Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes.

The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations.

Thoracoscopic repair of esophageal atresia with distal tracheoesophageal fistula: is it a safe procedure in infants weighing less than 2000 g?

BACKGROUND: Since Rothenberg first performed thoracoscopic repair for esophageal atresia with distal tracheoesophageal fistula (EA/TEF) successfully in 2000, thoracoscopic repair has achieved status as a routine procedure worldwide. Previously, an international multicenter study reported that this procedure was not inferior to conventional open surgery. However, thoracoscopic surgery is a highly difficult operation for surgeons and anesthesiologists; as a result, the safety and efficacy of the surgery is still under debate. Considering these circumstances, the purpose of this study was to analyze the results of single-center thoracoscopic surgery and to compare the outcomes relative to the patient's weight at the time of surgery. METHODS: We retrospectively analyzed patients with EA/TEF who underwent thoracoscopic surgery in a single center between October 2008 and February 2017. RESULTS: In total, 41 cases of thoracoscopic repair of EA/TEF were performed. Upon subgrouping by over and under 2000 g of body weight at the time of operation, 34 were found to be over 2000 g and seven were under 2000 g. Intraoperative factors and events were not significantly different between the two groups. Additionally, most of the postoperative outcomes, including the rate of postoperative leakage and strictures, showed no difference. On the other hand, the under 2000 g group had more gastroesophageal reflux requiring fundoplication than did the heavier group (P = 0.04). CONCLUSIONS: The results of this center's thoracoscopic repair of EA/TEF were not inferior to other centers' outcomes. Additionally, the intraoperative and postoperative outcomes were similar despite differences in weight at operation. Therefore, thoracoscopic repair might be a feasible surgical option for infants weighing less than 2000 g when performed by a surgeon and anesthesiologist team who are experienced in pediatric thoracoscopic surgery.

An Unusual Lung Mass of Heterotopic Pancreatic Tissue in a Neonate With an Elevated Immunoreactive Trypsinogen on Newborn Screen.

We present a case of a neonate with tracheoesophageal fistula and esophageal atresia along with a suspicious lung mass who had a false-positive newborn screen for cystic fibrosis due to an elevated serum immunoreactive trypsinogen with an additionally elevated serum lipase. The infant's lung mass was found to contain heterotopic pancreatic tissue consisting of acini, ducts, and islet cells, without an associated gastrointestinal duplication cyst. This constellation of congenital abnormalities has not been described in previous literature. Also, this is the first reported case of a neonate with elevated serum pancreatic enzymes in which the underlying etiology was discovered to be heterotopic pancreas.

Gastrointestinal disorders in Down syndrome.

Down syndrome is the most common human chromosomal disorder. Among clinical findings, one constant concern is the high prevalence of gastrointestinal system alterations. The aim of this study was to determine the prevalence of gastrointestinal disorders at a Down syndrome outpatient clinic during a 10-year follow-up period. Data from medical files were retrospectively reviewed from 1,207 patients. Gastrointestinal changes occurred in 612 (50.7%). The most prevalent disorder was chronic intestinal constipation. Intestinal parasite occurred in 22% (mainly giardiasis), gastroesophageal reflux disease in 14%, digestive tract malformations occurred in 5%: 13 cases of duodenal atresia, 8 of imperforate anus, 4 annular pancreases, 2 congenital megacolon, 2 esophageal atresias, 2 esophageal compression by anomalous subclavian and 1 case of duodenal membrane. We had 38/1,207 (3.1%) patients with difficulty in sucking and only three with dysphagia that resolved before the second year of life. Peptic ulcer disease, celiac disease, and biliary lithiasis were less prevalent with 3% each. Awareness of the high prevalence of gastrointestinal disorders promotes outstanding clinical follow-up as well as adequate development and greater quality of life for patients with Down syndrome and their families.

Sonographic demonstration of fetal esophagus using three-dimensional ultrasound imaging.

