The abnormal deposition of laminin and heparin sulfate proteoglycan in the basement membrane has been reported in patients with tufting enteropathy.12
An increase in the number and length of the desmosomes between enterocytes and an abnormal distribution of α2
integrin have been observed in pathological studies of tufting enteropathy,13
which suggests that changes in cell-cell adhesion play a role in the pathogenesis of tufting enteropathy.
has been identified as the gene involved in tufting enteropathy. EpCAM is a cell-adhesion molecule originally identified as a marker for carcinoma because it is highly expressed on rapidly proliferating tumors of epithelial origin. EpCAM functions as a typical adhesion molecule and is connected to the actin cytoskeleton.14
EpCAM interacts directly with claudin 7, a protein required for the formation of tight junctions, implying a role for EpCAM in cellular adhesion.15
However, recent data have revealed a more versatile role for EpCAM, which is not limited to cell adhesion but includes the migration, proliferation, and differentiation of cells.16
EpCAM mediates homotypic interactions between intraepithelial lymphocytes and intestinal epithelial cells during the generation of the innate immune system.17
The c.491+1G>A mutation found in these two siblings has been reported in Mexican Americans with tufting enteropathy. The homozygous mutation of this splice site is reported to result in the complete deletion of exon 4 and the reduced expression of EpCAM.11
p.Lys106X is a novel nonsense mutation, which may produce a truncated second epidermal growth factor (EGF)-like repeat in the extracellular domain. The second EGF-like repeat mediates the lateral interactions between EpCAM molecules. The truncation of the EGF-like repeat is known to inhibit the formation of homotypic cell adhesion.18
The lack of lateral interactions between the molecules may lead to the desmosomal abnormalities observed in tufting enteropathy.
There is some variation in the clinical severity in these siblings, who had the same types of mutations. The sister failed to thrive and her diarrhea was more severe. Factors other than EpCAM
gene mutations may modify the severity of the disease. The sister was diagnosed as having juvenile rheumatoid arthritis. This is the first report describing juvenile rheumatoid arthritis associated with tufting enteropathy. The siblings had a broad nasal bridge and micrognathia, which was reported in a new syndrome of tufting enteropathy and choanal atresia.10
The additional features of this syndrome are chronic corneal inflammation, episodic cytopenia, and abnormal hair texture. Wooly and easily removable hair was found in this study, but the abnormal hair was associated with deficiency of zinc and selenium. Further genetic studies are required to investigate the relationship between genotype and phenotype.
The long-term prognosis is variable. Most patients with tufting enteropathy have been treated with long-term parenteral nutrition, which can lead to liver failure, sepsis, and the loss of vascular access. Intestinal transplantation has become a feasible treatment for intestinal failure, with improving results over the past decade. Three patients with tufting enteropathy, including one Korean,4-6
have undergone small bowel transplantation. A successful pregnancy outcome was reported in a 27-year-old patient with tufting enteropathy.9
This is the first report of two siblings with tufting enteropathy attributable to EpCAM mutations. The identification of mutations makes it possible to confirm the diagnosis when the results of an intestinal biopsy are not definite. Analysis of the EpCAM gene will also be useful for genetic counseling and the prenatal diagnosis of tufting enteropathy.