Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell-Fibroblast Crosstalk.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. METHODS: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. RESULTS: TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. CONCLUSIONS: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.

MicroRNA expression profiles in the esophagus of children with caustic stenosis: A pathway towards esophageal cancer?

BACKGROUND: Eighty percent of caustic ingestions occur in children and esophageal neoplasms may develop as a late complication of such injury. The identification of biomarkers is a promising strategy to improve early diagnosis of esophageal cancer or caustic lesions that are at an increased risk of progression. STUDY DESIGN/AIMS: This study aimed at identifying global microRNA (miRNA) expression changes in esophageal mucosa from children with caustic stenosis. The study included 27 biopsy samples from 15 patients. Samples were divided into two groups, according to the time elapsed after injury (N = 15 in Group A, with less than five years of follow-up and N = 12 in Group B, with more than five years of follow-up). miRNA expression profiles were determined in each lesion, compared with normal esophageal tissues from control group. We used the TaqMan Human MicroRNA Arrays (Thermo Fisher) platform. Furthermore, bioinformatic algorithms were used to identify miRNA target genes and biological pathways including miRNAs and their target genes potentially associated with esophageal disease. RESULTS: Thirteen miRNAs were significantly deregulated (9 over- and 4 underexpressed) in patients from Group A. In patients from Group B, two miRNAs were over- and two were underexpressed. Of note, miR-374 and miR-574 were deregulated in Group B patients and have been linked to esophageal tumorigenesis. We identified signal transduction and transcription factor networks with genes strongly related to development and progression of esophageal cancer. CONCLUSION: miRNAs identified here contribute to a better understanding of pathways associated with malignant transformation from caustic stenosis to neoplastic lesions. This study may serve as a basis for validation of miRNAs, including miR-374 and miR-574, as potential biomarkers of early cancer detection.

Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice.

Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome.

Novel Genetic Variants Associated with Child Refractory Esophageal Stricture with Food Allergy by Exome Sequencing.

BACKGROUND: Refractory esophageal stricture (RES) may be attributed to food allergy. Its etiology and pathogenesis are not fully understood. Identification of novel genetic variants associated with this disease by exome sequencing (exome-seq) may provide new mechanistic insights and new therapeutic targets. METHODS: To identify new and novel disease-associating variants, whole-exome sequencing was performed on an Illumina NGS platform in three children with RES as well as food allergy. RESULTS: A total of 91,024 variants were identified. By filtering out 'normal variants' against those of the 1000 Genomes Project, we identified 12,741 remaining variants which are potentially associated with RES plus food allergy. Among these variants, there are 11,539 single nucleotide polymorphisms (SNPs), 627 deletions, 551 insertions and 24 mixture variants. These variants are located in 1370 genes. They are enriched in biological processes or pathways such as cell adhesion, digestion, receptor metabolic process, bile acid transport and the neurological system. By the PubMatrix analysis, 50 out of the top 100 genes, which contain most variants, have not been previously associated with any of the 17 allergy-associated diseases. These 50 genes represent newly identified allergy-associated genes. Those variants of 627 deletions and 551 insertions have also not been reported before in RES with food allergy. CONCLUSIONS: Exome-seq is potentially a powerful tool to identify potential new biomarkers for RES with food allergy. This study has identified a number of novel genetic variants, opening new avenues of research in RES plus food allergy. Additional validation in larger and different patient populations and further exploration of the underlying molecular mechanisms are warranted.

Prevention of esophageal stricture after endoscopic submucosal dissection using RNA-based silencing of carbohydrate sulfotransferase 15 in a porcine model.

Background and study aims Endoscopic submucosal dissection (ESD) for esophageal carcinoma frequently causes fibrotic strictures that require treatment. A possible preventive effect of small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) on esophageal stricture formation after ESD was investigated in 3 pigs. Materials and methods Two half-circumferential ESD ulcers were created in the oral and anal ends of the esophagus. CHST15 siRNA was injected submucosally in one of the two ESD ulcers. Endoscopic, macroscopic, histological, and polymerase chain reaction analyses were performed. Results On post-operative day 14, the non-treated ulcers were found to show histological fibrosis and increased expression of the CHST15 messenger RNA. A single endoscopic injection of CHST15 siRNA alleviated stricture development in post-ESD ulcers with significant reduction in the mucosal contraction rate. The deposition of collagen and accumulation of fibroblasts and myofibroblasts were diminished in ulcers treated with CHST15 siRNA, where significant suppression of CHST15, transforming growth factor-beta (TGF-ß), and collagen-1 messenger RNAs was also seen. Conclusion CHST15 siRNA alleviated esophageal post-ESD stricture formation via repression of fibrosis, revealing a novel therapeutic role for antifibrotic agents in the prevention of post-ESD strictures.

