Search

Introduction: Primary cilia play pivotal roles in the patterning and morphogenesis of a wide variety of organs during mammalian development. Here we examined murine foregut septation in the cobblestone mutant, a hypomorphic allele of the gene encoding the intraflagellar transport protein IFT88, a protein essential for normal cilia function. Results: We reveal a crucial role for primary cilia in foregut division, since their dramatic decrease in cilia in both the foregut endoderm and mesenchyme of mutant embryos resulted in a proximal tracheoesophageal septation defects and in the formation of distal tracheo(broncho)esophageal fistulae similar to the most common congenital tracheoesophageal malformations in humans. Interestingly, the dorsoventral patterning determining the dorsal digestive and the ventral respiratory endoderm remained intact, whereas Hedgehog signaling was aberrantly activated. Conclusions: Our results demonstrate the cobblestone mutant to represent one of the very few mouse models that display both correct endodermal dorsoventral specification but defective compartmentalization of the proximal foregut. It stands exemplary for a tracheoesophageal ciliopathy, offering the possibility to elucidate the molecular mechanisms how primary cilia orchestrate the septation process. The plethora of malformations observed in the cobblestone embryo allow for a deeper insight into a putative link between primary cilia and human VATER/VACTERL syndromes. Key Findings: Identifies Ift88 as a gene responsible for trachea‐esophageal septation.Identifies primary cilia as essential for the trachea‐esophageal septation process.Proposes a novel mechanism for cilia‐dependent septation. [ABSTRACT FROM AUTHOR]

VACTERL association is typically defined as the presence of three components among these birth defects: vertebral anomalies, anal atresia, cardiac anomalies, esophageal atresia/tracheoesophageal fistula (EA/TEF), renal anomalies, and limb defects. There is increasing recognition that VACTERL and other recurrent constellations of embryonic development often overlap clinically and might share pathogenesis. We conducted a comprehensive chart review of a large patient population with VACTERL association from two tertiary care centers in California. We included patients with incomplete VACTERL expression, which we denoted as "partial VACTERL" (pVACTERL). We assessed the occurrence of craniofacial (CF) findings in these two groups and the combined cohort. We collected data on potential risk factors and demographic information such as sex, Hispanic ancestry, pregnancy complications, and maternal age. The study included 409 participants, of whom 263 had VACTERL and 146 pVACTERL. CF abnormalities were found in 17.3% of VACTERL patients and 9.4% of pVACTERL patients. In the VACTERL group, ear anomalies were found in 10.2%, microtia in 5.9%, hearing loss (HL) in 13.90%, and orofacial clefts in 3.1%. In the pVACTERL group, ear anomalies were found in 7.2%, microtia in 5.0%, HL in 9.3%, and orofacial cleft in 2.2%. Maternal diabetes significantly increased the risk for HL in VACTERL (odds ratio [OR]: 3.71, 95% confidence interval [CI]: 1.5–7.3) and pVACTERL patients (OR: 6.7, 95% CI: 1.70–23.4). Poorly controlled maternal diabetes significantly increased the risk for all the outcomes in VACTERL patients including CF anomalies (OR: 4.2, 95% CI: 1.9–9.6), ear anomalies (OR: 4.7, 95% CI: 1.8–11.8), microtia (OR: 5.4, 95% CI: 1.7–16.6), and HL (OR: 8.1, 95% CI: 3.4–19.4). Twin status was significantly associated with the occurrence of microtia (p = 0.038) in VACTERL patients. Occurrence of CF features, particularly ear anomalies, microtia, and HL, might be considered as part of phenotypic diversity of VACTERL association. Diabetes and twinning might appear to play a role in increasing the risk for this phenotype in VACTERL association. [ABSTRACT FROM AUTHOR]

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2‐mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral‐Anal‐Cardiac‐Tracheo‐Esophageal‐Renal‐Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed‐up at the Necker‐Enfants Malades Hospital over a 10‐years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral‐Anal‐Cardiac‐Tracheo‐Esophageal‐Renal‐Limb defects (VACTERL) or VACTERL/Oculo‐Auriculo‐Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non‐Mendelian genetic models. [ABSTRACT FROM AUTHOR]

