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Background: The prognosis and early neonatal management of the VACTERL association depend mainly on the severity of malformations ascertained prenatally., Methods: Here we reviewed the spectrum of clinical features observed in cases of VACTERL association ascertained prenatally through ultrasound examination but examined at birth and compared them with cases ascertained postnatally., Results: From 1995 to 2011, a total of 19 cases of VACTERL association were observed in our center; 10 were ascertained prenatally and confirmed after birth whereas 9 were ascertained only after birth. The types and frequencies of malformations observed prenatally were as follows: renal malformations (45%), tracheoesophageal fistula (44%), cardiac malformations (20%), vertebral (13%), and limb (11%) defects. Anal atresia was never detected using routine prenatal ultrasound examination., Conclusion: Further studies of fetuses with the VACTERL association are necessary to better delineate the malformations spectrum observed prenatally to improve the early recognition of the VACTERL association., (© 2015 Wiley Periodicals, Inc.)

Purpose: The aim of this study was to compare the frequency and nature of VACTERL associations between children who underwent surgery for esophageal atresia/tracheoesophageal fistula (EA/TEF) and anorectal malformation (ARM)., Methods: We identified all children who underwent surgery for EA/TEF and/or ARM at hospitals participating in the Pediatric Health Information System (PHIS) database between 2004 and 2012. PHIS is an administrative database of free-standing children's hospitals managed by the Child Health Corporation of America (Overland Park, KS) that contains patient-level care data from 43 hospitals. The complete records of patients in this cohort were cross-referenced for diagnoses of vertebral, cardiac, renal and limb anomalies., Results: 2689 children underwent repair of esophageal atresia. Mean gestational age was 36.5±3.2weeks and mean birth weight was 2536.0±758.7g. Associated VACTERL diagnoses included vertebral anomaly in 686 (25.5%), ARM in 312 (11.6%), congenital heart disease in 1588 (59.1%), renal disease in 587 (21.8%) and limb defect in 192 (7.1%). 899 (33.4%) had 3 or more anomalies and met criteria for a VACTERL diagnosis. 4962 children underwent repair of ARM. Mean gestational age was 37.4±2.7weeks and mean birth weight was 2895.2±765.1g. Associated VACTERL diagnoses included vertebral anomaly in 1562 (31.5%), congenital heart disease in 2007 (40.4%), EA/TEF in 348 (7.0%), renal disease in 1723 (34.7%) and limb defect in 359 (7.2%). 1795 (36.2%) had 3 or more anomalies and met criteria for a VACTERL diagnosis., Conclusion: VACTERL associations are relatively common in children with EA/TEF and ARM and occur in specific clusters, with cardiac disease more common in EA/TEF and spinal and renal/urinary anomalies more common in ARM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs' malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next-generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild-type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss-of-function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death., (© 2015 WILEY PERIODICALS, INC.)

Mitochondrial DNA depletion syndromes are an important cause of mitochondrial cytopathies in both children and adults. We describe a newborn with multiple congenital malformations including a right aberrant subclavian artery and a trachea-oesophageal fistula in whom mitochondrial depletion syndrome was unmasked by perioperative muscle relaxation. After vecuronium infusion, the infant developed an irreversible postoperative paralysis, leading to death 32 days after surgery. The present case highlights (a) the clinical heterogeneity of mitochondrial depletion syndrome; (b) the importance of rigorous antemortem and postmortem investigations when the cause of a severe myopathy is uncertain; (c) the possible coexistence of mitochondrial depletion syndrome and congenital malformations as a result of a likely abnormal antenatal embryofetal development and (d) the importance of a careful anaesthetic management of children with mitochondrial depletion syndrome, which could be prone to complications related to the possible depressive effects on mitochondrial electron transport chain mediated by some anaesthetic agents., (© The Author(s) 2014.)

