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Although radiographs are generally performed in the neonatal period to evaluate for causes of respiratory distress or to evaluate line placement, close attention to the osseous structures can provide important clues to an underlying diagnosis. Although segmentation anomalies can be random, they are frequently associated with more complex entities such as VACTERL association. A butterfly vertebral body can hint at a possible diagnosis of Alagille syndrome even before jaundice develops in an infant with a murmur. Close evaluation of the sacrum can identify abnormalities that point to caudal regression or Currarino triad. Other classic musculoskeletal abnormalities in the extremities are readily apparent on physical exam but require radiographic evaluation to define anatomy. Diagnoses such as congenital pseudoarthrosis of the clavicle, Apert syndrome, constriction band syndrome, and proximal focal femoral deficiency have pathognomonic imaging findings. Given that treatment for these is usually delayed until later in life, extremity imaging might not occur in the neonatal period. [ABSTRACT FROM AUTHOR]

Background: Cardiac anomalies are prevalent in patients with bony spinal anomalies. Prior studies evaluating incidences of bony congenital anomalies of the spine are limited. The Kids’ Inpatient Database (KID) yields national discharge estimates of rare pediatric conditions like congenital disorders. This study utilized cluster analysis to study patterns of concurrent vertebral anomalies, anal atresia, cardiac malformations, trachea-esophageal fistula, renal dysplasia, and limb anomalies (VACTERL anomalies) co-occurring in patients with spinal congenital anomalies.Methods: Retrospective review of KID 2003-2012. KID-supplied hospital- and year-adjusted weights allowed for incidence assessment of bony spinal anomalies and cardiac, gastrointestinal, urinary anomalies of VACTERL. K-means clustering assessed relationships between most frequent anomalies within bony spinal anomaly discharges; k set to n − 1(n = first incidence of significant drop/little gain in sum of square errors within clusters).Results: There were 12,039,432 KID patients 0-20 years. Incidence per 100,000 discharges: 2.5 congenital fusion of spine, 10.4 hemivertebra, 7.0 missing vertebra. The most common anomalies co-occurring with bony vertebral malformations were atrial septal defect (ASD 12.3%), large intestinal atresia (LIA 11.8%), and patent ductus arteriosus (PDA 10.4%). Top congenital cardiac anomalies in vertebral anomaly patients were ASD, PDA, and ventricular septal defect (VSD); all three anomalies co-occur at 6.6% rate in this vertebral anomaly population. Cluster analysis revealed that of bony anomaly discharges, 55.9% of those with PDA had ASD, 34.2% with VSD had PDA, 22.9% with LIA had ASD, 37.2% with ureter obstruction had LIA, and 35.5% with renal dysplasia had LIA.Conclusions: In vertebral anomaly patients, the most common co-occurring congenital anomalies were cardiac, renal, and gastrointestinal. Top congenital cardiac anomalies in vertebral anomaly patients were ASD, PDA, and VSD. VACTERL patients with vertebral anomalies commonly presented alongside cardiac and renal anomalies. [ABSTRACT FROM AUTHOR]

The acronym VATER/VACTERL association (OMIM #192350) refers to the rare non-random co-occurrence of the following component features (CFs): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). According to epidemiological studies, the majority of patients with VATER/VACTERL association present with a 'Renal' phenotype comprising a large spectrum of congenital renal anomalies. This finding is supported by evidence linking all of the human disease genes for the VATER/VACTERL association identified to date, namely, FGF8, FOXF1, HOXD13, LPP, TRAP1, and ZIC3, with renal malformations. Here we review these genotype-phenotype correlations and suggest that the elucidation of the genetic causes of the VATER/VACTERL association will ultimately provide insights into the genetic causes of the complete spectrum of congenital renal anomalies per se. [ABSTRACT FROM AUTHOR]

Purpose: Anorectal malformations (ARM) can commonly occur in association with other congenital anomalies or as part of the combined anomaly. The present study aims to assess the outcome of patients with ARM and patients with ARM in VACTERL association. Methods: A 12-year retrospective analysis of all patients treated at a single tertiary children's institution with a diagnosis of ARM. We identified and compared patients with ARM to those with ARM in VACTERL association (3 or more anomalies). Data were collected for both groups to assess type of ARM, urinary incontinence (UI), constipation, soiling, dietary/laxative treatment, bowel management (BM) and surgical complications. Type of lesion and clinical outcomes were classified according to Krickenbeck International classification. Patients lost to follow-up, dead or not yet toilet-trained (or <4 years old) were excluded. Results: One hundred ninety-eight patients were identified, 174 enrolled in the study. Lesions were classified for each study group (VACTERL− vs VACTERL+) as perineal fistulas (36.4 vs 9.7 %, p = 0.0028), rectourethral fistulas (prostatic and bulbar) (23.1 vs 38.7 %, p = ns), rectovesical fistulas (3.5 vs 9.7 %, p = ns), rectovestibular fistulas (19.6 vs 22.6 %, p = ns), cloacal malformations (4.9 vs 9.7 %, p = ns), no fistula (4.9 vs 3.2 %, p=), others (7.7 vs 6.4 %, p = ns). The frequency of both dietary/laxative treatment and BM, as well as surgical complications were significantly higher in patients with VACTERL. Conclusions: The coexistence of VACTERL anomalies negatively affects not only the surgical outcome but also the bowel functioning. Therefore, a dedicated follow-up is strongly recommended. Further studies are needed to assess if this has an impact on the quality of life of these patients. [ABSTRACT FROM AUTHOR]

