Julie Salomon

Intestinal epithelial dysplasia (tufting enteropathy)

Intestinal epithelial dysplasia (IED), also known as tufting enteropathy, is a congenital enteropathy presenting with early-onset severe intractable diarrhea causing sometimes irreversible intestinal failure. To date, no epidemiological data are available, however, the prevalence can be estimated at around 1/50,000–100,000 live births in Western Europe. The prevalence seems higher in areas with high degree of consanguinity and in patients of Arabic origin. Infants develop within the first days after birth a watery diarrhea persistent in spite of bowel rest and parenteral nutrition. Some infants are reported to have associated choanal rectal or esophageal atresia. IED is thought to be related to abnormal enterocytes development and/or differentiation. Nonspecific punctuated keratitis was reported in more than 60% of patients. Histology shows various degree of villous atrophy, with low or without mononuclear cell infiltration of the lamina propria but specific histological abnormalities involving the epithelium with disorganization of surface enterocytes with focal crowding, resembling tufts. Several associated specific features were reported, including abnormal deposition of laminin and heparan sulfate proteoglycan (HSPG) in the basement membrane, increased expression of desmoglein and ultrastructural changes in the desmosomes, and abnormal distribution of α 2β 1 integrin adhesion molecules. One model of transgenic mice in which the gene encoding the transcription factor Elf3 is disrupted have morphologic features resembling IED. Parental consanguinity and/or affected siblings suggest an autosomal recessive transmission but the causative gene(s) have not been yet identified making prenatal diagnosis unavailable. Some infants have a milder phenotype than others but in most patients, the severity of the intestinal malabsorption even with enteral feeding make them totally dependent on daily long-term parenteral nutrition with a subsequent risk of complications. IED becomes an indication for intestinal transplantation, while timing of referral for it is crucial before the onset of severe complications.

A founder effect at the EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf

Mutations of the EPCAM gene have been recently identified in Congenital Tufting Enteropathy (CTE), a severe autosomal recessive gastrointestinal insufficiency of childhood requiring parenteral nutrition and occasionally intestinal transplantation. Studying seven multiplex consanguineous families from the Arabic peninsula (Kuwait and Qatar) we found that most patients were homozygote for a c.498insC mutation in exon 5. The others carried a novel mutation IVS4-2A→G. Both mutations were predicted to truncate the C-terminal domain necessary to anchorage of EPCAM at the intercellular membrane. Consistently, immunohistochemistry of intestinal biopsies failed to detect the EPCAM protein at the intercellular membrane level. The c.498insC mutation was found on the background of a minimal common haplotype of 473kb suggesting a very old founder effect (5000-6000 yrs).

Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity

Monolayered epithelia are composed of tight cell assemblies that ensure polarized exchanges. EpCAM, an unconventional epithelial-specific cell adhesion molecule, is assumed to modulate epithelial morphogenesis in animal models, but little is known regarding its cellular functions. Inspired by the characterization of cellular defects in a rare EpCAM-related human intestinal disease, we find that the absence of EpCAM in enterocytes results in an aberrant apical domain. In the course of this pathological state, apical translocation towards tricellular contacts (TCs) occurs with striking tight junction belt displacement. These unusual cell organization and intestinal tissue defects are driven by the loss of actomyosin network homoeostasis and contractile activity clustering at TCs, yet is reversed by myosin-II inhibitor treatment. This study reveals that adequate distribution of cortical tension is crucial for individual cell organization, but also for epithelial monolayer maintenance. Our data suggest that EpCAM modulation protects against epithelial dysplasia and stabilizes human tissue architecture.

Plasticity of the brush border - the yin and yang of intestinal homeostasis.

The brush border on the apical surface of enterocytes is a highly specialized structure well-adapted for efficient digestion and nutrient transport, whilst at the same time providing a protective barrier for the intestinal mucosa. The brush border is constituted of a densely ordered array of microvilli, protrusions of the plasma membrane, which are supported by actin-based microfilaments and interacting proteins and anchored in an apical network of actomyosin and intermediate filaments, the so-called terminal web. The highly dynamic, specialized apical domain is both an essential partner for the gut microbiota and an efficient signalling platform that enables adaptation to physiological stimuli from the external and internal milieu. Nevertheless, genetic alterations or various pathological stresses, such as infection, inflammation, and mechanical or nutritional alterations, can jeopardize this equilibrium and compromise intestinal functions. Long-time neglected, the intestinal brush-border shall be enlightening again as the central actor of the complex but essential intestinal homeostasis. Here, we review the processes and components involved in brush border organization and discuss pathological mechanisms that can induce brush border defects and their physiological consequences.

Intestinal absorption rate in children after small intestinal transplantation.

BACKGROUND Small bowel transplantation has now become a recognized treatment of irreversible, permanent, and subtotal intestinal failure. OBJECTIVE The aim of this study was to assess intestinal absorption at the time of weaning from parenteral nutrition in a series of children after intestinal transplantation. DESIGN Twenty-four children (age range: 14-115 mo) received intestinal transplantation, together with the liver in 6 children and the colon in 16 children. Parenteral nutrition was slowly tapered while increasing enteral tube feeding. The absorption rate was measured from a 3-d stool balance analysis performed a few days after the child had weaned from parenteral nutrition to exclusive enteral tube feeding. Results were analyzed according to the resting energy expenditure (REE; Schofield formula). RESULTS All children were weaned from parenteral nutrition between 31 and 85 d posttransplantation. Median intakes were as follows: energy, 107 kcal · kg(-1) · d(-1) (range: 79-168 kcal · kg(-1) · d(-1)); lipids, 39 kcal · kg(-1) · d(-1) (range: 20-70 kcal · kg(-1) · d(-1)); and nitrogen, 17 kcal · kg(-1) · d(-1) (range: 11-27 kcal · kg(-1) · d(-1)). Median daily stool output was 998 mL/d (range: 220-2025 mL/d). Median absorption rates were 88% (range: 75-96%) for energy, 82% (range: 55-98%) for lipids, and 77% (range: 61-88%) for nitrogen. The ratios for ingested energy to REE and absorbed energy to REE were 2.2 (range: 1.6-3.6) and 1.8 (range: 1.3-3.3), respectively. CONCLUSION These data indicate a suboptimal intestinal graft absorption capacity with fat malabsorption, which necessitates energy intakes of at least twice the REE.