OBJECTIVE: To evaluate the feasibility of antenatal direct visualization of normal and abnormal fetal esophagus using three-dimensional ultrasound (3D-US) with Crystal Vue rendering technology. METHODS: Between February and April 2018, 3D-US volumes were collected from a non-consecutive series of singleton pregnancies, referred for clinically indicated detailed prenatal ultrasound at 19-28 weeks' gestation to one of two fetal medicine units in Italy. 3D volumes were acquired from a midsagittal section of the fetal thorax and upper abdomen with the fetus lying in supine position. Postprocessing with multiplanar mode was applied to orientate the volume and identify the esophagus. The region of interest was angled by approximately 30° to the spine and its thickness was adjusted in order to optimize visualization of the intrathoracic and intra-abdominal course of the esophagus. Crystal Vue software was used for image rendering of the fetal trunk in the coronal plane. Postnatal follow-up was available in all cases. RESULTS: During the study period, 91 pregnancies met the inclusion criteria and were recruited. The study cohort included two pregnancies with suspicion of esophageal atresia due to suboptimal visualization of the stomach. Of the 89 cases with normal stomach on two-dimensional (2D) imaging, 3D-US with Crystal Vue rendering technology allowed direct evaluation of the whole course of the esophagus in 74 (83.1%). In the two cases with small or absent stomach bubble on 2D imaging, esophageal atresia was demonstrated antenatally on 3D Crystal Vue imaging and was confirmed postnatally. The mean time required for offline postprocessing and visualization of the esophageal anatomy was 4 min. CONCLUSIONS: Using 3D-US with Crystal Vue rendering, it is possible to visualize antenatally the normal fetal esophagus and demonstrate presence of esophageal atresia. This should facilitate prenatal counseling and management of cases with suspected esophageal atresia. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A new esophageal elongation technique for long-gap esophageal atresia: in vitro comparison of myotomy techniques.

BACKGROUND: Complications such as stricture, leakage, recurrent tracheoesophageal fistula and mucosal pouch are commonly seen in myotomy techniques used for long-gap esophageal atresia (LGEA) treatments. Therefore, we think that there is a clear need for other techniques which would enable us to create more robust and longer esophagus in such cases. In this study, we reviewed multiple V-myotomy (VM) technique and the differences of the said technique with Livaditis circular myotomy (LM) and Kimura spiral myotomy (KM) techniques using literature as an aid. METHODS: 21 esophagus samples from 21 male lambs aged 12 months were used in vitro for the study. All esophageal samples were matched to have a length of 120 mm. Samples were divided into 3 groups of 7 and VM, LM and KM techniques were used in each group, respectively. Post-op esophagus lengths, elongation amount with each incision and perforation pressures were measured. RESULTS: Post-op esophageal lengths were measured as 227, 210 and 200 mm for VM, LM and KM, respectively. Elongation amount per incision was measured as 5.1, 4 and 3.34 mm, again in previous order of VM, LM, and KM. Finally, perforation pressure following VM, LM, and KM was measured as 460, 400, and 410 mmHg. CONCLUSION: VM was found to significantly increase total esophagus length and elongation per incision over LM and KM. In addition, VM was also shown to have a higher perforation pressure. Although in vivo live animal studies are required, we can say that VM can be used to create longer and robust esophagus.

Early Postnatal Ventricular Dysfunction Is Associated with Disease Severity in Patients with Congenital Diaphragmatic Hernia.

OBJECTIVE: To assess patterns of postnatal ventricular function and their relationship to prenatal and postnatal markers of disease severity in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: In this observational case-control study of cardiac function in infants with CDH in the first 5 days of life, systolic and diastolic function in the right ventricle (RV) and left ventricle (LV) were assessed using speckle tracking echocardiography-derived global strain and tissue Doppler imaging. Correlation between cardiac function and prenatal observed:expected total fetal lung volume (TFLV), oxygenation index (OI), duration of intubation, and hospital length of stay were assessed. RESULTS: All measures of systolic and diastolic function were significantly reduced in the CDH group (n = 25) compared with controls (n = 20) at <48 hours, and were improved by 72-120 hours. LV global systolic longitudinal strain (GLS) correlated with prenatal TFLV (R2 = 0.32; P = .03), OI (R2 = 0.35; P < .001), duration of intubation (R2 = 0.24; P = .04), and length of stay (R2 = 0.4; P = .006). Mean (SD) LV GLS at <48 hours was significantly lower in infants with CDH who did not survive and/or required ECMO compared with those who did not: -11.5 (5.3)% vs -16.9 (5.3)% (P = .02). CONCLUSIONS: RV and LV function are impaired in the transitional period in infants with CDH. Early LV systolic function correlates with prenatal and postnatal markers of clinical disease severity and may be an important determinant of disease severity and therapeutic target in CDH. These findings support regular assessment of cardiac function in CDH and investigational trials of targeted cardiovascular therapies.

Location of TEF at the carina as an indicator of long-gap C-type esophageal atresia.