VATER/VACTERL association refers to the non-random co-occurrence of the following component features: vertebral defects, anal atresia, cardiac malformations, tracheoesophageal atresia, renal abnormalities, and limb defects. Recently, Solomon et al. (Hum Genet 127:731-733, ) observed an increased prevalence of component features among first-degree relatives of VATER/VACTERL patients suggesting that in some patients, the disorder may be inherited. To replicate these findings, we investigated 87 VATER/VACTERL patients with the presence of a minimum of three component features and their first-degree relatives ( n = 271). No increase in the overall prevalence of component features was observed in first-degree relatives compared to the general population (χ² = 2.68, p = 0.10). Separate analysis for the prevalence of single component features showed a higher prevalence of tracheoesophageal fistula/atresia among first-degree relatives compared to the general population (OR 17.65, 95 % CI 2.47-126.05). However, this was based on occurrence in one family only. Our findings suggest that although familial occurrence renders a genetic contribution likely, the overall risk of recurrence among the first-degree relatives of patients with VATER/VACTERL association is probably very low. Since the patients in the present study were young and no offspring could be studied, estimation of the role of de novo mutations in the development of VATER/VACTERL was not possible. [ABSTRACT FROM AUTHOR]

Background/purpose: Following a recent classification of the VATER Association provided by the CURE-Net consortium (submitted), we investigate medical predictors of psychological stress and anxieties in this particular condition.Methods: We developed a new set of questionnaires measuring psychological adjustment and quality of life outcome in conditions associated with anorectal and/or urogenital malformation (one self- report form to be completed by patients 7-17 years of age, two parent report forms with one relating to patients with an age range of 0-6 years, resp. 7-17 years of age). The questionnaire "Malformation-related Stress and Anxieties" comprises 26 items belonging to five subscales (I. Functional and cosmetic impairment, II. Intimacy and relationship, III. Social inclusion, IV. Psychological functioning, V. Family functioning). Every item can be responded to with respect to both actual, present problems already experienced as well as to future anxieties anticipating future development and adjustment (a perspective which especially applies in younger patients). Internal consistencies of the scales are good, resp. very good (Cronbach's α = .85 concerning present sources of anxiety scale, resp., .94 concerning future anxieties scale). The items are supplied with a Likert-type 5-point scale. We administered the questionnaire in N = 17 children and adolescents suffering from VATER via parental (proxy) report.Results: As most medical risk factors affected nearly the entire sample, statistical analysis excluded investigation of differential impact on psychological stress experience and anxieties in subjects exposed versus not exposed. Special attention, therefore, was paid to those medical parameters with the best statistical power to differentiate between individuals of high versus low psychological outcome. Medical predictors differentiating between individuals with high versus low adjustment comprise post-operative infections of the urinary tract (t[15] = -3.78, p = .09), wound infections (t[15] = -3.04, p < .01), stoma complications (t[15] = -2.11, p = .08) (e.g., prolapsed (t[13] = -2.37, p = .05), other treatment complications (t[15] = -2.59, p < .05) and presence of a megacolon (t[13] = -2.44, p = .06).Discussion and Conclusions: From the perspective of stress psychology, the findings may indicate that particular medical characteristics of a malformation may operate via two different pathways: (a) pathway of severity of a particular medical risk factor: the presence of a megacolon, for example, may restrict quality of life and successful adjustment via multiple and long term functional impairments associated and (b) pathway of subjective predictability and controllability of treatment course. In accordance with theoretical models from stress psychology, the psychological impact of complicating factors such as wound-healing infections is not operating via severity of impairment, but via implicit messages they convey, indicating a low predictability and controllability of course of disease and treatment. As a result, they may increase intensity of worry and anxieties upon further difficulties still to come during future development. As a conclusion, psychological counseling may not only address concrete functional impairments and stressors, but also basic feelings of insecurity, controllability and self-efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Urological anomalies are frequently seen in patients with anorectal malformations (ARM) and can result in upper urinary tract deterioration. Whether the current method of screening is valid, adequate and needed for all patients is not clear. We, therefore, evaluated the urological screening methods in our ARM patients for changes in urological treatment, outcome and follow-up.Methods: The medical records of 331 children born with an ARM in the period 1983-2003 were retrospectively studied. Documentation of diagnosis, screening method, urological anomalies, treatment, complications, follow-up and outcome were measured.Results: The overall incidence of urological anomalies was 52%. The incidence of urological anomalies and urological follow-up time decreased with diminishing complexity of the ARM. Hydronephrosis, vesico-urethral reflux, lower urinary tract dysfunction and urinary incontinence were encountered most. Treatment invasiveness increased with the increase of complexity of an ARM. Lower urinary tract dysfunction needing urological care occurred in 43% in combination with lumbosacral or spinal cord anomalies and in 8% with no abnormalities in the lumbosacral-/spinal region.Conclusions: Urological anomalies in patients with complex ARM are more severe than in patients with less complex ARM. Ultrasonography of the urinary tract should be performed in all patients. Voiding cysto-urethrography can be reserved for patients with dilated upper urinary tracts, urinary tract infections or lumbosacral and spinal abnormalities. All patients with complex ARM need urodynamic investigations. When using these indications, the screening for urological anomalies in ARM patients can be optimized with long-term follow-up in selected patients. [ABSTRACT FROM AUTHOR]

