Tufting enteropathy

Other Names: IED; Intestinal epithelial dysplasia; Congenital enteropathy; Congenital familial intractable diarrhea with enterocytes assembly abnormalities

Congenital Tufting Enteropathy is a rare congenital enteropathy presenting with early-onset severe and intractable diarrhea that leads to irreversible intestinal failure.

Epidemiology

No epidemiological data is available, however, the prevalence can be estimated at around 1/200,000 births in Europe. The prevalence is higher in areas with high degrees of consanguinity, but cases have been reported worldwide.

Cause

CTE is related to abnormal enterocyte development and differentiation. Mutations in the EPCAM gene (2p21) are seen in 73% of CTE patients and are associated with the isolated intestinal disease. Mutations in the SPINT2 gene (19q13.2) are seen in 21% of CTE cases which are clinically characterized by the syndromic form of the disease. Rarely, CTE patients may present with isolated diarrhea but have no mutations in either EPCAM or SPINT2.

Inheritance

Autosomal recessive inheritance, a 25% chance

CTE is transmitted in an autosomal recessive manner with high prevalence of consanguinity and affected siblings in families.

Signs and symptoms

Most affected patients develop digestive intolerance with vomiting and watery diarrhea within the first few months of life. Diarrhea is severe, chronic and persistent despite bowel rest, resulting in electrolyte imbalance and dehydration. Moreover, an intestinal insufficiency leads to malabsorption, malnutrition, and growth impairment.

Although most children present with isolated diarrhea, a small number of congenital tufting enteropathy (CTE) patients present with a syndromic form where diarrhea is associated with non-specific punctuated keratitis, and various malformations such as choanal atresia, esophageal atresia, imperforate anus, dysmorphic features, skeletal dysplasia, and (in one case) Dubowitz syndrome. In general, infants with IDE develop watery diarrhea within the first days after birth. It is severe in most of the cases. Stool volumes may be as high as 100–200 ml/kg body weight per day, with electrolyte concentrations similar to those seen in small intestinal fluid. In rare cases the diarrhea may be less abundant and sometimes may mislead the diagnosis . The growth is impaired. There is no past history of hydramnios suggesting congenital chloride diarrhea or sodium malabsorption diarrhea. Most patients have consanguineous parents and/or affected siblings, some of whom died during the first months of life from severe diarrhea of unknown origin.

Several cases of IED have been reported as being associated with phenotypic abnormalities, for example Dubowitz syndrome or malformative syndrome . Some affected children are reported to have dysmorphic facial features . An association between congenital intractable diarrhea of infancy (IDI) and choanal atresia has been reported in four children . We have observed malformations, including esophageal atresia, choanal atresia, or unperforated anus. Moreover, nonspecific punctuated keratitis is observed in more than 60% of patients . This associated keratitis is very intriguing since it is also an epithelial disease and therefore studies of keratitis might help to elucidate the molecular mechanisms of the intestinal epithelial disease. The fact that some children have ophthalmological symptoms and keratitis highlights the heterogeneity of IED (Salomon et al., manuscript in preparation).

Diagnosis

Diagnosis is based on the combination of clinical and histological criteria. A congenital chronic diarrhea in the absence of an infectious or an inflammatory process, in association with various degrees of small and large bowel villous atrophy and specific histological abnormalities involving the focal crowding of surface enterocytes resembling tufts, and branching crypts, allow for the diagnosis of CTE.

When not all criteria are obvious one can be helped by the association of the non-syndromic form of the disease with negative EpCAM immunostaining on patient's duodenal biopsies; or conversely in case of the syndromic form of the disease with a normal EpCAM immunostaining. To date, SPINT2 immunostaining on duodenal biopsies seems useless for the diagnosis. Molecular genetic testing, identifying a mutation in the EPCAM gene or SPINT2 can confirm diagnosis, however, some CTE patients do not have any identified genetic mutations.

Differential diagnosis The differential diagnosis primarily includes other protracted congenital diarrhea disorders such as microvillus inclusion disease, congenital chloride diarrhea, congenital sodium diarrhea, and syndromic diarrhea, as well as glucose-galactose malabsorption.

Antenatal diagnosis Prenatal diagnosis is available but can only be offered to families where a first case has already been described. The rarity of CTE and the absence of prenatal signs do not make it an appropriate candidate for either antenatal or postnatal mass screening.

Treatment

To date there is no known curative treatment for CTE. Oral or enteral feedings worsen the diarrhea, however they should be maintained at the minimum tolerated level. CTE patients require daily, long-term parenteral support in order to maintain an adequate nutritional status. Life threatening complications related to intestinal failure and long-term parenteral nutrition may become an indication for intestinal transplantation, thus timing of referral to an expert center is crucial before the onset of severe complications.

Prognosis

Currently, children with CTE reach adulthood if long-term parenteral nutrition is conducted appropriately in an experienced center, otherwise the long-term prognosis may be reserved due to the complications of this delicate palliative treatment.

NIH genetic and rare disease info

• NIH info on Tufting enteropathy

Tufting enteropathy is a rare disease.

Tufting enteropathy Resources
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