Purpose: Antenatal detection of limb anomalies is not uncommon, and pregnancies are usually terminated in view of the expected physical handicap. The aim of this retrospective observational study is to delineate the spectrum of fetal limb anomalies and provide evidence in support of complete postnatal evaluation in establishing recurrence risk. Methods: We present 54 cases of limb malformations detected antenatally and discuss the spectrum of abnormalities, the utility of fetal autopsy, and genetic testing to establish recurrence risk in subsequent pregnancies. Results: 16/54 cases were isolated radial ray anomalies. There were five cases of amniotic band syndrome, five limb body wall complex cases, three VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo‐esophageal fistula, renal anomalies, and limb abnormalities) associations, one case of sirenomelia, two cases of limb pelvis hypoplasia, and one case of OEIS (Omphalocele Exstrophy Imperforate anus and spinal defects). Four fetuses with non‐isolated radial ray anomaly had trisomy 18. One case with bilateral radial ray defect had a mutation in the FANC‐E gene confirming fanconi anemia. Twelve cases were unclassified. Conclusion: Autopsy is the most important investigation in fetuses with limb anomalies. We suggest chromosomal microarray (CMA) as a first‐tier test after autopsy. However, in cases of bilaterally symmetrical limb anomalies, in case of previous similarly affected child, or history of consanguinity, whole exome sequencing (WES) can be offered as the primary investigation, followed by CMA if WES is normal. [ABSTRACT FROM AUTHOR]

Pleiotropy is defined as the phenomenon of a single gene locus influencing two or more distinct phenotypic traits. However, nicotinamide adenine dinucleotide (NAD+) deficiency through diet alone can cause multiple or single malformations in mice. Additionally, humans with decreased NAD+ production due to changes in pathway genes display similar malformations. Here, I hypothesize NAD+ deficiency as a pleiotropic mechanism for multiple malformation conditions, including limb‐body wall complex (LBWC), pentalogy of Cantrell (POC), omphalocele‐exstrophy‐imperforate anus‐spinal defects (OEIS) complex, vertebral‐anal‐cardiac‐tracheoesophageal fistula‐renal‐limb (VACTERL) association (hereafter VACTERL), oculoauriculovertebral spectrum (OAVS), Mullerian duct aplasia‐renal anomalies‐cervicothoracic somite dysplasia (MURCS), sirenomelia, and urorectal septum malformation (URSM) sequence, along with miscarriages and other forms of congenital malformation. The term Congenital NAD Deficiency Disorder (CNDD) could be considered for patients with these malformations; however, it is important to emphasize there have been no confirmatory experimental studies in humans to prove this hypothesis. In addition, these multiple malformation conditions should not be considered individual entities for the following reasons: First, there is no uniform consensus of clinical diagnostic criteria and all of them fail to capture cases with partial expression of the phenotype. Second, reports of individuals consistently show overlapping features with other reported conditions in this group. Finally, what is currently defined as VACTERL is what I would refer to as a default label when more striking features such as body wall defects, caudal dysgenesis, or cloacal exstrophy are not present. [ABSTRACT FROM AUTHOR]

The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals. [ABSTRACT FROM AUTHOR]

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is one of the most common gastrointestinal birth defects. It can occur in isolation or in association with other birth defects or genetic syndromes. We retrospectively reviewed the EA/TEF cases evaluated at Rady Children's Hospital San Diego (San Diego, CA) between 2007 and 2016. Data were collected for 157 patients. The majority of patients (105, 66.8%) had an associated major malformation present, and 52 patients (33.1%) had isolated EA/TEF. The patients with associated malformations were distributed as follows: 16 patients (10.2%) had a known genetic syndrome (the most common being Trisomy 21 in 11 patients); six patients (3.8%) had a suspected genetic syndrome; one patient had a suspected teratogenic syndrome (diabetic embryopathy); 30 patients had VACTERL association (19.1%); 32 patients had a "partial VACTERL" association (only two VACTERL‐type defects without other malformation); nine patients (5.7%) had one additional non‐VACTERL‐type birth defect, two patients had VACTERL‐type defects plus auricular malformations; and nine patients (5.7%) were classified as "unknown syndrome." A classification of the patterns of malformation of patients with congenital EA/TEF is proposed based on reviewing the data of this relatively large and phenotypically diverse patient group. [ABSTRACT FROM AUTHOR]