Tracheal agenesis (TA) is a rare congenital anomaly of the respiratory tract. Many patients have associated anomalies, suggesting a syndromal phenotype. In a cohort of 12 patients, we aimed to detect copy number variations. In addition to routine cytogenetic analysis, we applied oligonucleotide array comparative genomic hybridization. Our patient cohort showed various copy number variations, of which many were parentally inherited variants. One patient had, in addition to an inherited 16p12.1 deletion, a 3.6 Mb deletion on chromosomal locus 5q11.2. This patient had a syndromic phenotype, including vertebral, anal, cardiovascular and tracheo-oesophageal associated anomalies, and other foregut-related anomalies, such as cartilage rings in the oesophagus and an aberrant right bronchus. No common deletions or duplications are found in our cohort, suggesting that TA is a genetically heterogeneous disorder. [ABSTRACT FROM AUTHOR]

Esophageal atresia and tracheoesophageal fistula (EA/TEF) are major congenital malformations affecting 1:3500 live births. Current research efforts are focused on understanding the etiology of these defects. We describe well-known animal models, human syndromes, and associations involving EA/TEF, indicating its etiologically heterogeneous nature. Recent advances in genotyping technology and in knowledge of human genetic variation will improve clinical counseling on etiologic factors. This review provides a clinical summary of environmental and genetic factors involved in EA/TEF. [ABSTRACT FROM AUTHOR]

The teratogenic effect of Adriamycin (doxorubicin) in the rat model, and more recently in the mouse, has provided paediatric surgeons with a reliable, easily reproducible method of studying the embryology and molecular biology for a range of complex congenital anomalies. Concomitantly these animal models have stimulated interest among embryologists for the effect on the notochord, shedding more light on the important organizational role of this structure in the developing embryo. Finally, as more is learnt of the pathogenesis of the various malformations induced by Adriamycin, future therapeutic interventions involving gene therapy, drugs or surgery may arise. This article reviews the establishment of the Adriamycin rat and mouse models, examines their impact on various congenital malformations, and suggests targets for further research. [ABSTRACT FROM AUTHOR]

The VACTERL complex refers to anomalies of the bony spinal column (V), atresias in the gastrointestinal tract (A), congenital heart lesions (C), tracheoesophageal defects (TE), renal and distal urinary tract anomalies (R) and limb lesions (L). The incidence of each of these components has not been precisely quantified in the recent literature and the full array of anomalies within each systemic class of the VACTERL complex has not been well described. Therefore, we reviewed our most recent 20-year experience of patients born with esophageal atresia to comprehensively delineate and accurately describe the type and incidence of associated lesions. A retrospective review was then conducted on all patients diagnosed with esophageal atresia between 1985 and 2005. Patient demographics recorded included gestational age, weight and gender. The specific types of lesions were carefully cataloged. The outcome measure recorded was survival. One hundred and twelve patients were diagnosed with esophageal atresia were identified during the study period. The gestational age range was 28-41 weeks with an average of 36.5 weeks. Average birth weight was 2,557 g (range 1,107-3,890). A male predominance was seen with 62 males and 50 females. The overall survival was 92.9%. The categorical breakdown of anomalies were vertebral (24.1%), atresia (14.3%), cardiac (32.1%), tracheoesophageal fistula (95.5%), urinary (17.0%), skeletal (16.1%) and other (10.8%). VACTERL anomalies are common in patients with esophageal atresia, however, they appear to have little impact on overall survival. [ABSTRACT FROM AUTHOR]

