June 2021 – Gastroenterology Pathology

The patient is a 4-month-old Arabic male with persistent, severe diarrhea. No other significant clinical history. 

Figure 1: H&E low power
Figure 2: H&E intermediate power
Figure 3: IHC BerEp4

Based on the histology and immunohistochemistry, what is your most likely diagnosis?

  • Congenital tufting enteropathy
  • Autoimmune enteropathy
  • Infectious enteropathy
  • Microvillus inclusion disease

The correct answer is ...

The correct answer is: Congenital tufting enteropathy.

  • Congenital tufting enteropathy (CTE), which is the correct answer, also known as intestinal epithelial dysplasia, is a rare autosomal recessive disorder, first described in 1994 by Reifen et al. Prevalence is 1/50,000-100,000 live births in Western Europe, but is higher in areas with a high degree of consanguinity and in patients of Arabic origin.

    Patients present in the first few months of life with chronic, watery diarrhea and may have choanal, rectal or esophageal atresia and nonspecific punctuated keratitis.

    Associated genetic mutations include: epithelial cell adhesion molecule (EPCAM) gene (chromosome 2p21), constituting 73% of CTE (isolated form) or the SPINT2 gene (chromosome 19q13.2), constituting 21% of CTE (syndromic form).

    Biopsies from small bowel show various degrees of villus atrophy, crypt hyperplasia, disorganization of surface enterocytes with focal crowding resembling tufts and absence of significant of inflammation.

    Negative staining for BerEP4 (EPCAM) immunohistochemical stain is integral for a correct diagnosis. Molecular genetic testing can help confirm the diagnosis.
  • Microvillus inclusion disease (MID) is an important differential diagnosis, a very rare autosomal recessive disorder of intestinal brush border (at least 200 cases have been reported in Europe).

    Affected infants often have failure to thrive, developmental delay and osteoporosis.

    The disease is caused by MYO5B gene mutation resulting in enterocytes' inability to properly form microvilli. Affected enterocytes form intracellular small clumps of abnormal microvilli mix (microvillus inclusions) that can be seen by electron microscopy. These intracellular inclusions are an important finding that help in differentiating it from. On light microscopy, severe atrophy of microvilli, crypt hyperplasia, and bubbly vacuolated apical cytoplasm with extensive or patchy absence of brush border (usually heighted by PAS and CD10) can be seen.
  • Autoimmune enteropathy is another consideration. The disease is due to autoimmune antibodies directed against the intestinal epithelial cells and affects 1 in 100,000 infants.

    It can be part of IPEX syndrome, an X-linked recessive disorder due to mutations in FOXP3. Patients do not respond to dietary restriction and treatment by immunosuppressive agents is needed. The most important finding on light microscopy is the absence of goblet and/or Paneth cells. Other histologic features include villus atrophy, crypt hyperplasia, expansion of lamina propria by a lymphoplasmacytic infiltrate, increased intraepithelial lymphocytes (IELs), and crypt apoptosis.
  • Infectious enteropathy is unlikely given the absence of significant inflammation and an identifiable offending microorganism.


  1. AlMahamed S, Hammo A. New mutations of EpCAM gene for tufting enteropathy in Saudi Arabia. Saudi J Gastroenterol. 2017;23(2):123-126.
  2. W. Overeem, Arend & Posovszky, Carsten & H. M. M. Rings, Edmond & Giepmans, Ben & C. D. van IJzendoorn, Sven. (2016). The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. Disease Models & Mechanisms. 9. 1-12. 10.1242/dmm.022269. 
  3. Salomon, J., Goulet, O., Canioni, D. et al. Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form. Hum Genet (2014) 133: 299. 
  4. Masia R, Peyton S, Lauwers GY, Brown I. Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases. Am J Surg Pathol. 2014;38(10):1319-29.
Photo of Farah Baban, M.B., Ch.B.

Baban Farah, M.B.Ch.B.

Resident, Anatomic Pathology
Mayo Clinic


Samar Said, M.D.

Consultant, Anatomic Pathology
Mayo Clinic

Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.