for relief of esophageal obstruction. This report shows the utility of neonatal cardiovascular magnetic resonance imaging to evaluate complex congenital aortic arch anomalies.

A pregnant woman with an operated bladder extrophy and a pregnancy complicated by placenta previa and preterm labor

Abstract Background Bladder exstrophy (BE) is a complex congenital anomaly that affects the urinary, reproductive, musculoskeletal and intestinal systems. Highlights This pregnancy case was complicated by BE, methylenetetrahydrofolate reductase (MTHFR) A1298C and plasminogen Activator inhibitör-1 (PAI) 4G/4G homozygous polymorphisms, placenta previa, preterm labor and preterm premature rupture of the membranes. The fetus was evaluated by ultrasonography daily and anhydramnios was detected on the 2nd day of the patient’s hospitalization. A cesarean section (C/S) was performed at 27 weeks and 6 days of gestation and a 1330 g male infant was delivered. Conclusions Adult female patients with BE can have successful pregnancy outcomes if they receive appropriate antenatal care. However, the follow-up of these patients must be carried out at experienced tertiary reference centers with a multidisciplinary approach. This difficult process must be managed by obstetricians, neonatologists, urologists and pediatric surgeons working together.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

The Case for Simulation-Based Mastery Learning Education Courses for Practicing Surgeons.

Pediatric surgeons rely on simulation courses to develop skills for safe minimally invasive repair of complex congenital anomalies. The majority of minimally invasive surgery (MIS) training courses occur during short "exposure courses" at annual conferences. Little data are available to support the benefit of these courses relative to the safe implementation of new skills. The purpose of this article is to determine the impact of an exposure course for advanced neonatal MIS on self-perceived comfort levels with independent performance of advanced MISs. Participants of a 4-hour hands-on course for neonatal MIS were surveyed regarding clinical practices and pre- and post-training perceived "comfort levels" of MIS skills for thoracoscopic esophageal atresia with tracheoesophageal fistula (tTEF) repair, thoracoscopic left upper lobe pulmonary lobectomy (tLobe), and laparoscopic duodenal atresia (lapDA) repair. Descriptive analyses were performed. Seventeen participants completed pre- and postcourse surveys. The majority of participants had no prior experience with tLobe (59%) or lapDA (53%), and 35% had no experience with tTEF repair. Similarly, the majority were "not comfortable" with these procedures. After the short course, the majority of surgeons reported that they were "likely to perform" these operations within 6 months, despite low levels of baseline experience and comfort levels. An exposure training course led to immediate perception of increased skills and confidence. However, these courses typically do not provide basic tenets of expert performance that demands deliberate practice. Future course design should transition to a mastery learning framework wherein regular skill assessments, milestones, and unlimited education time are prioritized before implementation of the new skills.

Multiple midline defects identified in a litter of golden retrievers following gestational administration of prednisone and doxycycline: a case series

BackgroundThe teratogenic effects of immunomodulatory and certain antimicrobial therapies are described in small rodents and humans. While the described teratogenic effects in small rodents have been extrapolated to make conclusions about its use in the pregnant dam, teratogenic effects of prednisone and doxycycline have not yet been reported in the dog. Here we report and describe midline defects observed in a litter of golden retriever puppies exposed to mid-gestational immunosuppressive and antimicrobial therapy.Case presentationTwenty-one days into gestation, the dam of a litter of eight golden retriever puppies was administered prednisone, doxycycline, and tramadol as treatment for immune-mediated polyarthritis. The individuals in the litter were subsequently diagnosed with a variety of midline defects and congenital cardiac defects. This case series describes the variety of identified defects and presents a descriptive account of complex congenital abnormalities that are likely secondary to teratogenic effects of one or more drugs administered during gestation. The available puppies, dam, and grand dam underwent thorough physical examination, complete echocardiogram, and where indicated, advanced imaging with various surgical corrections when possible.Numerous midline congenital defects and congenital heart disease were identified in the puppies evaluated. Ultimately 5 of 8 puppies born to the dam were presented for thorough evaluation. The midline defects include: gastroschisis (1), peritoneopericardial diaphragmatic hernias (4, PPDH), umbilical hernia (4), unilateral cryptorchidism (1 of 4 males), cleft palate (1), renal agenesis (1), renal abnormalities (1), sternal and vertebral abnormalities (3), remnant liver lobe (1) and malformations consistent with ductal plate malformations with congenital hepatic fibrosis (1). The congenital cardiac defects include: ventricular septal defect (4, VSD) and subaortic stenosis (4, SAS). The presence of greater than one congenital defect was noted in all 5 of the dogs evaluated. Surgical correction was necessary for PPDH in 4 puppies. Medical intervention was recommended for congenital cardiac disease in 1 puppy.ConclusionThis case report is the first to describe midline defects in dogs that have been exposed to immunomodulatory therapy during gestation. A causative relationship between mid-gestational immunomodulatory exposure and midline defects cannot be proven, however, this case supports a clear association and provides case-based evidence to support its avoidance when possible.

