• organ transplantation
• parenteral nutrition
• pediatrics
• short bowel syndrome
•  teduglutide

• Humans
• Retrospective Studies
• Parenteral Nutrition
• Male
• Female
• Infant
• Intestinal Failure/therapy
• Peptides
• Child, Preschool
• Body Weight
• Body Height/drug effects
• Intestines
• Gastrointestinal Agents/therapeutic use
• Infant, Newborn

• The study was funded by Takeda Pharmaceuticals USA, Inc, a wholly owned subsidiary of Takeda Pharmaceuticals Company Limited, Lexington, MA.
• The study was funded by Takeda Pharmaceuticals USA, Inc, a wholly owned subsidiary of Takeda Pharmaceuticals Company Limited, Lexington, MA.

• Chinese patients
• Congenital tufting enteropathy (CTE)
• EPCAM mutations
• case report
• children

• Follicle
• Ovary
• Transplantation
• Vitamin C
• Vitamin E

• Rats
• Female
• Animals
• Vitamin E/pharmacology
• Rats, Wistar
• Antioxidants/pharmacology
• Ovarian Follicle/metabolism
• Ascorbic Acid/pharmacology
• Vitamins/pharmacology
• Oxidative Stress
• Superoxide Dismutase/metabolism
• Epithelium/metabolism
• Body Weight

• Humans
• Intestines
• Diarrhea/genetics
• Mutation
• Epithelial Cells

• RC2 DK118640 NIDDK NIH HHS
• NIDDK
• Thomas K Onorato Strong Foundation

• Diagnostic molecular pathology
• Epithelial cell adhesion molecule
• Infantile diarrhea
• Whole exome sequencing

• Claudin stabilization
• Enteropathy
• Epithelial development
• Hyperkeratosis
• Proteinuria

• Immunosuppression
• Infection
• Intestinal failure
• Intestinal transplant
• Post-transplant lymphoproliferative disease
• Post-transplant outcomes

• Crohn’s disease
• Inflammatory bowel diseases
• bacterial infections
• diagnostic imaging
• diverticulosis
• drug-induced abnormalities
• endoscopy
• fungal infections
• immune checkpoint inhibitors
• ischaemic colitis
• parasitic infections
• pathology
• radiation-induced abnormalities
• tuberculosis
• ulcerative colitis
• vasculitis
• viral infections

• Age of Onset
• Aged
• Child
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/therapy
• Diagnosis, Differential
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Phenotype

• GVHD
• congenital disorders
• histopathology
• immunodeficiencies
• intestinal lymphangiectasia
• necrotizing enterocolitis
• pediatric diseases
• small bowel

• Child
• Duodenum
• Enterocolitis, Necrotizing
• Humans
• Infant, Newborn
• Intestine, Small

• Paediatric
• coeliac disease
• gastrointestinal disorders
• inflammatory bowel disease

• ARX
• Congenital enteropathy
• EPCAM
• Enteroendocrine cell function
• MYO5B
• Microvillous inclusion disease
• NEUROG3
• PCSK1
• PERCC1
• RFX6
• SKIV2L
• SPINT2
• STX3
• TTC37
• Tricho-hepato-enteric syndrome
• UNC45A
• congenital tufting enteropathy

• Bartter syndrome
• Chronic diarrhea
• Malabsorption
• Pseudo-Bartter syndrome
• Staghorn calculi
• Tufting enteropathy

• Children
• Home parenteral nutrition
• Intestinal failure
• Intestinal transplantation
• Short bowel syndrome
• Taurolidine lock procedure

• Congenital chloride diarrhea
• Congenital tufting enteropathy
• Microvillus inclusion disease
• Monogenetic mutation
• Neonatal-onset diarrhea
• Whole-exome sequencing

• Chloride-Bicarbonate Antiporters/genetics
• Diarrhea/genetics
• Asia, Eastern
• Humans
• Infant, Newborn
• Metabolism, Inborn Errors/genetics
• Mutation/genetics
• Myosin Heavy Chains/genetics
• Myosin Type V/genetics
• Retrospective Studies
• Sulfate Transporters/genetics

