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.

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.

Absence of the RING domain in MID1 results in patterning defects in the developing human brain.

The X-linked form of Opitz BBB/G syndrome (OS) is a monogenic disorder in which symptoms are established early during embryonic development. OS is caused by pathogenic variants in the X-linked gene MID1 Disease-associated variants are distributed across the entire gene locus, except for the N-terminal really interesting new gene (RING) domain that encompasses the E3 ubiquitin ligase activity. By using genome-edited human induced pluripotent stem cell lines, we here show that absence of isoforms containing the RING domain of MID1 causes severe patterning defects in human brain organoids. We observed a prominent neurogenic deficit with a reduction in neural tissue and a concomitant increase in choroid plexus-like structures. Transcriptome analyses revealed a deregulation of patterning pathways very early on, even preceding neural induction. Notably, the observed phenotypes starkly contrast with those observed in MID1 full-knockout organoids, indicating the presence of a distinct mechanism that underlies the patterning defects. The severity and early onset of these phenotypes could potentially account for the absence of patients carrying pathogenic variants in exon 1 of the MID1 gene coding for the N-terminal RING domain.

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.

Substantial incidence of bladder dysfunction in patients with VACTERL association: Implications for surveillance.

VACTERL association is defined as the nonrandom co-occurrence of a minimum of three of the following six key components: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. Patients presenting with two components may also belong in the same spectrum. Additional components have been associated with VACTERL defects, including single umbilical artery, tethered spinal cord (TSC), and genital malformations. We observed a significant proportion of patients with bladder dysfunction (often called neurogenic bladder in the medical record) when reviewing a cohort of patients with VACTERL defects at our clinical center. Our finding calls attention to bladder dysfunction as an additional VACTERL phenotypic component. The prevalence of bladder dysfunction is greatest in those with genital anomalies, anorectal malformations, sacral dysplasia, renal anomalies, and TSC. We propose that patients with two or more VACTERL malformations be monitored for symptoms of bladder dysfunction if one or more of the identified risk factors are present until the achievement of urinary continence.

A novel genotype-phenotype between persistent-cloaca-related VACTERL and mutations of 8p23 and 12q23.1.

The mechanism underlying anorectal malformations (ARMs)-related VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, and renal and limb abnormalities) remains unclear. Copy number variation (CNV) contributed to VACTERL pathogenicity. Here, we report a novel CNV in 8p23 and 12q23.1 identified in a case of ARMs-related VACTERL association. This 12-year-old girl presented a cloaca (urethra, vagina, and rectum opening together and sharing a single tube length), an isolated kidney, and a perpetuation of the left superior vena cava at birth. Her intelligence, growth, and development were slightly lower than those of normal children of the same age. Array comparative genomic hybridization revealed a 9.6-Mb deletion in 8p23.1-23.3 and a 0.52-Mb duplication in 12q23.1 in her genome. Furthermore, we reviewed the cases involving CNVs in patients with VACTERL, 8p23 deletion, and 12q23.1 duplication, and our case was the first displaying ARMs-related VACTERL association with CNV in 8p23 and 12q23.1. These findings enriched our understanding between VACTERL association and the mutations of 8p23 deletion and 12q23.1 duplication. IMPACT: This is a novel case of a Chinese girl with anorectal malformations (ARMs)-related VACTERL with an 8p23.1-23.3 deletion and 12q23.1 duplication. Cloaca malformation is presented with novel copy number variation in 8p23.1-23.3 deletion and 12q23.1 duplication.

Clinical Presentations and Diagnostic Imaging of VACTERL Association.

Background: VACTERL association consists of Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal, and Limb defects. The diagnosis depends on the presence of at least three of these structural abnormalities. Methods: The clinical presentation and diagnostic prenatal imaging of VACTERL association are comprehensively reviewed. Results: The most common feature is a vertebral anomaly, found in 60-80% of cases. Tracheo-esophageal fistula is seen in 50-80% of cases and renal malformations in 30% of patients. Limb defects including thumb aplasia/hypoplasia, polydactyly, and radial agenesis/hypoplasia are present in 40-50% of cases. Anorectal defects, like imperforate anus/anal atresia, are challenging to detect prenatally. Conclusion: The diagnosis of VACTERL association mostly relies on imaging techniques such as ultrasound, computed tomography, and magnetic resonance. Differential diagnosis should exclude similar diseases such as CHARGE and Townes-Brocks syndromes and Fanconi anemia. New insights into genetic etiology have led to recommendations of chromosomal breakage investigation for optimal diagnosis and counseling.

