CASE PRESENTATION Khuloud Abu Qasida The Royal Hospital Muscat, Sultanate of Oman
Contents ■ Case presentation ■ Case discussion
Clinical Information: 3 months old boy • Presented at the age of 2 weeks : secretory diarrhea & recurrent vomiting • Developmental delay • Muscular hypotonia • Failure to thrive • Nutritional rickets
Clinical Information: Past medical history: ■ Unremarkable antenatal and natal period Family history: ■ Parents are consanguineous ■ A sibling died due to secretory diarrhea
Esophagogastroduodenoscopy (EGD) ■ OESOPHAGUS; Normal ■ Stomach : normal ■ Duodenum: Normal Biopsy was taken from the stomach, duodenum and colon
Duodenal Biopsy ■ Additional stains were performed at the university of Michigan: – PAS & CD10: preserved brush border – Chromogranin : within normal limits – MOC-31 (EPCAM anti-body) : absent
EPCAM negative membranous staining pattern EPCAM normal membranous staining pattern OC17-16277 OC17-16262
Duodenal biopsy: The overall morphologic and immunostaining are consistent with tuftin ting enter eropa opath thy.
■ Whole Exome Sequencing : EpCAM gene homozyguous variant mutation Class III: Variant of uncertain significance
Follow up: The patient died at the age of 7 months
DISCUSSION
Tufting Enteropathy Synonym yms ■ Congenital tufting enteropathy ■ Intestinal epithelial dysplasia (original name)
Tufting Enteropathy Defin initi tion: n: ■ Intractable watery diarrhea ■ Present in neonatal period ■ Frequent history of parental consanguinity
Tufting Enteropathy Incide idence nce: ■ 1 in 50000 – 100,000 in western Europe live births Inheritance eritance pattern: n: ■ Autosomal recessive
Tufting Enteropathy: Clinical nical prese senta ntati tion on: ■ Intractable watery diarrhea ■ Vomiting ■ Failure to thrive
Tufting Enteropathy Clini nica cal l present sentat ation on ■ Associated abnormality: Choanal atresia Imperforate anus Skeletal defects Superficial punctate keratitis
Tufting Enteropathy ■ Mutation in EpCAM gene (on chromosome 2p21) – EpCAM is a transmembrane glycoprotein – Present on basolateral membrane of enterocytes – Promotes cells-cell adhesion and cell proliferation and inhibits cell differentiation
HISTOLOGY
Tufting Enteropathy Histologic Features: ■ Epith theli elial l tufts ts (may be focal) ■ Foci of disorganized surface epithelium resulting in crowded “tufts” of enterocytes ■ Clusters of epithelial cells sheds into the lumen may be present
Tufting Enteropathy Histologic Features: ■ Villous atrophy ■ Crypt hyperplasia ■ Dilated (pseudocyst) crypts ■ Crypt branching ■ Paneth cell hyperplasia
Tufting Enteropathy Histologic features: ■ Lamina propria inflammation is mild to reduced ■ Scattered intraepithelial lymphocytes may be seen ; however marked lymphocytosis is not characteristic of TE ■ Preserved brush border
Ranganathan S, et al. Tufting enteropathy revisited: The utility of MOC31 (EpCAM) immunohistochemistry in diagnosis. Am J Surg Pathol 2014;38:265 ‐ 72.
Tufting Enteropathy Histologic features: ■ Mucosal changes in colon, appendix & Meckel diverticulum and in gastric biopsy
EPCAM IMMUNOSTAIN
Tufting Enteropathy Immunohi hist stoche ochemistr stry: y: ■ Staining with EpCAM antibody (MOC31) found to have sensitivity and specificity of 100%. ■ Characteristically shows lack of membranous staining.
Ranganathan S, et al. Tufting enteropathy revisited: The utility of MOC31 (EpCAM) immunohistochemistry in diagnosis. Am J Surg Pathol 2014;38:265 ‐ 72.
Tuf ufting ting Ent nter eropath opathy Immunoh nohist istoch ochemi emist stry: y: ■ Lack of staining in the small intestine, appendix, colon & gastric mucosa
Ranganathan S, Schmitt LA, Sindhi R. Tufting enteropathy revisited: The utility of MOC31 (EpCAM) immunohistochemistry in diagnosis. Am J Surg Pathol 2014;38:265 ‐ 72.