Background: Patients born with esophageal atresia (EA) have a higher incidence of infantile hypertrophic pyloric stenosis (IHPS), suggestive of a relationship. A shared etiology makes sense from a developmental perspective as both affected structures are foregut derived. A genetic component has been described for both conditions as single entities and EA and IHPS are variable components in several monogenetic syndromes. We hypothesized that defects disturbing foregut morphogenesis are responsible for this combination of malformations. Methods: We investigated the genetic variation of 15 patients with both EA and IHPS with unaffected parents using exome sequencing and SNP array‐based genotyping, and compared the results to mouse transcriptome data of the developing foregut. Results: We did not identify putatively deleterious de novo mutations or recessive variants. However, we detected rare inherited variants in EA or IHPS disease genes or in genes important in foregut morphogenesis, expressed at the proper developmental time‐points. Two pathways were significantly enriched (p < 1 × 10−5): proliferation and differentiation of smooth muscle cells and self‐renewal of satellite cells. Conclusions: None of our findings could fully explain the combination of abnormalities on its own, which makes complex inheritance the most plausible genetic explanation, most likely in combination with mechanical and/or environmental factors. As we did not find one defining monogenetic cause for the EA/IHPS phenotype, the impact of the corrective surgery could should be further investigated. [ABSTRACT FROM AUTHOR]

Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a foregut defect that is a major component of the VATER/VACTERL association. The specific diagnostic criteria for the VATER/VACTERL association phenotype have changed over time. The current definition is presence of at least three of the following: Vertebral defects, Anal atresia, Cardiac defects, TE fistula, or Renal and Limb anomalies in the absence of a specific genetic diagnosis. Using the Texas Birth Defect Registry, 1,175 cases of EA+/−TEF (174 EA; 1,001 EA + TEF) were evaluated against strict definitions of VATER/VACTERL. Nine (5.2%) cases of EA alone and 164 (16.3%) cases of EA + TEF met criteria for a diagnosis of VATER; and 20 (11.5%) and 223 (22.2%), respectively, met criteria for VACTERL. Trisomy 21, Trisomy 18, 22q11 deletion, and CHARGE were the most common syndromic diagnoses. About 88.5% (154) cases of EA and 77.8% (778) cases of EA + TEF were likely not to meet the criteria for VACTERL. EA+/−TEF is more likely to be an isolated defect or part of a multiple malformation syndrome in a pattern other than VACTERL, than be part of the defined association. This study reinforces the need to consider broader evaluation for alternate diagnoses in the presence of these defects. [ABSTRACT FROM AUTHOR]

The combination of vertebral, anal, cardiac, tracheo‐esophageal, renal and limb anomalies termed VACTERL association, also referred to as VATER, has been used as a clinical descriptor and more recently, a diagnosis of exclusion, for a specific group of phenotypic manifestations that have been observed to co‐occur non‐randomly. Though the causes remain elusive and poorly understood in most patients, VACTERL association is thought to be due to defects in early embryogenesis and is likely genetically heterogeneous. We present data on 36 patients diagnosed with VACTERL association in addition to describing the phenotypic diversity of each component feature. Unique cases in our cohort include a patient with a 498.59 kb microdeletion in the 16p11.2 region and another with a 215 kb duplication in the 3p25.2 region. Our findings expand upon the current understanding of VACTERL association and guide future research aimed at determining its etiology. [ABSTRACT FROM AUTHOR]

The most impressive phenotypic appearance of sirenomelia is the presence of a 1808-rotated, axially positioned, single lower limb. Associated gastrointestinal and genitourinary anomalies are almost always present. This rare anomaly is still the subject of ongoing controversies concerning its nosology, pathogenesis, and possible genetic etiology. Sirenomelia can be part of a syndromic continuum, overlapping with other complex conditions including caudal dysgenesis and VATER/VACTERL/VACTERL-H associations, which could all be part of a heterogeneous spectrum, and originate from an early defect in blastogenesis. It is imaginable that different “primary field defects," whether or not genetically based, induce a spectrum of caudal malformations. In the current study, we review the contemporary hypotheses and conceptual approaches regarding the etiology and pathogenesis of sirenomelia, especially in the context of concomitant conditions. To expand on the latter, we included the external and internal dysmorphology of one third trimester sirenomelic fetus from our anatomical museum collection, in which multiple concomitant but discordant anomalies were observed compared with classic sirenomelia, and was diagnosed as VACTERL-H association with sirenomelia. [ABSTRACT FROM AUTHOR]