The Importance of Screening for Additional Anomalies in Patients with Anorectal Malformations: A Retrospective Cohort Study.

BACKGROUND: In children with anorectal malformations (ARM), additional anomalies can occur within the VACTERL-association. Routine screening is of great importance for early identification and potential treatment. However, uniformity in screening protocols is lacking and only small cohorts have been described in literature. The aim of this study was to assess and describe a unique large cohort of ARM patients who underwent VACTERL screening in the neonatal period. METHODS: A retrospective mono-center cohort study was performed. Included were all neonates born between January 2000 and December 2020 who were diagnosed with ARM and screened for additional anomalies. Full screening consisted of x-ray and ultrasound of the spine, cardiac and renal ultrasound, and physical examination for limb deformities, esophageal atresia, and ARM. Criteria for VACTERL-classification were predefined according to the EUROCAT-definitions. RESULTS: In total, 216 patients were included, of whom 167 (77.3%) underwent full VACTERL-screening (66% in 2000-2006 vs. 82% in 2007-2013 vs. 86% in 2014-2020). Median age at follow-up was 7.0 years (IQR 3.0-12.8). In 103/167 patients (61.7%), additional anomalies were identified. Some 35/216 patients (16.2%) fulfilled the criteria of a form of VACTERL-association. In 37/216 patients (17.1%), a genetic cause or syndrome was found. CONCLUSIONS: The majority of ARM patients underwent full screening to detect additional anomalies (77%), which improved over time to 86%. Yet, approximately a quarter of patients was not screened, with the potential of missing important additional anomalies that might have severe consequences in the future. Forms of VACTERL-association or genetic causes were found in 16% and 17% respectively. This study emphasizes the importance of routine screening. LEVEL OF EVIDENCE: III.

Anorectal malformation associated with delayed presentation of right Bochdalek type diaphragmatic hernia.

Patients with an imperforate anus frequently present with congenital abnormalities, most commonly as a component of VACTERL (Vertebral anomalies, Anorectal malformations, Cardiac defect, Tracheo-Oesophageal fistula and Oesophageal atresia, Renal anomalies, and Limb defects) anomalies. It is, however, unusual for infants to present with a concurrent anorectal malformation (ARM) and a Bochdalek type diaphragmatic hernia. We describe an infant with an ARM and a delayed presentation of a right-sided Bochdalek type diaphragmatic hernia. In this case, the Bochdalek type diaphragmatic hernia presented 10 months after a laparoscopic-assisted anorectal plasty was performed. Despite both ARM and congenital diaphragmatic hernia known to be associated with other congenital malformations, the association of these particular congenital abnormalities in an individual patient is uncommon.

Manejo enfermero de la atresia esofágica en el paciente neonatal / Nursing management of oesophageal atresia in neonatal patients

La atresia de esófago se describe como una anomalía congénita del aparato digestivo en el que existe una interrupción en el desarrollo del esófago y donde puede haber o no comunicación con la vía aérea, es decir, con la tráquea, pudiendo agravar así la función respiratoria del recién nacido. En este artículo se presenta el caso clínico de un recién nacido a término con esta patología que es intervenido quirúrgicamente a los dos días de vida. Tras la cirugía se traslada a la Unidad de Cuidados Intensivos Neonatal (UCIN) para una vigilancia y monitorización estrecha. Se detectan las complicaciones potenciales: infección secundaria y aspiración secundaria, ambas secundarias a procedimiento invasivo. Como diagnósticos enfermeros se identifican: riesgo de desequilibrio del volumen de líquidos, riesgo de úlcera por presión y deterioro de la integridad cutánea. Tras poner en marcha el plan de cuidados, la evolución del paciente es satisfactoria. Es fundamental el seguimiento clínico de estos pacientes para evitar complicaciones no solo a corto plazo, sino también a largo plazo, en el domicilio.(AU)

