**Background:** Tufting enteropathy (TE) is a rare inherited enteropathy (OMIM #613217) characterized by intractable watery diarrhea, impaired growth, and distinct histological features including villous atrophy, crypt hyperplasia, and focal crowding of surface epithelium resembling tufts. Mutations in the EPCAM gene were first identified in 2008 as a cause of TE. The condition has a wide range of severity, and patients often require parenteral nutrition (PN) for years, with complications including sepsis, thrombosis, liver disease, and poor quality of life. Small bowel transplant is an option but has a 3-year survival rate of around 30%. This study reports the long-term outcome and histopathology in two Turkish siblings with TE and the EPCAM mutation p.Asp253Asn.
**Methods:** Two siblings from consanguineous parents (first cousins) were evaluated. Patient 1, a 3-year-old female, presented with intractable diarrhea since age 13 days, chronic malnutrition, dehydration, vomiting, and bulky diarrhea (2000-2500 g stool output daily). Patient 2, her 12-year-old sister, presented at age 18 months with intractable diarrhea and failure to thrive. Both underwent duodenal biopsy, which showed disorganization of epithelial enterocytes and villus tufts. Molecular genetic testing was performed using whole-exome sequencing (WES) in patient 2, and the identified mutation was confirmed in patient 1. Immunohistochemistry for EPCAM was performed on duodenal biopsies using a monoclonal EPCAM antibody (Clone Ber-EP4).
**Key Results:** A homozygous EPCAM missense mutation c.757G>A (p.Asp253Asn) was identified in patient 2 and segregated with disease in the family. The mutation is located within a 29-Mb region of homozygosity on chromosome 2p21, consistent with identity-by-descent due to consanguinity. It is predicted damaging by all three in silico programs and is not listed in ExAC or gnomAD databases. Immunohistochemistry showed complete lack of EPCAM staining in duodenal biopsies from both patients, compared to positive staining in on-slide control. Patient 1 had severe growth failure at presentation (weight SDS –9.4, height SDS –5.5 at age 3 years). She received total parenteral nutrition (TPN), octreotide infusion (1 mcg/kg/min), and later enteral nutrition with hydrolyzed formula. At age 4 years, her weight was 9.8 kg (–4.9 SDS) and height 80 cm (–5.3 SDS), showing catch-up growth. She also experienced six episodes of painful hand swelling (tenosynovitis) without fever or rash, with elevated CRP, serum amyloid A, and thrombocyte counts. Patient 2 presented at 18 months with weight SDS –9.5 and height SDS –7.7. She was initially TPN-dependent but was gradually weaned; partial parenteral nutrition (PPN) was stopped at age 4 years. At age 12 years, her weight was 32 kg (–1.8 SDS) and height 138 cm (–2.3 SDS), with complete resolution of intractable diarrhea and normal daily activities. She had one episode of catheter infection and thrombosis that was treated successfully.
**Clinical Implications:** This report provides one of the rare long-term follow-up studies of TE. Both patients achieved weaning from PN and significant catch-up growth, despite complete absence of EPCAM protein expression. The severity of diarrhea decreased after age 4 years, and both tolerated increased enteral nutrition. The authors note that among 90 reported TE patients, 13 underwent intestinal transplant and 12 died, highlighting the morbidity and mortality of the condition. The favorable outcome in these siblings suggests that factors other than EPCAM genotype (e.g., nutritional management, use of hydrolyzed formula, somatostatin therapy) may influence prognosis. The observation of tenosynovitis in patient 1 adds to the evidence that TE patients are prone to chronic arthritis, possibly due to impaired intestinal barrier function and immune activation. The authors conclude that severe diarrhea and growth failure due to TE should be followed closely before considering transplantation, and that somatostatin and hydrolyzed formula may reduce PN requirements and avoid bowel transplant in the long term.