Key Clinical Message This case report describes a patient with a 22q11.2 duplication. His features, which include VACTERL association with an esophageal atresia/tracheo-esophageal fistula and a vascular ring, expand the previously described phenotype for this duplication. [ABSTRACT FROM AUTHOR]

Cases diagnosed as the VACTERL Association are heterogeneous, and can involve other associations arising from different developmental processes with midline effects. However, these often lack the classic radial ray anomalies that help make VACTERL distinct. A more specific association can be delineated based on teratogenic disturbances affecting vulnerabilities associated with the establishment of cell fate through positional information, with two basic weaknesses: (i) The midline, where topological properties such as reduced lateral information should make information losses more likely; (ii) Increased distal sensitivity at the end of a morphogen gradient in the limbs, where both duplications and deficiencies can arise from similar disturbances. Vertebral, cardiac, anal-rectal, and tracheo-esophaeal findings are primary midline derivatives. While the kidneys are bilateral, they can be influenced by the midline, although there may also be effects on the ureteral buds as distal structures. The pre-axial area is the most distal in limb development, giving radial/tibial deficiencies and duplications. Alternatively, spina bifida and orofacial clefts originate from bilateral structures that are less likely to be affected by problems with midline determination, explaining the rarity of these disorders with VACTERL. Suggested human genetic models typically involve the midline, but lack radial findings, and true Mendelian forms are rare. However, developmental genes such as Sonic Hedgehog may have a pathogenetic role without being causal. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Associations of anomalies, with VACTERL as the prototype, have been the source of much debate, including questions about the validity and definition of this category. Evidence is presented for a teratologic basis for associations involving interactions between disruptive events and specific vulnerabilities. Because the embryo is organized in time and space, differences in the timing, location, and severity of exposures will create variable sequelae for any specific vulnerability, creating associations. The blastogenetic stage of development involves distinct properties that affect the nature of associations arising during this time, including relatively undifferentiated developmental fields and causally nonspecific malformations. With this, single anomalies can be part of the spectrum of findings that comprise a specific association. A specific defect defines a subset of disturbances, biasing frequencies of other defects. Processes are basic, integrated, and general, so disruptions are often lethal, and can have multiple effects, accounting for high incidences of multiple anomalies, and overlaps between associations. Blastogenetic disturbances also do not affect the late 'fine tuning' of minor anomalies, although pathogenetic sequences can occur. This model suggests that certain combinations of congenital anomalies can arise from causally nonspecific teratogenetic fields determined by timing, location, and vulnerabilities, rather than polytopic developmental fields. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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. Birth Defects Research (Part A) 103:880-886, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. [ABSTRACT FROM AUTHOR]