Oesophageal atresia is described as a congenital anomaly of the digestive tract where there is an interruption in the development of the oesophagus, and there can be communication or not with the airway, that is to say, with the trachea, which could worsen the respiratory function of the newborn. This article presents the case report of a full-term newborn with this condition who underwent a surgical procedure two days after birth. After surgery, he was transferred to the Neonatal Intensive Care Unit (NICU) for close monitoring. Potential complications secondary to the invasive procedure were detected: secondary infection and secondary aspiration. The nursing diagnoses identified were: risk of fluid volume imbalance, risk of pressure ulcer, and deterioration of the skin integrity. After implementing the plan of care, the evolution of the patient was satisfactory. Clinical follow-up at home for these patients is essential in order to prevent complications, not only at short term but also at long term.(AU)

Further description of two patients with biallelic variants in NADSYN1 in association with cardiac and vertebral anomalies.

Congenital nicotinamide adenine dinucleotide (NAD) deficiency disorders are associated with pathogenic variants in the genes NADSYN1, HAAO, and KYNU. These disorders overlap with the anomalies present in vertebral, anal, cardiac, tracheoesophageal, radial and renal, and limb anomalies (VATER/VACTERL) association and often result in premature death. Children who survive typically have developmental delays or intellectual disability. Here, we describe two patients with compound heterozygous variants in NADSYN1 who presented with cardiac and vertebral defects overlapping with the VATER/VACTERL association, although the patients did not satisfy criteria for the diagnosis of VATER/VACTERL due to their lack of limb anomalies and significant renal anomalies. One patient survived into childhood with developmental delays and may represent an expansion of the survival data for NADSYN1-associated NAD deficiency disorders. Interestingly, one patient had hypoplastic left heart syndrome (HLHS) and one had an aortic coarctation and transverse hypoplasia of the aortic arch, suggesting that NADSYN1 sequencing should be performed in children presenting with congenital anomalies related to VATER/VACTERL association and with HLHS and aortic arch abnormalities.

Understanding of the transition to adult healthcare services among individuals with VACTERL association in Sweden: A qualitative study.

Current knowledge of transitional care from the perspective of individuals with congenital malformations is scarce. Their viewpoints are required for the development of follow-up programs and transitional care corresponding to patients' needs. The study aimed to describe expectations, concerns, and experiences in conjunction with transfer to adult health care among adolescents, young adults, and adults with VACTERL association, (i.e. vertebral defects, anorectal malformations (ARM), cardiac defects (CHD), esophageal atresia (EA), renal, and limb abnormalities). Semi-structured telephone interviews were performed and analyzed with qualitative content analysis. Of 47 invited individuals, 22 participated (12 males and 10 females). An overarching theme emerged: Leaving the safe nest of pediatric health care for an unfamiliar and uncertain follow up yet growing in responsibility and appreciating the adult health care. The participants described expectations of qualified adult health care but also concerns about the process and transfer to an unfamiliar setting. Individuals who were transferred described implemented or absence of preparations. Positive and negative experiences of adult health care were recounted including being treated as adults. The informants described increasing involvement in health care but were still supported by their parents. Ongoing follow up of health conditions was recounted but also uncertainty around the continuation, missing follow up and limited knowledge of how to contact health care. The participants recommended information ahead of transfer and expressed wishes for continued health care with regular follow up and accessibility to a contact person. Based on the participants' perspective, a transitional plan is required including early information about transfer and follow up to prepare the adolescents and reduce uncertainty concerning future health care. Meetings with the pediatric and adult team together with the patient and the parents are essential before transfer. Follow up should be centralized to centers with multi-professional teams well-experienced with the condition. Further studies are warranted to evaluate the transition process for adolescents and young adults with complex congenital health conditions.

Re-sequencing of candidate genes FOXF1, HSPA6, HAAO, and KYNU in 522 individuals with VATER/VACTERL, VACTER/VACTERL-like association, and isolated anorectal malformation.