Communicating bronchopulmonary foregut malformations (CBPFMs) are unusual congenital structures composed of a segment of lung tissue connected to the foregut. We present what we believe is the first reported case of identical twins concordant for CBPFM who are discordant for the VACTERL association. Their nonfunctional lung tissue was successfully removed and the fistulae were corrected, and they are expected to live normal life spans. We review the literature concerning these malformations and the proposed theories of their etiology. This case report of concordance in identical twins suggests that a possible genetic component to CBPFMs cannot be ruled out. The discordance for the VACTERL association implies that the etiology is most likely multifactorial. [ABSTRACT FROM AUTHOR]

Background: The VACTERL association is a spectrum of clinical conditions, including esophageal atresia (EA) and tracheoesophageal fistula (TEF), which affects approximately 1 in 5,000 live human births. The administration of intraperitoneal Adriamycin to pregnant rats reliably induces anomalies, such as EA and TEF, in their offspring, in what is known as the Adriamycin rat model (ARM). In affected embryos the presence of gross notochord abnormalities is commonly found, with typical features being ectopic ventral branches and adherence of the notochord to the foregut. Fibronectin (FN) is an extracellular matrix (ECM) glycoprotein present on most cell surfaces, in extracellular fluids and in plasma. FN is involved in various functions, including cell adhesion, cell motility and wound healing. Previous studies in rats have shown that a single dose of Adriamycin can produce an appreciable rise in FN levels in various organs such as kidney and heart. We hypothesised that Adriamycin administration could promote upregulation of FN expression contributing to increased gut-notochord adherence and the development of abnormal ventral notochordal branching in the ARM. This study was designed to investigate FN expression in ARM embryos.Methods: Adriamycin (1.75 mg/kg) was administered intraperitoneally to pregnant rats on days 7,8 and 9 of gestation (E7, E8 and E9 respectively). Control animals were given saline. Embryos recovered on E10-E14 were fixed, embedded in paraffin and sectioned. Immunohistochemistry using an anti-FN rabbit polyclonal antibody was performed.Results: FN expression in both Adriamycin and control embryos on E10, E11 and E12 was comparable. However, the levels of FN expression in Adriamycin embryos on E13 and E14 were significantly greater in embryos with abnormal notochords than in equivalent control embryos.Conclusion: Adriamycin-induced increased expression of FN, in the ARM, may contribute to abnormal notochord development leading to the VACTERL association. [ABSTRACT FROM AUTHOR]

Adriamycin is an anthracycline, anti-neoplastic drug with known teratogenic effects on foetal rats in what is known as the Adriamycin rat model (ARM). This includes conditions similar to those in newborn humans, known collectively as the VACTERL association. This comprises vertebral (V), anorectal (A), cardiac (C), tracheoesophageal (TE), renal (R) and limb (L) anomalies. We designed this study to test the hypothesis that the administration of Adriamycin to chick embryos would cause similar anomalies to those in the VACTERL association seen in the ARM. Fertilized Ross eggs received Adriamycin doses from 2–50 μg into the air sac and from 0.9–6 μg into the albumin. Administration varied from day 0–3 (D0–3) with D0 being the first day of incubation. Control eggs received saline. Embryos were incubated at 38°C and a relative humidity of 70%. Embryos were recovered on D14, paraffin-embedded and transverse sections studied for morphological abnormalities. In the air sac group (n=142), 71% of Adriamycin embryos survived versus 86% of controls (n=29). In the albumin group (n=121), 42% of Adriamycin embryos survived versus 55% of controls (n=69). No embryos demonstrated anomalies consistent with the VACTERL association. Ventral defects affected 1% of surviving Adriamycin embryos versus 4% of controls in the air sac group. In the albumin group, 19.8% of surviving Adriamycin embryos had ventral defects compared to 15.7% of surviving controls. Anophthalmia affected 1% of the surviving embryos in the Adriamycin air sac group and 2% of the Adriamycin albumin group. No controls developed anophthalmia. Exencephaly affected 2% of the survivors in the Adriamycin air sac group but none of the albumin group or controls. The administration of Adriamycin to chick embryos in comparable doses and times to those used in the ARM does not appear to produce comparable effects in relation to developmental anomalies, such as the VACTERL association. Despite examining different administration routes and mimicking the ARM, by giving Adriamycin to embryos at gastrulation, we were unable to re-create the anomalies seen in the ARM. [ABSTRACT FROM AUTHOR]