Tufting Enteropathy

Reifen, Ram; Cutz, Ernest; Griffiths, A; Ngan, Bo; Sherman, Philip M.

doi:10.1097/00005176-199404000-00022

Cited by 138 publications

(44 citation statements)

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“…There are several causes of congenital enteritis and FTT, including the loss of normal maintenance of enterocyte adhesion and trafficking, such as apico-basal polarity. For example, patients with tufting enteropathy (Reifen et al 1994) were reported to have mutations in the EpCAM gene (Sivagnanam et al 2008), which affects normal intestinal epithelial cell adhesion. Patients with mutations in the TTC7A gene also develop apoptotic colitis (Ngan et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Abnormal apoptosis causes colitis and enteritis in patients with Hoyeraal–Hreidarsson syndrome due to DKC1 mutations

Ovadia

Ngan

2016

LymphoSign Journal

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Background: Hoyeraal–Hreidarsson syndrome (HHS), the severe clinical variant of X-linked dyskeratosis congenita, is caused by germline mutations in telomere associated genes. HHS usually manifests within the first years of life and is characterized by progressive bone marrow failure, immunodeficiency, neurological features including microcephaly and developmental delay, as well as intrauterine growth retardation. The typical mucocutaneous manifestations are nail dysplasia, lacy skin pigmentation, and oral leukoplakia. Importantly, gastrointestinal involvement is reported in most patients with HHS, and may be the presenting feature. Given the spectrum of gastrointestinal diseases with a similar presentation, recognizing the unique gastrointestinal histopathology of HHS may facilitate earlier diagnosis and treatment. Methods: This case series highlights the gastrointestinal pathology findings of 2 patients with HHS caused by DKC1 gene mutations. Results: Gastrointestinal biopsies reveal loss of mucosal glands, regenerative glandular alterations and increased colonic epithelial cell apoptosis. Immunostaining of biopsies for cleaved caspase 3, a marker of cellular apoptosis, demonstrates abnormal nonapical and random locations of enterocyte exit which was further exacerbated by enteritis. Conclusion: Gastrointestinal involvement is usually the presenting feature of patients with HHS. This case series highlights the important role on gastrointestinal histopathology in facilitating a diagnosis of HHS. Statement of novelty: Detailed gastrointestinal biopsy images associated with HHS involving DKC1 mutations.

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Section: Discussionmentioning

confidence: 99%

Abnormal apoptosis causes colitis and enteritis in patients with Hoyeraal–Hreidarsson syndrome due to DKC1 mutations

Ovadia

Ngan

2016

LymphoSign Journal

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“…Tufting enteropathy (TE) is a rare inherited enteropathy (Mendelian Inheritance in Man #613217) presenting with intractable watery diarrhea and impaired growth in infancy. Histologically, it is characterized by disorganization of surface epithelium with focal crowding, resembling tufts, villous atrophy without mononuclear cell infiltration, and basement membrane abnormalities [1,2]. TE shows intra-and interfamilial variation in clinical severity; however, patients generally require parenteral nutrition (PN) for several years, most often throughout childhood, to avoid dehydration and to provide adequate growth [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…TE was first described in 1994 [1], and less than 100 patients with molecularly confirmed etiology were reported [9]. Its prevalence is higher in countries with frequent consanguineous marriages.…”

Section: Introductionmentioning

confidence: 99%

Three Novel EPCAM Variants Causing Tufting Enteropathy in Three Families

et al. 2021

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Tufting enteropathy (TE) is caused by recessive EPCAM mutations, and is characterized by intractable diarrhea of congenital onset and disorganization of enterocytes. TE generally requires parenteral nutrition (PN) during childhood or intestinal bowel transplantation. We report three unrelated families with six children with TE. We highlight the high rate of disease-related mortality. We observe adequate weight gain with PN, but low to normal and stunted body length, supporting the recent notion that a short stature might be intrinsic to TE. The diagnosis of TE in the index patients from each family was delayed for months to years, even when clinical data, duodenal biopsies, or exome sequencing data were obtained early on. We identified three novel pathogenic EPCAM variants: a deletion of exon 1 that removes the ATG initiation codon, a missense variant c.326A > G (p.Gln109Arg), and nonsense mutation c.429G > A (p.Trp143*) in a compound heterozygous state with the Mediterranean splice site variant c.556-14A > G (Tyr186Phefs*6). Homozygosity for p.Gln109Arg was associated with absent EPCAM staining, and compound heterozygosity for p.Trp143*/Tyr186Phefs*6 was associated with reduced EPCAM staining in duodenal biopsies; such observations might contribute to a genotype–phenotype correlation in larger cohorts of TE patients. This study extends the clinical and molecular spectrum of TE.

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“…Congenital tufting enteropathy (CTE) belongs to a family of congenital diarrhea and enteropathies that cause persistent and severe diarrhea in infants and often lead to life-threatening intestinal failure. It is characterized by partial villous atrophy, crypt hyperplasia, and focal "tufts" of enterocytes of the intestinal epithelium [1,2]. Most patients with CTE depend on parenteral nutrition and no direct treatments are currently available for the management of this disease.…”

Section: Introductionmentioning

confidence: 99%

Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease

Das

Okamoto

Rabalais

et al. 2020

Cells

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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.

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Tufting Enteropathy

Cited by 138 publications

References 0 publications

Abnormal apoptosis causes colitis and enteritis in patients with Hoyeraal–Hreidarsson syndrome due to DKC1 mutations

Abnormal apoptosis causes colitis and enteritis in patients with Hoyeraal–Hreidarsson syndrome due to DKC1 mutations

Three Novel EPCAM Variants Causing Tufting Enteropathy in Three Families

Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease

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