Background VACTERL association refers to a combination of congenital anomalies that can include: vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula with esophageal atresia, renal anomalies (typically structural renal anomalies), and limb anomalies. Methods We conducted a description of a case series to characterize renal findings in a cohort of patients with VACTERL association. Out of the overall cohort, 48 patients (with at least three component features of VACTERL and who had abdominal ultrasound performed) met criteria for analysis. Four other patients were additionally analyzed separately, with the hypothesis that subtle renal system anomalies may occur in patients who would not otherwise meet criteria for VACTERL association. Results Thirty-three (69%) of the 48 patients had a clinical manifestation affecting the renal system. The most common renal manifestation (RM) was vesicoureteral reflux (VUR) in addition to a structural defect (present in 27%), followed by unilateral renal agenesis (24%), and then dysplastic/multicystic kidneys or duplicated collected system (18% for each). Twenty-two (88%) of the 25 patients with a structural RM had an associated anorectal malformation. Individuals with either isolated lower anatomic anomalies, or both upper and lower anatomic anomalies were not statistically more likely to have a structural renal defect than those with isolated upper anatomic anomalies ( p = 0.22, p = 0.284, respectively). Conclusion Given the high prevalence of isolated VUR in our cohort, we recommend a screening VCUG or other imaging modality be obtained to evaluate for VUR if initial renal ultrasound shows evidence of obstruction or renal scarring, as well as ongoing evaluation of renal health. Birth Defects Research (Part A) 100:801-805, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Gastrulation is the process in which the three germ layers are formed that contribute to the formation of all major tissues in the developing embryo. We here review mouse genetic models in which defective gastrulation leads to mesoderm insufficiencies in the embryo. Depending on severity of the abnormalities, the outcomes range from incompatible with embryonic survival to structural birth defects, such as heart defects, spina bifida, or caudal dysgenesis. The combined evidence from the mutant models supports the notion that these congenital anomalies can originate from perturbations of mesoderm specification, epithelial-mesenchymal transition, and mesodermal cell migration. Knowledge about the molecular pathways involved may help to improve strategies for the prevention of major structural birth defects. Birth Defects Research (Part A) 100:608-622, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND Congenital heart disease (CHD) is estimated to affect between 3 and 5% of all newborns. Extra-cardiac malformations are observed in 7 to 50% of patients with CHD. One relatively well-known association that can occur in the context of CHD is VACTERL. Controversy still remains regarding the definition of VATER association and its expansion to VACTERL, the appropriate diagnostic criteria and the overall incidence. METHODS We conducted a description of a case series to characterize the cardiac findings present in a cohort of patients meeting the criteria for VACTERL association. RESULTS Forty-six of 220 were eligible for inclusion into the study, 67% (31 of 46) had CHD. The most common CHD was ventricular septal defect, present in 18 of 31 patients (58%). There was no statistically significant association between CHD severity and the presence or absence of other VACTERL component features, specifically anorectal malformation ( p = 0.18) or tracheo-esophageal fistula ( p = 0.72). CHD presence also did not correlate with the presence of tracheo-esophageal fistula or anorectal malformation. CONCLUSION Although this study does not, by design, provide further evidence toward the questions of whether CHD is a defining feature of VACTERL association, the frequency of CHD in our cohort does lend support to it being an important medical consideration in patients with VACTERL association. Based on our experience, we strongly recommend a screening echocardiogram to evaluate for CHD in individuals with a potential diagnosis of VACTERL association. Birth Defects Research (Part A) 97:792-797, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Structural rearrangements of chromosome 19p are rare, and their resulting phenotypic consequences are not well defined. This is the first study to report a cohort of eight patients with subtelomeric 19p13.3 microdeletions, identified using clinical chromosomal microarray analysis (CMA). The deletion sizes ranged from 0.1 to 0.86 Mb. Detailed analysis of the patients' clinical features has enabled us to define a constellation of clinical abnormalities that include growth delay, multiple congenital anomalies, global developmental delay, learning difficulties, and dysmorphic facial features. There are eight genes in the 19p13.3 region that may potentially contribute to the clinical phenotype via haploinsufficiency. Moreover, in silico genomic analysis of 19p13.3 microdeletion breakpoints revealed numerous highly repetitive sequences, suggesting LINEs/SINEs-mediated events in generating these microdeletions. Thus, subtelomeric 19p13.3 appears important for normal embryonic and childhood development. The clinical description of patients with deletions in this genomic interval will assist clinicians to identify and treat individuals with similar deletions. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations ( ARMs). Design A population-based case-control study. Setting Seventeen EUROCAT ( European Surveillance of Congenital Anomalies) registries, 1980-2008. Population The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM- VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. Methods Multiple logistic regression analyses were used to calculate adjusted odds ratios ( ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. Main outcome measures Adjusted ORs for pregnancy-related risk factors for ARM. Results The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). Conclusions This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL. [ABSTRACT FROM AUTHOR]

Pleiotropy is defined as the phenomenon of a single gene locus influencing two or more distinct phenotypic traits. However, nicotinamide adenine dinucleotide (NAD+) deficiency through diet alone can cause multiple or single malformations in mice. Additionally, humans with decreased NAD+ production due to changes in pathway genes display similar malformations. Here, I hypothesize NAD+ deficiency as a pleiotropic mechanism for multiple malformation conditions, including limb-body wall complex (LBWC), pentalogy of Cantrell (POC), omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex, vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association (hereafter VACTERL), oculoauriculovertebral spectrum (OAVS), Mullerian duct aplasia-renal anomalies-cervicothoracic somite dysplasia (MURCS), sirenomelia, and urorectal septum malformation (URSM) sequence, along with miscarriages and other forms of congenital malformation. The term Congenital NAD Deficiency Disorder (CNDD) could be considered for patients with these malformations; however, it is important to emphasize there have been no confirmatory experimental studies in humans to prove this hypothesis. In addition, these multiple malformation conditions should not be considered individual entities for the following reasons: First, there is no uniform consensus of clinical diagnostic criteria and all of them fail to capture cases with partial expression of the phenotype. Second, reports of individuals consistently show overlapping features with other reported conditions in this group. Finally, what is currently defined as VACTERL is what I would refer to as a default label when more striking features such as body wall defects, caudal dysgenesis, or cloacal exstrophy are not present., (© 2022 The Author. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