BACKGROUND: The acronym VATER/VACTERL association describes the combination of at least three component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Individuals presenting two CFs have been termed VATER/VACTERL-like. Recently, FOXF1, HSPA6, HAAO, KYNU, TRAP1, and ZIC3 have been proposed as candidate genes for VATER/VACTERL, VATER/VACTERL-like, and ARM. Re-sequencing studies identified disease-causing variants in TRAP1 and ZIC3, the contribution of other genes was not independently investigated. One affected variant carrier in FOXF1 was previously identified. Here we re-sequenced FOXF1, HSPA6, HAAO, and KYNU in 522 affected individuals. METHODS: Using molecular inversion probe (MIP) technology, re-sequencing was performed in 63 individuals with VATER/VACTERL association, 313 with VATER/VACTERL-like association, and 146 with ARM. All individuals were of European ethnicity. Variant filtering considered variants with a minor allele frequency (MAF) ≤0.01 for putative recessive disease-genes HSPA6, HAAO, and KYNU. For the putative dominant disease-gene FOXF1 we considered variants with a MAF ≤0.0001. In silico prediction tools were used for further prioritization. RESULTS: Only two variants in FOXF1 in two independently affected individuals [c.443G>T, p.(Cys148Phe); c.850T>C, p.(Tyr284His)] passed our filter criteria. One individual presented with ARM, the second presented with TE and C comprising atrial and ventricular septal defects. Sanger sequencing confirmed both variants but also their inheritance from the healthy mother. CONCLUSION: Our analysis suggests that FOXF1, HSPA6, HAAO and KYNU do not play a major role in the formation of VACTER/VACTERL phenotypes or ARM.

A case report of serpentine-like syndrome and review of literature.

BACKGROUND: Serpentine-like syndrome (SLS) is a rare foetal abnormality, characterized by brachioesophagus, secondary intrathoracic stomach and vertebral deformity. Herein, we report a case of SLS diagnosed based on imaging, genetic examination and autopsy findings. CASE PRESENTATION: From the 19th to 23rd weeks of gestation, the foetus presented with brachioesophagus, secondary intrathoracic stomach, intrathoracic spleen with poly-spleen malformation, spinal deformity and diaphragm dysplasia, and some abdominal organs were partly located in the thoracic cavity. After extensive counselling, the couple opted to terminate the pregnancy. Whole genome sequencing and autopsy were performed. Then, the foetus was diagnosed with SLS. DISCUSSION AND CONCLUSIONS: SLS is characterized by multiorgan deformities and is associated with poor prognosis. Multiorgan deformities can be detected on prenatal sonography using three-dimensional ultrasound technology.

SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.

Opitz G/BBB syndrome (OS) is a rare genetic developmental condition characterized by congenital defects along the midline of the body. The main clinical signs are represented by hypertelorism, laryngo-tracheo-esophageal defects and hypospadias. The X-linked form of the disease is associated with mutations in the MID1 gene located in Xp22 whereas mutations in the SPECC1L gene in 22q11 have been linked to few cases of the autosomal dominant form of this disorder, as well as to other genetic syndromes. In this study, we have undertaken a mutation screening of the SPECC1L gene in samples of sporadic OS cases in which mutations in the MID1 gene were excluded. The heterozygous missense variants identified are already reported in variant databases raising the issue of their pathogenetic meaning. Recently, it was reported that some clinical manifestations peculiar to OS signs are not observed in patients carrying mutations in the SPECC1L gene, leading to the proposal of the designation of 'SPECC1L syndrome' to refer to this disorder. Our study confirms that patients with diagnosis of OS, mainly characterized by the presence of hypospadias and laryngo-tracheo-esophageal defects, do not carry pathogenic SPECC1L mutations. In addition, SPECC1L syndrome-associated mutations are clustered in two specific domains of the protein, whereas the missense variants detected in our work lies elsewhere and the impact of these variants in the function of this protein is difficult to ascertain with the current knowledge and will require further investigations. Nonetheless, our study provides further insight into the SPECC1L syndrome classification.