Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form

Hum Genet. 2014 Mar;133(3):299-310. doi: 10.1007/s00439-013-1380-6. Epub 2013 Oct 19.


Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73 %) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21 %) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (p < 10(-4)) and, for half of them, with choanal atresia (p < 10(-4)). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556-14A>G (abnormal splicing) was significantly associated with a better outcome (p = 0.032) with milder PN dependency to weaning in some cases. Finally, four patients (7 %) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / metabolism
  • Base Sequence
  • Case-Control Studies
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism
  • Child
  • Child, Preschool
  • Cohort Studies
  • Diarrhea, Infantile / genetics*
  • Epithelial Cell Adhesion Molecule
  • Female
  • Genetic Association Studies
  • Humans
  • Immunohistochemistry
  • Infant
  • Malabsorption Syndromes / genetics*
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Mutation
  • Parenteral Nutrition
  • Phenotype
  • Sequence Analysis, DNA
  • Treatment Outcome


  • Antigens, Neoplasm
  • Cell Adhesion Molecules
  • EPCAM protein, human
  • Epithelial Cell Adhesion Molecule
  • Membrane Glycoproteins
  • SPINT2 protein, human

Supplementary concepts

  • Diarrhea 5, With Tufting Enteropathy, Congenital