We analyzed retrospectively the outcomes in long gap Gross type C esophageal atresia. We hypothesized that outcomes in type C (long gap) atresia differ from type C (normal gap) and be similar with outcomes in Gross type A and B esophageal atresia. Location of the distal tracheoesophageal fistula (TEF) at the carina was chosen as the hallmark of type C atresia (long gap). We compared the type of esophageal repair, major reoperations for anastomotic complications and gastroesophageal reflux, and long-term mucosal changes between type C (normal gap), type C (long gap), and type A/B. We analyzed the hospital charts of 247 successive patients from 1984 to 2014 who either underwent repair of esophageal atresia in our institution (n = 232) or were referred from elsewhere because of anastomotic complications (n = 15). Among the 232 patients of our institution, 181 had type C and 21 type A or B esophageal atresia. Twenty-two (12%) of type C patients had TEF at the carina and were considered as type C (long gap). The referred patients included a disproportionately high number (42%) of patients with type C (long gap). We attempted primary anastomosis in 98% of patients with type C (normal gap), in 95% with type C (long gap), and 53% with type A/B underwent delayed primary anastomosis. Leakage after primary anastomosis occurred in 40% of patients with type A/B and in 23% with type C (long gap) compared with 6% in patients with type C (normal gap) (P < 0.05). Recalcitrant anastomotic stricture that eventually required esophageal resection occurred in 30% of patients with type A/B and in 18% with type C (long gap) compared with 3% in patients with type C (normal gap) (P < 0.05). The overall rate of major reoperations for anastomotic complications after primary anastomosis, type A/B (36%), type C (long gap) (27%), and antireflux surgery, type A/B (100%) and type C (long gap) (61%) were higher than in type C (normal gap), (9% and 24%), (P < 0.05 in both). Ten (47%) patients with type A/B esophageal atresia (primary anastomosis not possible n = 10), three (14%) with type C (long gap) (primary anastomosis not possible n = 1, significant loss of esophageal length after complications n = 2) and two (1%) with type C (normal gap) (significant loss of esophageal length after complications n = 2) underwent esophageal reconstruction. Endoscopic follow-up, median length 7.0 (IQR: 3.0-14) years, disclosed gastric metaplasia in 31% and 33% of patients with type A/B and type C (long gap) compared with 11% in type C (normal gap) (P < 0.05). Intestinal metaplasia was found in one patient type C (normal gap) (0.7%) and one with type C (long gap) (5.6%), (P = 0.21), only. The outcomes of type C (long gap) esophageal atresia are associated with more frequent complications, gastroesophageal reflux and esophageal mucosal changes than outcomes in type C (normal gap). Outcomes in type C (long gap) esophageal atresia resemble those in type A/B. The percentage of patients who remain with their native esophagus is, however, higher in type C (long gap) atresia (86%) than in type A/B (53%).

Intestinal Metaplasia of the Esophagus in Children With Esophageal Atresia.

OBJECTIVES: Patients with esophageal atresia/tracheoesophageal fistula (EA-TEF) can develop Barrett esophagus as a long-term consequence of their condition. Intestinal metaplasia (IM), a risk factor for developing adenocarcinoma of the esophagus, has not been well characterized in the pediatric population. METHODS: Retrospective review of patients with EA-TEF followed at 3 academic pediatric centers between the years 1997 and 2014. RESULTS: Among 542 children and adolescents, 1.3% (7 patients, 5 girls) were diagnosed with IM based on endoscopy and pathology. Six of the patients had EA-TEF type C, whereas the last patient had a "long gap" type A atresia. Patients were diagnosed with gastric metaplasia either before the IM diagnosis in 4 patients or concomitantly in 3. The median (range) age of diagnosis for gastric metaplasia was 7.9 (range 2-17.2) and for IM 10.9 (2-17.2) years. Gastroesophageal reflux (GER) symptoms were nonspecific. Five patients were on proton pump inhibitor therapy for symptomatic GER at the time of diagnosis of IM. 2 of the 7 patients had previously undergone Nissen fundoplication. One patient, who had undergone a Nissen fundoplication, was restarted on proton pump inhibitor once the diagnosis of IM was made. All patients had repeated endoscopy and dysplasia was not observed with a median follow-up of 1.7 (range 1-4.9) years. CONCLUSIONS: IM occurs in patients with EA-TEF, some as young as 2 years. Therefore, early endoscopic surveillance should be considered in this GER-prone population.

Prevalence and descriptive epidemiology of esophageal atresia in the Russian Federation.