Microvillous atrophy: atypical presentations.

Objectives: Microvillous inclusion disease (MVID) is a cause of intractable diarrhea in infancy. In its classic form, the disease is characterized by a severe persistent watery diarrhea starting within the first days of life. Parenteral nutrition and small bowel transplantation are the only known treatments for the affected children. Histologically, periodic acid-Schiff (PAS) staining shows accumulation of periodic acid-Schiff–positive staining material along the apical pole of enterocytes, whereas transmission electron microscopy exhibits microvillus inclusion bodies within the cytoplasm of enterocytes with rarefied and shortened microvilli and secretory granules. The objective of this work was to explore clinical, morphological, and genetic findings in cases of MVID with unusual presentations. Methods: Clinical, histological, and genetic findings are reported for 8 cases of MVID with atypical presentation. Results: The diarrhea started after several months in 3 cases. It was usually less abundant and 3 patients were weaned off parenteral nutrition. None required intestinal transplantation. Three patients experienced malformations, dysmorphy, sensory disabilities, and severe mental retardation. One had a hydrocephaly. Three patients had a cholestasis with low &ggr;-glutamyl transferase levels. Light microscopy showed histological abnormalities consistent with MVID in all of the cases, but the lesions were sometimes focal or delayed. Transmission electron microscopy retrieved some criteria of MVID in 4 patients. Finally, 6 patients were homozygotes or compound heterozygotes for MYO5B mutations. Conclusions: This study extends the spectrum of MVID to less severe clinical presentations.

Superficial Punctate Keratitis and Conjunctival Erosions Associated With Congenital Tufting Enteropathy

PURPOSE To study the value of conjunctival biopsy in congenital tufting enteropathy diagnosis. DESIGN Case-comparative study. METHODS Between January 2000 and June 2007, all children seeking treatment with an early onset of intractable diarrhea were examined in the ophthalmology department of Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, France. Children underwent complete ophthalmologic examination with concurrent conjunctival and intestinal biopsies. Main outcome measures were age at diagnosis, associated disorders, parenteral nutrition, and ophthalmologic symptoms. Conjunctival biopsies support diagnosis in the presence of specific alteration. RESULTS Twenty patients were included. The mean age of the population was 30.2 months. Congenital tufting enteropathy was diagnosed in 15 cases. In the congenital tufting enteropathy group, 10 children exhibited ophthalmic functional disorders since the first months of life, with superficial punctate keratitis and conjunctivitis and in addition alacrima and cataract in 1 case, respectively, whereas 5 children had asymptomatic conjunctival hyperemia at presentation. Conjunctival biopsies showed epithelial parakeratosis, hyperplasia, basal cells hyperplasia, and tufts. In some cases, the lamina propria contained inflammatory cells or fibrosis, and the density of goblet cells then was abnormal. In the comparison group of 5 children with early-onset intractable diarrhea but without congenital tufting enteropathy diagnosis, no tuft occurrence was observed. CONCLUSIONS In cases of intractable diarrhea in infancy, even without ocular symptoms, a systematic ophthalmologic examination should be performed. It also should be associated with the pathologic examination of both the conjunctival and the intestine mucosae, which helps to diagnose congenital tufting enteropathy (adhesion molecules disease). Specific conjunctival findings allow affirmation of congenital tufting enteropathy before the genetic confirmation of an EpCAM gene mutation.

Syndromic congenital diarrhea because of the spint2 mutation showing enterocyte tufting and unique electron microscopy findings

Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, Department of Laboratory Medicine and Pathology, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada, Departments of Genetics, Pediatric Gastroenterology, Hepatology and Nutrition and Pathology, Necker-Enfants Malades Hospital, Paris Descartes University, Paris, France Correspondence to Hien Q. Huynh, MBBS, FRACP, FRCPC (Hon), Division of Pediatric Gastroenterology and Nutrition, Stollery Children’s Hospital, University of Alberta, Edmonton Clinic Health Academy (ECHA), 4th Floor, Room 4-579, 11405, 87th Avenue, Edmonton, Alberta, Canada T6G 1C9 Tel: + 1 780 248 5420; fax: + 1 780 248 5628; e-mail: hien.huynh@ualberta.ca

Tufting enteropathy with EpCAM mutation: case report

Tufting enteropathy (TE), also known as intestinal epithelial dysplasia (IED), is a rare congenital enteropathy related to an earlyonset of severe intractable diarrhea due to specific abnormalities of the intestinal epithelium and mutations of the EpCAM gene. TE is characterized by clinical and histological heterogeneity, such as with low or without mononuclear cell infiltration of the lamina propria, and abnormalities of basement membrane. TE can be associated with malformations, other epithelial diseases, or to abnormal enterocytes development and/or differentiation. The authors report a case of a Brazilian child with TE associated with c.556-14A>G mutation in the EpCAM gene (NM_002354.2).