Winging it: maternal perspectives and experiences of breastfeeding newborns with complex congenital surgical anomalies.

ObjectiveTo describe the experience of breastfeeding (inclusive of breast milk expression/pumping, provision of breast milk via devices, and at-breast feeding) among mothers of newborns with complex congenital surgical anomalies and the contexts under which pro-breastfeeding behaviors and attitudes are facilitated or compromised.Study DesignWe used qualitative description to analyze 23 interviews conducted with 15 mothers of newborns undergoing surgery for gastrointestinal, cardiac, or neural tube defects.ResultsBreastfeeding experiences were characterized by naivety regarding the importance and rationale for exclusive breast milk feedings and best practices to facilitate milk supply maintenance and transition to at-breast feeds. Maternal breastfeeding views and behaviors were impacted by indeterminate prenatal plans to breastfeed/provide breast milk, limited prior breastfeeding exposure and knowledge, and gaps in postnatal lactation support.ConclusionFuture research should investigate methods to improve exclusive breast milk feeding and facilitate transitions to at-breast feeds among mothers of newborns with surgical congenital anomalies, with consideration of identified barriers.

Uncovering the genetic lesions underlying the most severe form of Hirschsprung disease by whole-genome sequencing.

Hirschsprung disease (HSCR) is a complex birth defect characterized by the lack of ganglion cells along a variable length of the distal intestine. A large proportion of HSCR patients remain genetically unexplained. We applied whole-genome sequencing (WGS) on 9 trios where the probands are sporadically affected with the most severe form of the disorder and harbor no coding sequence variants affecting the function of known HSCR genes. We found de novo protein-altering variants in three intolerant to change genes-CCT2, VASH1, and CYP26A1-for which a plausible link with the enteric nervous system (ENS) exists. De novo single-nucleotide and indel variants were present in introns and non-coding neighboring regions of ENS-related genes, including NRG1 and ERBB4. Joint analysis with those inherited rare variants found under recessive and/or digenic models revealed both patient-unique and shared genetic features where rare variants were found to be enriched in the extracellular matrix-receptor (ECM-receptor) pathway (p = 3.4 × 10-11). Delineation of the genetic profile of each patient might help finding common grounds that could lead to the discovery of shared molecules that could be used as drug targets for the currently ongoing cell therapy effort which aims at providing an alternative to the surgical treatment.

Results and factors associated with adverse outcome after tricuspid valve replacement.