BACKGROUND: This study examined the prevalence of esophageal atresia (EA) and the relationship between EA and demographic factors in the Russian Federation. METHODS: Data were obtained from a population-based congenital malformations registry across 14 years (2000-2013) in 24 regions of the Russian Federation and included cases of EA among live births and stillbirths. RESULTS: The total number of births was 6,478,706. There were 1317 cases of isolated EA, resulting in a rate of 2.03 (95% confidence interval [CI], 1.92-2.15) per 10,000 births or 1 case per 4926 births. There were differences in the prevalence of EA among regional registries of the Russian Federation. The prevalence of EA during the study period was stable. 57.3% of all cases were cases of EA with tracheo-esophageal fistula (compared with 42.7% of cases without fistula). The male/female sex ratio was 1.3. The relative risk of EA was higher for live births with birth weight less than 3000 g (relative risk [RR] = 2.58 (95% CI, 2.36-2.82), for older maternal age (RR = 1.47 (95% CI, 1.24-1.75), for males (RR = 1.09; 95% CI, 1.03-1.17), and for the first gravidity (RR = 1.17; 95% CI, 1.09-1.25). CONCLUSION: In this study, the prevalence of EA across different regions of the Russian Federation was analyzed. The prevalence of EA in the period under study remained stable, and the relative risk of EA was associated with maternal age, birth weight and gravidity. Birth Defects Research (Part A) 106:854-859, 2016. © 2016 Wiley Periodicals, Inc.

Macrophage Phenotype Is Associated With the Regenerative Response in Experimental Replacement of the Porcine Esophagus.

A porcine model for bridging circumferential defects in the intrathoracic esophagus has been developed in order to improve the treatment of children born with long-gap esophageal atresia. The aim of this study was to identify factors beneficial for tissue regeneration in the bridging area in this model and to describe the histological progression 20 days after replacement with a silicone-stented Biodesign mesh. Resection of 3 cm of intrathoracic esophagus and replacement with a bridging graft was performed in six newly weaned piglets. They were fed through a gastrostomy for 10 days, and then had probe formula orally for another 10 days prior to sacrifice. Two out of six piglets had stent loss prior to sacrifice. In the four piglets with the stent in place, a tissue tube, with visible muscle in the wall, was seen at sacrifice. Histology showed that the wall of the healing area was well organized with layers of inflammatory cells, in-growing vessels, and smooth muscle cells. CD163+ macrophages was seen toward the esophageal lumen. In the animals where the stent was lost, the bridging area was narrow, and histology showed a less organized structure in the bridging area without the presence of CD163+ macrophages. This study indicates that regenerative healing was seen in the porcine esophagus 20 days after replacement of a part of the intrathoracic esophagus with a silicone-stented Biodesign mesh, if the bridging graft is retained. If the graft is lost, the inflammatory pattern changes with invasion of proinflammatory, M1 macrophages in the entire wall, which seems to redirect the healing process toward scar formation.

De novo GLI3 mutation in esophageal atresia: reproducing the phenotypic spectrum of Gli3 defects in murine models.

Esophageal atresia is a common and life-threatening birth defect with a poorly understood etiology. In this study, we analyzed the sequence variants of coding regions for a set of esophageal atresia-related genes including MYCN, SOX2, CHD7, GLI3, FGFR2 and PTEN for mutations using PCR-based target enrichment and next-generation sequencing in 27 patients with esophageal atresia. Genomic copy number variation analysis was performed using Affymetrix SNP 6.0. We found a de novo heterozygous mutation in the N-terminal region of the GLI3 gene (c.332T>C, p.M111T) in a patient with esophageal atresia and hemivertebrae. The N-terminal region (amino acids 1-397) of GLI3 contains the repressor domain, which interacts with SKI family proteins. Using the co-immunoprecipitation assay, we found that interaction of GLI3 with the SKI family protein SKIL was significantly compromised by the p.M111T mutation of GLI3. Thus far, all the identified mutations mapped within the repressor domain of GLI3 were nonsense and frame-shift mutations. In this study, a missense mutation was initially detected in this region. Our finding is the first to link this GLI3 gene mutation with esophageal atresia in humans, which was previously suggested in an animal model.

Ultrastructural Changes of the Smooth Muscle in Esophageal Atresia.