A novel germline KIT mutation (p.L576P) in a family presenting with juvenile onset of multiple gastrointestinal stromal tumors, skin hyperpigmentations, and esophageal stenosis.

Familial gastrointestinal stromal tumor (GIST) syndrome is a rare autosomal dominant genetic disorder. We report on a kindred in which 3 family members carry a germline mutation (c.1727T>C, p.L576P) in exon 11 of the KIT gene. This mutation was not reported so far in familial GISTs. Apart from multiple GISTs in 2 of the mutation carriers, all of them had multiple hyperpigmented skin macules and a history of achalasia-like stenosis of the esophagus in early childhood. In the index patient >100 tumors and a diffuse Cajal cell hyperplasia of the small bowel occurred. Sequencing of DNA extracted from tumor tissue of one of his GISTs revealed the KIT mutation in exon 11 (c.1727T>C). By array comparative genomic hybridization whole chromosomal gains 3, 5, 7, 9, 12, 15, and 18 were detected. In addition, we could identify a gain on chromosome 4, spanning the KIT gene. Together with the family described here, 24 unrelated cases with proven germline mutations in KIT have been reported. In these families the diagnosis was established from the age of 30 years onwards. Because in 1 patient reported here the GIST was a coincidental finding at the age of 15 years, the tumors might occur at a very young age and remain unnoticed until they-either due to increasing size, ulceration, or malignant progression-become symptomatic. Therefore, we propose to start screening patients with known KIT mutations from a younger age.

The original family revisited after 37 years: odontoma-dysphagia syndrome is most likely caused by a microduplication of chromosome 11q13.3, including the FGF3 and FGF4 genes.

OBJECTIVES: Fibroblast growth factors consist of receptor tyrosine kinase binding proteins involved in growth, differentiation, and regeneration of a variety of tissues of the head and neck. Their role in the development of teeth has been documented, and their presence in human odontogenic cysts and tumors has previously been investigated. Odontoma­dysphagia syndrome (OMIM 164330) is a very rare disorder characterized by clustering of teeth as compound odontoma, dysplasia and aplasia of teeth, slight craniofacial abnormalities, and dysphagia. We have followed the clinical course of the disease in a family over more than 30 years and have identified a genetic abnormality segregating with the disorder. MATERIALS AND METHODS: We evaluated clinical data from nine different family members and obtained venous blood probes for genetic studies from three family members (two affected and one unaffected). RESULTS: The present family with five patients in two generations has remained one out of only two known cases with this very rare syndrome. All those affected showed teeth dysplasia, oligodontia, and dysplasia and odontoma of the upper and lower jaw. Additional signs included dysphagia and strictures of the oesophagus. Comorbidity in one patient included aortic stenosis and coronary artery disease, requiring coronary bypasses and aortic valve replacement. Genome-wide SNP array analyses in three family members (two affected and one unaffected) revealed a microduplication of chromosome 11q13.3 spanning 355 kilobases (kb) and including two genes in full length, fibroblast growth factors 3 (FGF3) and 4 (FGF4). CONCLUSION: The microduplication identified in this family represents the most likely cause of the odontoma­dysphagia syndrome and implies that the syndrome is caused by a gain of function of the FGF3 and FGF4 genes. CLINICAL RELEVANCE: Mutations of FGF receptor genes can cause craniofacial syndromes such as odontoma­dysphagia syndrome. Following this train of thought, an evaluation of FGF gene family in sporadic odontoma could be worthwhile.

Esophageal stenosis in a child presenting a de novo 7q terminal deletion.