Abstract: Communicating bronchopulmonary foregut malformations are extremely rare congenital malformations, characterized by a communicating fistula between an isolated part of the respiratory system and the esophagus or the stomach. In this article, we present a case of esophageal atresia type C, later diagnosed as a rare form of a communicating bronchopulmonary foregut malformation, an esophageal atresia combined with right main bronchus originating from the lower esophagus. Therapeutic resection of the right lung was complicated by postpneumonectomy syndrome. [Copyright &y& Elsevier]

Background The VACTERL association is a non-random association of congenital defects with an unknown aetiology in the majority of patients. Methods A male newborn is reported with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-esophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. As the clinical picture of this patient overlaps with that of X-linked heterotaxy caused by ZIC3 mutations, the ZIC3 coding region was sequenced. Results In a patient with the VACTERL association a 6-nucleotide insertion was found in the GCC repeat of the ZIC3 gene, which is predicted to expand the amino-terminal polyalanine repeat from 10 to 12 polyalanines. The polyalanine expansion is a novel ZIC3 mutation which was not found in 336 chromosomes from 192 ethnically matched controls. The mutation was also not present in the mother, suggesting it occurred de novo in the patient and is therefore a pathogenetic mutation. Conclusion It is hypothesized that this novel and de novo polyalanine expansion in ZIC3 contributes to the VACTERL association in this patient. A newborn male is described with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-oesophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. As the clinical picture of the VACTERL association overlaps with X-linked heterotaxy caused by ZIC3 mutations, the ZIC3 coding region was sequenced, and a 6-nucleotide insertion was found that is predicted to expand the amino-terminal polyalanine repeat from 10 to 12 polyalanines. This novel mutation was not present in the mother, nor in 336 chromosomes from 192 ethnically matched controls. It is hypothesised that this novel and de novo polyalanine expansion in the ZIC3 gene contributes to the VACTERL association in this patient. [ABSTRACT FROM AUTHOR]

Introduction: Congenital atresia of the common and external iliac arteries is a rare vascular anomaly that may be associated with congenital renal or genitourinary malformations. In ESRD patients, its presence may pose potential problems during renal transplantation., Case Presentation: We report a rare case of kidney transplantation in a patient with VACTERL syndrome who was found to have absent right common and external iliac arteries during pre-operative imaging. Vascular supply to the right lower limb is derived from an anomalous branch from the left internal iliac artery which takes on a convoluted course across the pelvis. Kidney transplantation was performed successfully with implantation performed on the left side., Discussion: Isolated cases of congenital iliac artery atresia have been described in association with urological abnormalities but no clear association has yet been established. However, we feel that it may be useful to perform routine angiographic evaluation for ESRD patients with congenital genitourinary abnormalities being planned for kidney transplantation. While most cases of congenital iliac artery anomalies are symptomatic with claudication, some remain asymptomatic with normal physical examination findings. There is some evidence in literature suggesting the usefulness of routine pre-operative CT in a selective group of patients., Conclusion: Kidney transplantation in such cases is safe and we recommend routine pre-operative imaging of patients known to have congenital genitourniary abnormalities. The kidney should be implanted heterotopically to the contralateral side of the vascular anomaly and care must be taken to preserve vascular supply to the lower limbs., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Copy number variations (CNVs), either DNA gains or losses, have been found at common regions throughout the human genome. Most CNVs neither have a pathogenic significance nor result in disease-related phenotypes but, instead, reflect the normal population variance. However, larger CNVs, which often arise de novo, are frequently associated with human disease. A genetic contribution has long been suspected in VACTERL (Vertebral, Anal, Cardiac, TracheoEsophageal fistula, Renal and Limb anomalies) association. The anomalies observed in this association overlap with several monogenetic conditions associated with mutations in specific genes, e.g. Townes Brocks (SALL1), Feingold syndrome (MYCN) or Fanconi anemia. So far VACTERL association has typically been considered a diagnosis of exclusion. Identifying recurrent or de novo genomic variations in individuals with VACTERL association could make it easier to distinguish VACTERL association from other syndromes and could provide insight into disease mechanisms. Sporadically, de novo CNVs associated with VACTERL are described in literature. In addition to this literature review of genomic variation in published VACTERL association patients, we describe CNVs present in 68 VACTERL association patients collected in our institution. De novo variations (>30 kb) are absent in our VACTERL association cohort. However, we identified recurrent rare CNVs which, although inherited, could point to mechanisms or biological processes contributing to this constellation of developmental defects.