• Foundation of Shanghai Municipal Health Commission
• Foundation of Science and Technology Commission of Shanghai Municipality
• Clinical Research Plan of SHDC
• National Natural Science Foundation of China

• Adolescent
• Child
• Child, Preschool
• Diarrhea, Infantile/complications
• Diarrhea, Infantile/genetics
• Epithelial Cell Adhesion Molecule/genetics
• Female
• Humans
• Immunohistochemistry
• Infant
• Liver/pathology
• Liver Diseases/etiology
• Liver Diseases/pathology
• Malabsorption Syndromes/complications
• Malabsorption Syndromes/genetics
• Male

• Congenital Diarrhea
• Congenital Tufting Enteropathy
• Defective Enterocyte
• EpCAM
• Intestinal Cell Differentiation
• Intestinal Failure

• EPCAM
• intra-familial variability
• mutation
• novel mutations
• parental nutrition
• tufting enteropathy

• 17968 Oesterreichische Nationalbank

• EpCAM
• congenital tufting enteropathy
• intestinal epithelial dysplasia
• pathogenesis

• R01 DK107764 NIDDK NIH HHS
• R01DK107764 NIH HHS

Congenital tufting enteropathy (CTE) is a rare cause of diarrhea in children. However, it can result in early-onset of chronic diarrhea and failure to thrive. Children with this disease have to depend on total parenteral nutrition (TPN), and eventually small intestine transplantation. The epithelial cell adhesion molecule (EPCAM) gene was identified to be associated with CTE. Here, we present a case of an infant with CTE due to a mutation not reported in the literature before.

A 1-year and 7-mo infant boy exhibited intractable watery diarrhea and mushy stool within 1 wk after birth, for which he had required medical treatment and hospitalization several times. His sister presented similar symptoms and died at the age of two. On admission, his body weight was 5700 g (-4.8SDS) and measured 66 cm (-5.4SDS) in height. Meanwhile, he cannot speak or climb. He exhibited mild anemia, hypocalcemia, hypomagnesemia, and an infection in the upper respiratory tract. Microvilli sparse and vacuolar degeneration of epithelial cells were reported by small intestine biopsy. Whole-exome sequencing showed a novel homozygous splice mutation (c.657+1[IVS6] G>A) in the EPCAM gene. He was treated with TPN and recombinant human growth hormone. After 2 mo, his body weight was up to 8500 g and he has been waiting for small bowel transplantation.

CTE is rare but fatal. Patients with CTE require rapid diagnosis and therapy to improve their survival.

• Congenital tufting enteropathy
• Congenital diarrhea
• Failure to thrive
• Children
• Case report

• Epithelial cell adhesion molecule
• Metastasis
• TACSD
• Trop2

TROP1 (EpCAM) and TROP2 are homologous cell surface proteins that are widely expressed, and often co-expressed, in developing and adult epithelia. Various functions have been ascribed to EpCAM and TROP2, but responsible mechanisms are incompletely characterized and functional equivalence has not been examined. Adult intestinal epithelial cells (IEC) express high levels of EpCAM, while TROP2 is not expressed. EpCAM deficiency causes congenital tufting enteropathy (CTE) in humans and a corresponding lethal condition in mice. We expressed TROP2 and EpCAM in the IEC of EpCAM-deficient mice utilizing a villin promoter to assess EpCAM and TROP2 function. Expression of EpCAM or TROP2 in the IEC of EpCAM knockout mice prevented CTE. TROP2 rescue (T2R) mice were smaller than controls, while EpCAM rescue (EpR) mice were not. Abnormalities were observed in the diameters and histology of T2R small intestine, and Paneth and stem cell markers were decreased. T2R mice also exhibited enlarged mesenteric lymph nodes, enhanced permeability to 4 kDa FITC-dextran and increased sensitivity to detergent-induced colitis, consistent with compromised barrier function. Studies of IEC organoids and spheroids revealed that stem cell function was also compromised in T2R mice. We conclude that EpCAM and TROP2 exhibit functional redundancy, but they are not equivalent.