Tufting ng Enteropa path thy Immun munoh ohist stochemi ochemist stry: y: ■ Lack of staining in biopsy with no histological evidence of TE. ■ EpCAM immunostain in duodenal biopsy after transplantation
Tufting Enteropathy Electron Microscopy: ■ Helps to exclude other differential diagnosis ■ Increase in the length and number of the desmosomes
DIFFERENTIAL DIAGNOSIS
Tufting Enteropathy Different erential al diagnosis: gnosis: ■ Microvillus inclusion disease (MVID) ■ Enteroendocrine cell dysgenesis ■ Autoimmune enteropathy
Microvillus inclusion disease (MID): ■ Congenital enteropathy ■ Characterized by intractable watery diarrhea presenting in infancy ■ Severe atrophy of microvilli with apical accumulation of secretory granules ■ More severe than TE with persistent life threatening watery diarrhea
Microvil illus us inclusio usion n disea ease se (MID): ): ■ PAS stain, CD10 and villin immunohistochemical stains highlight intracytoplasmic vacuoles and brush border Electr tron on microsc oscop opy: y: ■ Absent or short apical microvilli ■ Intracytoplasmic inclusions containing aggregates of microvilli
Ranganathan S, et al. Tufting enteropathy revisited: The utility of MOC31 (EpCAM) immunohistochemistry in diagnosis. Am J Surg Pathol 2014;38:265 ‐ 72.
Enteroendocrine cell dysgenesis ■ Autosomal recessive disorder. ■ Congenital absence of enteroendocrine cells in the small and large bowel. ■ Mutation in the NEUROG3 gene(10q21.3). ■ Affected patient exhibits congenital diarrheal syndrome.
Enteroendocrine cell dysgenesis ■ Normal +/- vollous atrophy ■ The brush border is normal ■ Enteroendorine cells absent in the small intestine and colon ■ chromogranin A.
Autoimmu mune ne enteropath opathy: ■ Intractable watery diarrhea presenting in in older infants (within 6 months of age) ■ Inappropriate humoral response to intestinal tract antigens
Autoim oimmun une e enter eropat opathy: y: ■ Villous atrophy ■ Crypt hyperplasia ■ Lymphocytosis involving deep crypts ■ Increased crypt apoptotic bodies ■ Crypt abscess may be present ■ Goblet and paneth cells may be markedly reduced in number
TREATMENT & PROGNOSIS
Tufting Enteropathy Treatment: ■ Parenteral nutrition is the initial therapy for TE ■ Small intestine transplant
Tufting Enteropathy Prognosis: ■ Variable ■ Reports of patient weaned off total parenteral nutrition over time with recovery of more normal histology on biopsies. ■ Authors suggested this could be due to variant mutations.
CONCLUSION
Conclusion ■ TE is a rare disease that has to be included in the differential diagnosis of congenital diarrhea. ■ The characteristic histological features might not be evident at an early stage. ■ EPCAM immunostain should be performed in biopsy from patients with a strong clinical suspicion. ■ Immunohistochemical panel of antibodies targeting other causes of congenital enteropathy that includes PAS, CD10 & chromogranin.
Ac Ackno nowledg wledgmen ent t ■ We would like to express our sincere gratitude to our advisor, Prof. Raja Rabah, MD, Professor and Director, Pediatric and Perinatal Pathology, University of Michigan Health System, For her review of the case and valuable comments and kind review of the presentation.
References: 1. Ranganathan S, Schmitt LA, Sindhi R. Tufting enteropathy revisited: The utility of MOC31 (EpCAM) immunohistochemistry in diagnosis. Am J Surg Pathol 2014;38:265 ‐ 72. 2. AlMahamed S, Hammo A. New mutations of EpCAM gene for tufting enteropathy in Saudi Arabia. Saudi J Gastroenterol 2017;23:123 ‐ 6. 3. Kelly Haas, Brock Martin, Mart ́ ın Mart ́ ın, John Kerner. Intractable Diarrhea in Two Brothers: Late Diagnosis of Tufting Enteropathy in Adolescence. Dig Dis Sci 2016 61:381 – 383 4. Jitsupa Treetipsatit,and Florette K. Hazard,, Features of Gastric and Colonic Mucosa in Congenital Enteropathies. A Study in Histology and Immunohistochemistry. Am J Surg Pathol Volume 38, Number 12, December 2014 5. Julie Lemale, Aurore Coulomb, Be ́ atrice Dubern, Sabah Boudjemaa, Sheila Viola, Patrice Josset, Patrick Tounian, and Jean-Philippe Girardet. Intractable Diarrhea With Tufting Enteropathy: A Favorable Outcome Is Possible. JPGN Volume 52, Number 6, June 2011
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