VACTERL/VATER association is a group of congenital malformations characterized by at least 3 of the following findings: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. To date, no unifying etiology for VACTERL/VATER association has been established, and there is strong evidence for causal heterogeneity. VACTERL/VATER association has many overlapping characteristics with other congenital disorders that involve multiple malformations. In addition to these other conditions, some of which have known molecular causes, certain aspects of VACTERL/VATER association have similarities with the manifestations of disorders caused by mitochondrial dysfunction. Mitochondrial dysfunction can result from a number of distinct causes and can clinically manifest in diverse presentations; accurate diagnosis can be challenging. Case reports of individuals with VACTERL association and confirmed mitochondrial dysfunction allude to the possibility of mitochondrial involvement in the pathogenesis of VACTERL/VATER association. Further, there is biological plausibility involving mitochondrial dysfunction as a possible etiology related to a diverse group of congenital malformations, including those seen in at least a subset of individuals with VACTERL association.

Maternal diabetes mellitus is one of the strongest human teratogens. Despite recent advances in the fields of clinical embryology, experimental teratology and preventive medicine, diabetes-related perturbations of the maternofetal unit maintain a considerable impact on the Healthcare System. Classic consequences of prenatal exposure to hyperglycemia encompass (early) spontaneous abortions, perinatal death and malformations. The spectrum of related malformations comprises some recurrent blastogenic monotopic patterns, i.e. holoprosencephaly, caudal dysgenesis and oculoauriculovertebral spectrum, as well as pleiotropic syndromes, i.e. femoral hypoplasia-unusual face syndrome. Despite this, most malformed fetuses display multiple blastogenic defects of the VACTERL type, whose (apparently) casual combination preclude recognizing recurrent patterns, but accurately testifies to their developmental stage at onset. With the application of developmental biology in modern medicine, the effects of diabetes on the unborn patient are expanded to include the predisposition to develop insulin resistance in adulthood. The mechanisms underlying the transgenerational correlation between maternal diabetes and proneness to adult disorders in the offspring remain unclear, and the epigenetic plasticity may represent the missing link. In this scenario, a development-driven summary of the multifaced consequences of maternal diabetes on fertility and child health may add a practical resource to the repertoire of available information on early stages of embryogenesis.

Background: Predicting the presence of long-gap esophageal atresia (EA) prior to the surgery is of clinical importance. No comparison between short-gap and long-gap EA for the prevalence of VACTERL and non-VACTERL-type anomalies has yet been performed., Objective: The aim of this study was to compare VACTERL and non-VACTERL-type anomalies between patients with short-gap and long-gap EA., Methods: Retrospectively, medical records of all newborns managed for EA/tracheoesophageal fistula (TEF) in Tabriz Children's Hospital and Tehran Mofid Hospital between 2007 and 2010 were evaluated. Demographic data and associated anomalies including both the VACTERL and non-VACTERL-type defects were listed. The VACTERL spectrum defects covered vertebral/costal, anorectal, cardiovascular, TEF, and renal- or radial-type limb anomalies. The non-VACTERL-type anomalies included hydrocephalus, orofacial defects, respiratory system anomalies, gastrointestinal anomalies, genital anomalies, and non-VACTERL limb defects. Demographic data, and the VACTERL and non-VACTERL-type anomalies were compared among children with long-gap EA and those with short-gap EA., Results: Two hundred and seventy-six children were included in the study: 230 (83.3%) in the short-gap EA group and 46 (16.7%) in the long-gap EA group. Although prevalence of the VACTERL spectrum anomalies did not differ between the two groups, the non-VACTERL anomaly was more common in the long-gap EA group (P = 0.02). Among the VACTERL-type defects, TEF was detected in 30 (65.2%) and 218 (94.7%) patients in long-gap and short-gap EA groups, respectively (P = 0.0001)., Conclusion: The non-VACTERL-type anomalies, but not the VACTERL spectrum defects, are more frequent in patients with long-gap EA than those with short-gap EA.