Abstract
Congenital tufting enteropathy (CTE) is an autosomal recessive disease of infancy that causes severe intestinal failure with electrolyte imbalances and impaired growth. CTE is typically diagnosed by its characteristic histological features, including villous atrophy, crypt hyperplasia and focal epithelial tufts consisting of densely packed enterocytes. Mutations in the EPCAM and SPINT2 genes have been identified as the etiology for this disease. The significant morbidity and mortality and lack of direct treatments for CTE patients demand a better understanding of disease pathophysiology. Here, the latest knowledge of CTE biology is systematically reviewed, including clinical aspects, disease genetics, and research model systems. Particular focus is paid to the pathogenesis of CTE and predicted mechanisms of the disease as these would provide insight for future therapeutic options. The contribution of intestinal homeostasis, including the role of intestinal cell differentiation, defective enterocytes, disrupted barrier and cell–cell junction, and cell-matrix adhesion, is vividly described here (see Graphical ). Moreover, based on the known dynamics of EpCAM signaling, potential mechanistic pathways are highlighted that may contribute to the pathogenesis of CTE due to either loss of EpCAM function or EpCAM mutation. Although not fully elucidated, these pathways provide an improved understanding of this devastating disease.
Highlights
According to the World Health Organization (WHO), diarrhea remains a leading cause of malnutrition and the second leading cause of mortality for children under the age of five
Along with microvillus inclusion disease, a severe disorder belonging to the defective enterocyte trafficking and polarity category of congenital diarrhea and enteropathies (CODEs) is congenital tufting enteropathy (CTE)
The association of the cytoplasmic domain of EpCAM to Novel Protein Kinase C (nPKC) leads to subsequent inhibition of kinase, which plays an important role in the sustainability of cellular attachments [56]
Summary
According to the World Health Organization (WHO), diarrhea remains a leading cause of malnutrition and the second leading cause of mortality for children under the age of five. Along with microvillus inclusion disease, a severe disorder belonging to the defective enterocyte trafficking and polarity category of CODEs is congenital tufting enteropathy (CTE). CTE, known as intestinal epithelial dysplasia, is a rare, autosomal recessive disease of infancy presenting with profuse watery diarrhea, electrolyte imbalances, and impaired growth [3,4]. CTE or epithelial dysplasia was reportedly identified in 1994 [4], though a historically similar disease phenotype was first reported in 1978 [9], where it was termed as familial enteropathy. The patients with familial enteropathy reported having persistent diarrhea with villous atrophy, crypt hyperplasia, without an increase of inflammatory cells in laminar propria, absence of brush-border villous enterocytes and were dependent on total parenteral nutrition [9]. This review aims to highlight predicted or probable mechanisms of this disease based on the known dynamics of EpCAM and CTE models
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