We report on the first case of a child with a de novo 7q terminal deletion [46,XX,del(7)(q35 → qter)] presenting esophageal stenosis. This cytogenetic abnormality was confirmed by FISH, using subtelomeric probes, and by a whole-genome array-CGH assay. The child also had phenotypic features previously described in patients with a similar deletion, as growth retardation, microcephaly, coloboma of papilla, ptosis, hearing loss, urinary tract anomalies, partial agenesis of sacrum, hypotonia and neuropsychomotor delay. The odontoid hypoplasia identified, in similarity with the esophageal stenosis, represents an uncommon finding. This report is also the first clinical description of a patient with an abnormality involving the sonic hedgehog gene and an esophageal alteration. It is discussed the possibility of a specific association between them, according to some results observed in studies with animal models.

Dysphagia in the young male: the ringed esophagus.

The endoscopic view of the multi-ringed esophagus readily explains why the term "tracheal esophagus" is applicable. This entity may be undiagnosed until dysphagia and impactions secondary to strictures occur in the young male. Several factors point to a congenital rather than an acquired disorder. Treatment consists of slow, progressive dilatations that are repeated for recurrent dysphagia.

Aortic coarctation, vascular ring, and right aortic arch with aberrant subclavian artery.

Right aortic arch, in all situations, is relatively rare. In association with coarctation and vascular compression, it is extremely rare. We present a patient with a right aortic arch and an aberrant left subclavian artery, in addition to coarctation. This was dealt with through a left thoracotomy by dividing the ligamentum arteriosum and placing a Dacron graft from the ascending aorta to the descending aorta.

Familial clustering of reflux symptoms.

OBJECTIVE: A number of case reports describe multiple family members with gastroesophageal reflux disease and Barrett' s esophagus. The wider importance of familial factors in gastroesophageal reflux disease has not been established. Therefore, we have studied the prevalence of reflux symptoms and medication use among relatives of patients with documented gastroesophageal reflux disease. METHODS: A postal questionnaire study of the first degree relatives of six groups of matched patients. The groups comprised patients with 1) no dyspeptic symptoms; 2) reflux symptoms and a normal pH study; 3) reflux symptoms, an abnormal pH study, and a lower esophageal sphincter (LOS) pressure more than 10 mm Hg; 4) reflux symptoms, an abnormal pH study, and a LOS pressure less than 10 mm Hg; 5) Barrett's esophagus; and 6) peptic stricture. RESULTS: Four hundred eighteen subjects replied (78% response). Infrequent reflux symptoms were equally common in all groups of relatives. Frequent reflux symptoms, however, were more common among relatives of patients with an abnormal pH study and normal (26%, p = 0.007) or low LOS pressure (27%, p = 0.01) or Barrett's esophagus (30%, p = 0.003), compared with relatives of nondyspeptic patients (9%). Frequent reflux symptoms were no more common among relatives of patients with a normal pH study (16%) or peptic stricture (18%). Reflux medication use showed a similar pattern. CONCLUSIONS: Familial clustering of reflux symptoms is seen in relatives of patients with reflux symptoms and increased esophageal acid exposure and in relatives of patients with Barrett's esophagus.

Ectodermal dysplasia syndrome in siblings with true keloids, stenosis of the esophagus after operations for congenital achalasia and renovascular hypertension due to stenosis of renal artery.

Ectodermal dysplasia syndrome (EDS) is a rare hereditary disease, with symptoms brought about by dysplasia of ectodermal tissue (such as skin, teeth, nails, and hair). This report details the cases of two siblings (41 and 43 year old sisters) with autosomal recessive and hydrotic EDS complicated by esophageal achalasia, postoperative stenosis of esophagus, true keloids, renovascular hypertension, incomplete malrotation of the bowel, and demyelination of the brain.

New clinical aspects of hereditary mucoepithelial dysplasia.

Hereditary mucoepithelial dysplasia (HMD) is a multiepithelial disorder. It is transmitted as an autosomal dominant trait (McKusick: Mendelian Inheritance in Man-Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes, 8th edition. Baltimore: The Johns Hopkins University Press, pp 499, 1988). HMD is characterized by variable combinations of lesions of skin, hair, orificial mucosa, gingiva, eyes, and lungs. In some previously described patients, the corneal and pulmonary lesions were progressive and led to blindness, recurrent pneumonia, and/or premature death. On light microscopy, the lesion is characterized by dyskeratosis, and, on electron microscopy, by a paucity of gap junctions and desmosomes. Here, we describe a new 5-generation kindred in which affected individuals had the same histologic characteristics but a somewhat different clinical spectrum and a more benign course. HMD should be considered in the differential diagnosis of childhood alopecia, follicular hyperkeratosis, keratoconjunctivitis, juvenile cataracts, gingival hyperemia, restrictive lung disease, and esophageal stenosis or webs.