ABSTRACT The present case report describes two patients with a novel combination of VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, limb), neural tube defect and crossed renal ectopia. Though cases of VACTERL associated with crossed renal ectopia have been described, the present case report is the first to describe its combination with neural tube defect. The cases reported here are significant because central nervous system manifestations are scarce in VACTERL syndrome. The role of sonic hedgehog pathway has been proposed in VACTERL association and neural tube defects. Axial Sonic hedgehog signaling has also been implicated in the mediolateral positioning of the renal parenchyma. With this knowledge, the etiopathogenesis of this novel combination is discussed to highlight the role of sonic hedgehog signaling as a point of coherence. [ABSTRACT FROM AUTHOR]

Rhombencephalosynapsis (RES) is an uncommon cerebellar malformation characterized by fusion of the hemispheres without an intervening vermis. Frequently described in association with Gómez-López-Hernández syndrome, RES also occurs in conjunction with VACTERL features and with holoprosencephaly (HPE). We sought to determine the full phenotypic spectrum of RES in a large cohort of patients. Information was obtained through database review, patient questionnaire, radiographic, and morphologic assessment, and statistical analysis. We assessed 53 patients. Thirty-three had alopecia, 3 had trigeminal anesthesia, 14 had VACTERL features, and 2 had HPE with aventriculy. Specific craniofacial features were seen throughout the cohort, but were more common in patients with alopecia. We noted substantial overlap between groups. We conclude that although some distinct subgroups can be delineated, the overlapping features seen in our cohort suggest an underlying spectrum of RES-associated malformations rather than a collection of discrete syndromes. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: The VACTERL association (VA) is the non-random co-occurrence of vertebral anomalies, anal atresia, cardiovascular malformations, tracheoesophageal fistula and/or esophageal atresia, renal anomalies, and/or limb anomalies, and is referred to by the first letters of its components. Studies investigating the clinical characteristics of VA patients and probing of the observed current six component types are limited, and none of them is focused on neonates. We investigated the clinical characteristics of our patients diagnosed as having VA in the newborn period. Methods: We retrospectively reviewed the neonates whose final diagnosis was VACTERL association. Presence of at least three components of previously reported six anomalies was accepted as VACTERL association. Sex, birthweight, gestational age, postnatal age, anomalies of the systems that are included in VA, and the other features were recorded. Results: There was a male predominance (14/11) of 28 patients; and there were three patients with ambiguous genitalia. The most common observed VACTERL component was vertebral anomalies ( n= 26), followed by anal atresia ( n= 19), tracheoesophageal fistula/esophageal atresia ( n= 17), renal anomalies ( n= 15), limb anomalies ( n= 15) and cardiac anomalies ( n= 14). The most frequent combination was VCTL ( n= 4). Fifteen (57%) patients had non-VACTERL anomalies and the most frequent of these was ambiguous genitalia ( n= 3). Conclusion: VA patients may have different clinical characteristics in different populations, and clinicians may miss some component features if the patients are evaluated after the neonatal period. [ABSTRACT FROM AUTHOR]

Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement, and functional distress. This review explores (1) recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation; and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and nonsyndromic congenital vertebral malformation. Discussion includes exploration of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation, and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families. [ABSTRACT FROM AUTHOR]

Oesophageal atresia (OA) and/or tracheo-oesophageal fistula (TOF) are frequent malformations observed in approximately one in 3500 births. OA/TOF can be divided clinically into isolated OA (IOA) and syndromic OA (SOA) when associated with other features, the most frequent being cardiac, limb and vertebral malformations or anal atresia. SOA is observed in 50% of patients and can be subdivided into several causative groups comprising environmental agents, chromosomal disorders, malformative associations (CHARGE syndrome and VATER/VACTERL association), and other multiple congenital anomaly disorders. The observation of chromosomal disorders with SOA, as well as mouse models of OA provide support for the involvement of genetic factors in OA. Yet, epidemiological data (twin and family studies) do not support the major role of genetic factors in the majority of cases of IOA but rather a multifactorial model. However, several genes involved in SOA have been recently identified, namely N-MYC, SOX2, and CHD7 involved in Feingold (MIM 164280), anophthalmia-oesophageal-genital (MIM 600992) and CHARGE syndromes respectively (MIM 214800), suggesting that OA/TOF, at least in their syndromic forms, may be a highly genetically heterogeneous group. [ABSTRACT FROM AUTHOR]