This retrospective analysis of patients with severe tricuspid valve disease, who underwent tricuspid valve replacement (TVR) for either tricuspid regurgitation or stenosis, has been designed to determine the factors that predict poor hospital and long-term survival. The study population comprised 86 patients, 65 women and 21 men, who underwent TVR with or without con-comitant surgical procedures between 2000 and 2010 at our institution. Patients with Ebstein's or other complex congenital anomalies were excluded from the study. Average age at operation was 58.5 ± 12.5 (range 16-78) years. Fifty (58.1%) patients had undergone previous cardiac surgery. Forty-two patients were in New York Heart Association (NYHA) class III functional capacity, and 18 were in class IV. Symptoms of right heart failure (HF) were present in 66 patients, of whom 19 had ascites. Bioprosthetic tricuspid valves were implanted in 84 patients and mechanical prostheses in two. The choice to proceed to TVR instead of repair was individualised and based on the surgeon's preference. In-hospital mortality was 18 (20.9%) patients, caused mainly by multi-organ and HF, and was significantly related to NYHA class and symptoms of right HF before surgery, with no mortality in patients with NYHA class I and II, 19% mortality with NYHA class III, and 55.6% mortality with NYHA class IV. Eighteen (20.9%) patients died during postoperative follow-up. The main risk factors associated with perioperative mortality were: the presence of severe symptoms at the time of surgery, low preoperative haematocrit, postoperative complications, postoperative ventilation time longer than 72 h, and renal failure requiring dialysis. Elevated pulmonary artery pressure, preoperative symptoms of right HF, and low haematocrit unfavourably affected the long-term results. Many earlier studies reported high mortality and morbidity after TVR in both early and late postoperative peri-ods. Our main finding is that good outcomes for TVR are achievable in properly selected patients. Sixty of 86 patients in our group had preoperative NYHA functional class III and IV, which suggests that surgical timing was late in many patients. Based on our observations, we propose that surgical correction of severe tricuspid valve disease should be considered before the development of advanced HF, when patients are asymptomatic or only oligosymptomatic.

PWS Preparations

Prader-Willi Syndrome is a complex chromosomal birth defect that causes neurological disorders, health issues, and insatiable appetites. Lifelong care for PWS patients is complex because their physical health issues cause psychological behavior issues that require unique strategies. PWS patients have unique needs in schools, community programs, and adult care programs and if they do not receive proper care it is life threatening. Therefore, parents must seek professional expert support to develop lifelong preparations with securities plans to foster the best interest of their PWS child. The Children’s Institute (TCI) Center for PWS in Pittsburgh, Pennsylvania and PWSA USA are resources for PWS expert support in America with over 20 years of experience. The challenges PWS families face with adult programs is a crisis that requires national support from the Department of Health and Human Services.

Amniotic band syndrome

Amniotic band syndrome is a rare and complex congenital disorder characterized by constricting rings, acrosyndactyly, or often amputations of extremities of neonates. It is a heterogeneous condition, with a broad spectrum of anomalies, where intrinsic alternate with extrinsic causes as amniotic band rupture. The condition can be diagnosed prenatally with an abdominal ultrasound. However, in most reported cases, the diagnosis was made at birth. Treatment includes surgery and rehabilitation. The author reports the first documented case in the north western Nigeria in a term male neonate. The malformation included a constriction band in the right upper arm and distal lower limb with ipsilateral congenital talipes equinovarus. He was stabilized and referred to orthopedic surgeon for expert management.

Burden of congenital heart diseases in a tertiary cardiac care institute in Western India: Need for a national registry

Objective: Congenital heart disease (CHD) is very common disease, and it is the major cause of childhood mortality and morbidity. Not much of Indian data are available particularly from the western part of the country. There are needs to further explicate the spectrum and epidemiology of the CHD. Materials and Methods: This retrospective study collected data of the paediatric patients received in our institute from January 2016 to June 2017. All simple and complex congenital anomalies diagnosed on echocardiography were included in our study. Results: Of total 22,275 cases, CHDs were diagnosed in 9728 cases with a male-to-female ratio of 1:0.6. Most CHDs (62.77%) were diagnosed between 1 month and 6 years of age. Incidence of cyanotic CHD was 27.14% and acyanotic CHDs was 72.86% with a ratio of cyanotic-to-acyanotic CHD being 1:2.7. Ventricular septal defect (26.24%) was the most common acyanotic CHD found followed by 2089 patients of atrial septal defect. Tetralogy of Fallot (13.57%) was the most common cyanotic CHD found followed by double-outlet right ventricle in 276 patients (2.84%). Conclusions: Ours is the largest Indian study till date in this spectrum which yielded new data on the epidemiology, incidence, and prevalence of CHD. Majority of the patients with CHD had acyanotic CHD with most common anomaly being ventricular septal defect. Tetralogy of Fallot was the most common cyanotic defect. This study will increase awareness in the people with a family history of CHD and health-care providers and will assist in early diagnosis.