Esophageal atresia (EA) with or without tracheo-esophageal fistula (TEF) is a relatively rare congenital anomaly. Despite the advances in the management techniques and neonatal intensive care, esophageal dysmotility remains a very common problem following EA/TEF repair. Our current study aimed to describe the most significant ultrastructural changes of the smooth muscle cells (SMCs) trying to highlight some of the underlying mechanisms of esophageal dysmotility following EA/TEF repair. Twenty-three biopsies were obtained from the tip of the lower esophageal pouch (LEP) of 23 patients during primary repair of EA/TEF. Light microscopic examination was performed with hematoxylin and eosin (HE), and Van Gieson's stains. Ultrastructural examination was done using transmission electron microscopy (TEM). Histopathological examination showed distortion of smooth muscle layer and deposition of an abundant amount of fibrous tissue in-between smooth muscles. Using TEM, SMCs exhibited loss of the cell-to-cell adhesion, mitochondrial vacuolation, formation of myelin figures, and apoptotic fragmentation. There were also plasmalemmal projections and formation of ghost bodies. Interestingly, SMCs were found extending pseudopodia-like projections around adjacent collagen fibers. Engulfed collagen fibers by SMCs underwent degradation within autophagic vacuoles. Degeneration of SMCs and deposition of abundant extracellular collagen fibers are prominent pathological changes in LEP of EA/TEF. These changes might contribute to the pathogenesis of esophageal dysmotility in patients who have survived EA/TEF.

[Congenital Esophageal Atresia].

In this report, we describe the esophageal atresia in terms of current surgical management on the basis of our experience and literatures. Traditionally, infants with esophageal atresia have presented shortly after birth because of an inability to pass an orogastric tube, respiratory distress, or an inability to tolerate feeding. And also, an isolated trachea-esophageal fistula (TEF) usually cases coughing, recurrent pneumonia, or choking during feedings. To ignore these symptoms is to risk a delayed diagnosis. The condition may be associated with other major congenital anomalies such as those seen in the vertebral, anal, cardiac, tracheo-esophageal, renal/radial (VACTER) association, or it may be an isolated defect. Therapeutic strategies for esophageal atresia are a prevention of pulmonary complication by TEF closing and an early establishment of enteral alimentation. We promptly repair healthy infants without performing a gastrostomy and delay repair in infants with high-risk factors such as associated severe cardiac anomaly and respiratory insufficiency. Esophageal atresia has been classically approached through a thoracotomy. The disadvantages of such a thoracotomy have been recognized for a long time, for example winged scapula, elevation of fixation of shoulder, asymmetry of the chest wall, rib fusion, scoliosis, and breast and pectoral muscle maldevelopment. To avoid such disadvantages, thoracoscopic repair was recently reported.

Short-gap Isolated Esophageal Atresia Causing Stridor Due to Compression of the Trachea.

Isolated esophageal atresias are reported always to be associated with long gap in the literature. In this manuscript, we aimed to discuss the imaging and surgical treatment methods of an isolated esophageal atresia case with 'short gap' who had stridor due to compression of the trachea by dilated upper esophageal pouch and had not identified previously in the literature.

Escobar syndrome with heterotaxia and esophageal atresia: case report.

Escobar syndrome (ES) or multiple pterygia syndrome (MIM#265000) is an infrequent condition characterized by facial dysmorphism, multiple webbing (pterygia), congenital contractures (arthrogryposis) and other internal anomalies. We describe an 8-days-old male newborn from consanguineous parents with ES who also presented heterotaxia syndrome and esophageal atresia, anomalies that not have been previously reported as associated to ES.

Esophagitis with eosinophil infiltration associated with congenital esophageal atresia and stenosis.

BACKGROUND: The esophagus is physiologically devoid of eosinophils, so their presence would suggest some underlying pathology. The prevalence of eosinophilic esophagitis (EoE) has steadily increased in Western countries. Previous studies have described EoE in association with congenital esophageal atresia (CEA), which is the most common congenital anomaly of the esophagus. However, the association remains unclear. METHODS: We performed a retrospective histological analysis examining for eosinophil infiltration in the esophagus of patients with CEA following surgical repair or congenital esophageal stenosis (CES) who underwent esophageal biopsy or surgical resection in our hospital between 2005 and 2012. RESULTS: There were 6 patients with CEA following surgical repair or CES who had eosinophil-dominant infiltration in the esophagus. All had associated allergic disorders, including food allergies in 4. Moreover, all except for one fulfilled the histological criteria of EoE. Impairment of eosinophil infiltration and symptomatic improvement were observed in those treated with a proton pump inhibitor (PPI), either alone or in combination with steroids after esophageal dilatation. CONCLUSIONS: These findings suggest that CEA repair or CES in conjunction with allergic conditions and coexisting gastroesophageal reflux disease (GERD) may induce greater esophageal eosinophilic inflammation. In addition, esophageal dilatation followed by PPI treatment, alone or with steroids, may be a therapeutic strategy that can provide symptomatic relief by reducing eosinophilic inflammation in esophageal strictures or GERD associated with CEA or CES.