• CTE
• TROP1(EpCAM)
• TROP2
• intestinal epithelial cells

• Animals
• Antigens, Neoplasm/physiology
• Cell Adhesion Molecules/physiology
• Diarrhea, Infantile/genetics
• Epithelial Cell Adhesion Molecule/physiology
• Epithelial Cells/metabolism
• HEK293 Cells
• Humans
• Intestinal Mucosa/cytology
• Malabsorption Syndromes/genetics
• Mice, Inbred C57BL
• Mice, Knockout
• Promoter Regions, Genetic

• Congenital enteropathy
• EPCAM mutation
• Founder effect
• Tufting enteropathy
• c.499dup mutation

Congenital tufting enteropathy (CTE) is a rare chronic diarrheal disease of infancy caused by mutations in epithelial cell adhesion molecule (EpCAM). Previously, a murine CTE model showed mis-localization of EpCAM away from the basolateral cell surface in the intestine. Here we demonstrate that mutant EpCAM accumulated in the endoplasmic reticulum (ER) where it co-localized with ER chaperone, GRP78/BiP, revealing potential involvement of ER stress-induced unfolded protein response (UPR) pathway in CTE. To investigate the significance of ER-localized mutant EpCAM in CTE, activation of the three UPR signaling branches initiated by the ER transmembrane protein components IRE1, PERK, and ATF6 was tested. A significant reduction in BLOS1 and SCARA3 mRNA levels in EpCAM mutant intestinal cells demonstrated that regulated IRE1-dependent decay (RIDD) was activated. However, IRE1 dependent XBP1 mRNA splicing was not induced. Furthermore, an increase in nuclear-localized ATF6 in mutant intestinal tissues revealed activation of the ATF6-signaling arm. Finally, an increase in both the phosphorylated form of the translation initiation factor, eIF2α, and ATF4 expression in the mutant intestine provided support for activation of the PERK-mediated pathway. Our results are consistent with a significant role for UPR in gastrointestinal homeostasis and provide a working model for CTE pathophysiology.

• ER stress
• congenital tufting enteropathy
• mutant EpCAM
• unfolded protein response

• Animals
• Chronic Disease
• Diarrhea, Infantile/genetics
• Disease Models, Animal
• Endoplasmic Reticulum Chaperone BiP
• Epithelial Cell Adhesion Molecule/genetics
• Humans
• Infant, Newborn
• Malabsorption Syndromes/genetics
• Mice
• Unfolded Protein Response/genetics

• R01 DK107764 NIDDK NIH HHS
• R01 GM087415 NIGMS NIH HHS

Congenital tufting enteropathy (CTE) is a rare disease that manifests as intractable diarrhea during the neonatal period which is associated with mutations of the epithelial cell adhesion molecule (EpCAM) gene.

A male infant who presented with vomiting, diarrhea, abdominal distention, malnutrition and growth failure was admitted to our department when he was 2 months old. His parents were healthy and nonconsanguineous. Etiologic examinations of stool, inflammatory markers, blood gas and electrolytes levels, serum albumin level, serum immunoglobin levels were all normal. And there was no indication for metabolic diseases. Additionally, gastrointestinal contrast did not reveal abnormality of gastrointestinal. The patient was diagnosed with intestinal malabsorptive syndrome and severe malnutrition without definite cause. He was on supportive treatment and nutritional therapy for 13 months. However, he did not gain weight obviously. He was discharged at the age of 15 months and was fed with partial hydrolyzed formula and rice paste at home. Three months later he developed hypoglycemia and severe respiratory infection. Finally, he died due to sepsis and multiple organs failure. The next generation sequencing revealed one homozygous mutation of EpCAM gene and one complex heterozygous mutation of TTC7A gene. He was diagnosed CTE according to the genetic results and clinical manifestations.

CTE is rarely reported in Asia. Patients present with congenital diarrhea, poor weight gain and growth failure are recommended to perform endoscopy examination with proper immunohistochemistry study as early as possible, and genetic testing is necessary when suspecting congenital diarrhea and enteropathy.