[Dilatation treatment of esophageal stenoses in young patients with recessive epidermolysis bullosa dystrophica]. / Dilatationsbehandlung von Osophagusstenosen bei jungen Patienten mit rezessiver Epidermolysis bullosa dystrophica.

Recessive dystrophic epidermolysis bullosa is a hereditary disorder affecting both skin and esophageal mucosa. The esophagus is frequently affected resulting in almost complete obstruction. We report here the use of inflatable dilatator balloons as a new treatment of esophageal stenosis in three young patients. Dilatation therapy was tolerated well in all three cases and lead to a long standing success. The patients lived without complaints and they did eat normally up to 2.5 years following dilatation.

Congenital stenosis of the lower esophagus associated with leiomyoma and leiomyosarcoma of the gastrointestinal tract.

The purpose of this paper is to report our analysis of four generations of a family with congenital strictures of the lower esophagus associated with leiomyoma of the gastrointestinal tract. Two members of the family died of sarcomatous degeneration of the leiomyoma and one is still alive 2 years after resection of the malignancy. Three family members had surgical repair of the congenital stricture. Surgical repair was unnecessary in one, for whom repeated dilatations alleviated the symptoms. Since there were no direct female descendants in this family, it is unknown whether this hereditary disease is carried by a sex-linked dominant gene. There are no reports in the literature of a familial tendency to congenital strictures of the esophagus, nor are there any reports of strictures in association with gastrointestinal leiomyoma and the later development of sarcomatous degeneration. The literature is reviewed, syndromes of leiomyoma of the esophagus and gastrointestinal tract are detailed, the particulars of the family tree and the patients are described, and the study is summarized.

[Recessive dystrophic epidermolysis bullosa (with esophageal involvement)]. / Epidermolisis ampollosa distrófica recesiva (con afectación esofágica).

We are presenting a young man with Epidermolysis Bullosa (Dystrophica recessive type) who had lesions in hands, feet and face; some plaques of alopecia were noted on the scalp. Three years ago the patient showed marked dysphagia due to some esophagus erosions, which have been appearing regularly. One year ago it was necessary to take the patient to the Hospital where a esophagectomy was performed replacing the esophagus by a piece of colon.

[Therapy of esophageal stenoses in recessive epidermolysis bullosa dystrophica]. / Zur Therapie von Osophagusstenosen bei rezessiver Epidermolysis bullosa dystrophica.

Stenosis or complete occlusion of the oesophagus are potentially life-threatening complications of recessive dystrophic epidermolysis bullosa. Consequences are malnutrition, growth retardation, aspiration, or cachexia. Total replacement of the oesophagus by colon interposition has been recommended in such patients. We report on successful conservative management. We applied recently developed knowledge concerning the defective collagenase involved in this disorder and oesophageal dilatation. Phenytoin has been shown to reduce the excessive production of collagenase and thereby to diminish blistering of skin and mucous membranes and stricture formation of the oesophagus. Stepwise dilatation of oesophageal strictures instead of bouginage represents a less traumatic way to restore the oesophageal lumen. The lumen can be maintained by soft nasogastric feeding tubes which may be removed later on after successful dilatation. Oesophageal passage has been maintained for up to 4 years. The management of these severe complications of recessive dystrophic epidermolysis bullosa requires interdisciplinary efforts of dermatologists, internists and otorhinolaryngologists.

[Genetics of congenital esophageal defects]. / Genetika vrozhdennykh porokov pishchevoda.

An analysis of 304 cases of esophageal atresia in fetuses and neonates showed that frequency of other congenital malformations is 43.1% including 10% of chromosomal disorders and monogenous syndromes. Summarizing the authors' own data and evidences from literature the genetic risk for sibs is calculated to be 0.88% and heredity--57.3 +/- 5.1%. The hypothesis that esophageal atresia is a malformation of multifactorial genesis with polygenic hereditary component is confirmed.

Intramural diverticulosis of the esophagus in an eight-year-old boy.

A third pediatric case of intramural diverticulosis of the esophagus is reported in an 8-year-old boy. A hiatal hernia, chronic nonspecific esophagitis and defective esophageal motility was also documented in his 10-year-old brother.