Specific biochemical amniotic fluid pattern of fetal isolated esophageal atresia.

BACKGROUND: Perinatal care of esophageal atresia (EA) may be improved by prenatal diagnosis. Ultrasound findings (polyhydramnios and/or nonvisualization of fetal stomach) lead to a detection rate of ~50%. An amniotic fluid (AF) biochemical pattern characterized by high total protein, γ-glutamyl transpeptidase (GGTP), and normal l-leucine-aminopeptidase (AMP) leads to a 100% detection rate. The aim of this study was to explain this specific pattern. METHODS: On the basis of enzyme activities assay, the following four objectives were sought: (i) comparing AF markers between EA and other digestive tract atresias, (ii) determining local GGTP synthesis in the esophagus (immunohistobiochemistry), (iii) determining the presence of a specific AF-AMP activity inhibitor, and (iv) comparing AF-AMP and AF-GGTP half-lives. RESULTS: The AF-EA pattern was similar to that observed in upper duodenal atresia (above the Oddi sphincter). No local synthesis of GGTP was observed in the esophagus. No AF-AMP activity inhibitor was found. AF-GGTP had a longer half-life than AF-AMP. CONCLUSION: Due to the swallowing anomaly observed in EA, GGTP and AMP values physiologically observed at 18 wk will decrease on the basis of the half-lives of markers, with a flat slope for GGTP and a sharp slope for AMP, therefore explaining the differences observed in the AF-EA pattern.

Microdeletion 11q13.1.q13.2 in a patient presenting with developmental delay, facial dysmorphism, and esophageal atresia: possible role of the GSTP1 gene in esophagus malformation.

BACKGROUND: Esophageal atresia is a major congenital malformation characterized by a complete interruption of the esophageal continuity. It is frequently observed in associations and syndromes. As an isolated finding, it has a multifactorial etiology whose genetic factors are poorly known. Recently, the GST family, especially the GSTM1 null genotype (but not the GSTP1 polymorphism I105V), has been associated with esophageal atresia. These enzymes play a role in phase II detoxification of xenobiotics. Here we present the clinical and molecular findings observed in a patient suggesting that the loss of the GSTP1 allele might predispose to this malformation. CASE: We describe a patient presenting with esophageal atresia associated with developmental delay and facial dysmorphism, whose mother used tobacco and alcohol during the first 2 months of her pregnancy. Microdeletion/microduplication analysis was performed using comparative genomic hybridization and a 180K Agilent array. It detected a de novo 2 Mb chromosome 11q13.1.q13.2 deletion. CONCLUSION: The deleted chromosomal segment includes the GSTP1 gene. We hypothesize that the deletion of one GSTP1 allele (an isoform highly expressed in embryonic tissues), associated with specific environmental factors, such as tobacco and alcohol, could cause the esophageal atresia observed in our patient.

Second study on the recurrence risk of isolated esophageal atresia with or without trachea-esophageal fistula among first-degree relatives: no evidence for increased risk of recurrence of EA/TEF or for malformations of the VATER/VACTERL association spectrum.

BACKGROUND: Esophageal atresia with/without trachea-esophageal fistula (EA/TEF) denotes a spectrum of severe congenital malformations. The aim of this systematic study was to determine both the recurrence risk for EA/TEF, and the risk for malformations of the VATER/VACTERL association spectrum, in first-degree relatives of patients with isolated EA/TEF. METHODS: A total of 108 unrelated patients with isolated EA/TEF were included. These individuals had 410 first-degree relatives including 194 siblings. The presence of EA/TEF and malformations of the VATER/VACTERL association spectrum in relatives was systematically assessed. Data from the EUROCAT network were used for comparison. RESULTS: None of the first-degree relatives displayed any form of EA/TEF. In two families, a first-degree relative presented with malformations from the VATER/VACTERL association spectrum. However, no increase in the risk for malformations of the VATER/VACTERL association spectrum was found compared with the control cohort (p = 0.87). In three families, one more distantly related relative presented with EA/TEF. CONCLUSION: In contrast to previous studies, our results suggest a very low recurrence risk for isolated EA/TEF and/or for malformations of the VATER/VACTERL association spectrum among first-degree relatives.