• Chronic diarrhea
• EpCAM
• Growth failure
• TTC7A

• Congenital diarrhea
• Enteropathy
• VEOIBD

• congenital tufting enteropathy
• differentiation
• enteroid
• epithelial cell adhesion molecule

• Constitutional mismatch repair deficiency
• Immune checkpoint inhibitor
• Lynch syndrome
• Microsatellite instability
• Mismatch repair gene

• EPCAM
• Lynch syndrome
• congenital tufting enteropathy
• genotype-phenotype correlation
• in silico simulation
• protein modeling

• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/pathology
• Diarrhea, Infantile/genetics
• Diarrhea, Infantile/pathology
• Epithelial Cell Adhesion Molecule/chemistry
• Epithelial Cell Adhesion Molecule/genetics
• Epithelial Cells/metabolism
• Genetic Association Studies
• Humans
• Malabsorption Syndromes/genetics
• Malabsorption Syndromes/pathology
• Models, Molecular
• MutS Homolog 2 Protein/genetics
• Mutation, Missense/genetics
• RNA Splice Sites/genetics

• R01 DK107764 NIH HHS
• R01 GM26017 NIH GM
• RC2 DK118640 NIDDK NIH HHS
• R01 DK107764 NIDDK NIH HHS
• K08 DK078672 NIDDK NIH HHS
• P30 DK041301 NIDDK NIH HHS
• R01 CA072851 NCI NIH HHS
• T32 DK007202 NIH HHS
• R01 DK083762 NIDDK NIH HHS
• DK083762 NIH HHS
• RT2-01985 California Institute for Regenerative Medicine
• R01 CA72851 NIH CA
• Ludwig Institute for Cancer Research
• NIH
• California Institute for Regenerative Medicine
• Ludwig Institute for Cancer Research

Intestinal epithelial dysplasia (tufting enteropathy) is an uncommon congenital disorder. Furthermore, its association with chronic inflammatory arthropathy is rarely documented in the literature. Low prevalence rates of 1 in 100,000 live births in Western Europe exist, with higher rates in North Africa and Middle Eastern countries. Malta, being a small Mediterranean island at the cusp between Europe and North Africa, has an anecdotal sevenfold prevalence rate. This is the first documented case report of a patient with both intestinal epithelial dysplasia and severe bilateral hip and knee arthropathy that required simultaneous bilateral hip followed by, after a short interval, unilateral knee arthroplasties. Our aim is to highlight the rapid progression of associated arthropathy as well as the successful treatment with joint arthroplasties in such extreme cases. Surgical treatment may be a necessity despite best medical efforts to halt the disease.

EpCAM (epithelial cell adhesion molecule) is a type I transmembrane glycoprotein, which was originally identified as a tumor-associated antigen due to its high expression level in rapidly growing epithelial tumors. Germ line mutations of the human EpCAM gene have been indicated as the cause of congenital tufting enteropathy. Previous studies based on cell models have revealed that EpCAM contributes to various biological processes including cell adhesion, signaling, migration and proliferation. Due to the previous lack of genetic animal models, the in vivo functions of EpCAM remain largely unknown. However, EpCAM genetic animal models have recently been generated, and are useful for understanding the functions of EpCAM. The authors here briefly review the functions and mechanisms of EpCAM in physiological processes and different diseases.

• Children
• Enteropathy
• Histopathology
• Inflammatory bowel disease

We report a case of an infant with congenital tufting enteropathy (CTE) who presented with severe failure to thrive despite multiple interventions. This study illustrates that CTE may be missed by endoscopy, and the use of chromosomal microarray and immunohistological analysis may be integral to diagnosis.

• Congenital tufting enteropathy
• EPCAM mutations
• consanguinity
• failure to thrive

• Inflammatory bowel disease
• genetics
• immunodeficiency
• infantile-onset
• next-generation sequencing
• paediatrics
• phenotype

• congenital chronic diarrhea
• intestinal failure
• intestinal transplant
• saudi arabia
• tufting enteropathy

Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD^ENT) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD^ENT. Here, we review recent progress in understanding the cellular mechanisms of CDD^ENT. We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD^ENT and expediting the discovery of novel therapeutic strategies.

Summary: Overview of the recent progress in our understanding of congenital diarrheal disorders, and the available models to study these diseases.

• Brush border
• Cell polarity
• Congenital diarrheal disorder
• Enterocyte
• Intracellular trafficking
• Microvillus inclusion diseases