Intraintestinal meconium calcification in the fetus and newborn is a rare finding, occurring in patients with intestinal obstruction. The intraluminal location of the enterolithiasis enables differentiation from calcifications that are secondary to bowel perforation and meconium peritonitis. We report on a term male neonate with VACTERL (vertebral defects, imperforate anus, cardiac anomalies, tracheoesophageal fistula, renal anomalies, limb anomalies) association and rectourethral fistula, in whom enterolithiasis was documented by prenatal ultrasound imaging at 21 weeks' gestation. A review of the literature and a summary of all previously described cases of neonates with intraluminal meconium calcifications are provided. Prenatal ultrasonographic detection of enterolithiasis in fetuses with anal atresia may indicate the presence of an enterourinary fistula. [ABSTRACT FROM AUTHOR]

To date the etiology of the association called VACTERL remains a mystery. Interestingly, clues as to the origin of this collection of defects may reside in an old hypothesis concerning the midline as a developmental field as postulated by Dr. John Opitz. This theory suggested that the midline was not a separate entity, but could be influenced by other developmental signals. With new information concerning the origin of the left-right axis (laterality) and the importance of communications between this axis and the cranio-caudal (anterior-posterior) axis for normal development, it has become clear that coordination of the molecular signals responsible for specification of these domains is essential for normal development. In fact, if the signals regulating laterality are disrupted, then midline and other defects can occur as has been observed in cases of heterotaxy, presumably because of a disruption in this coordinated signaling effort. Thus, the origins of the defects commonly observed in the VACTERL association may be due to altered signaling responsible for establishing the left-right axis. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In this single‐center retrospective study, we analyzed kidney transplant outcomes in nine pediatric patients with VACTERL [vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, limb abnormalities] association—making this the largest study of its kind. Of 743 pediatric kidney transplant recipients at our center (1980‐2017), nine had documented diagnoses of VACTERL association. All nine had congenital anorectal malformations and renal anomalies, five had vertebral defects, and one had a bifid thumb and tracheoesophageal fistula. Renal anomalies included dysplasia (n = 6), aplasia (n = 3), and horseshoe kidney (n = 2). Congenital lower urinary tract anomalies included neurogenic bladder (n = 6), obstructive uropathy (n = 4), anovesicular fistula (n = 1), rectourethral fistula (n = 1), and posterior urethral valves (n = 1). Age at transplant ranged from 1.2 to 15 years (mean, 7.3; standard deviation [SD], 5.5); 6 (67%) were male, and 3 (33%) were female; 6 (67%) had a living related donor, and 3 (33%) had a deceased donor. The overall graft survival rate was 78% (range, 1.5 to 25.2 years; mean, 10.5; SD, 8.9). One month post‐transplant, one recipient died with a functioning graft. At 3.7 years post‐transplant, one graft failed because of recurrent pyelonephritis. Post‐transplant urologic complications included pyelonephritis (n = 6), vesicoureteral reflux (n = 5), and graft hydronephrosis (n = 4). We conclude that pediatric patients with VACTERL association can be safely transplanted—careful patient selection with vigilance and intervention for pre‐ and post‐transplant urologic complications is essential. [ABSTRACT FROM AUTHOR]

VACTERL association is a condition involving the presence of multiple congenital anomalies. The condition was first described more than four decades ago, and is not extremely rare. However, relatively little is understood about the causes and underlying biology of the condition as a whole. There are many reasons for this, but there is increasing recognition that VACTERL is extremely clinically as well as etiologically heterogeneous, and this heterogeneity--as well as other hypothesized factors--have caused challenges to identifying the causes for a substantial proportion of patients. Current knowledge about the causes of this condition (or group of conditions) are described, followed by a discussion of possibilities that may reveal more answers for patients as well as researchers and clinicians who work related to this disorder., (© 2018 Wiley Periodicals, Inc.)

The article presents a case study of a Japanese male infant diagnosed with Fanconi's anemia (FA). Esophageal atresia was noted upon birth and multiple congenital anomalies were observed upon admission. Four of the criteria associated with vertebral anomalies, anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies, and limb anomalies (VACTERL) were present. Twenty-two lesions found in 100 cells in the blood culture led to the FA diagnosis.