Primer reporte en Cuba de enteropatía congénita en penachos / First report of congenital tufting enteropathy in Cuba

Introducción: La enteropatía en penacho, conocida como displasia epitelial intestinal, es una afección congénita muy poco frecuente que se presenta con diarrea refractaria en lactantes. Objetivo: Describir el primer reporte en Cuba de enteropatía congénita en penachos. Presentación del caso: Se presentó el primer caso de la enfermedad en Cuba a partir de los hallazgos histopatológicos y se describieron los aspectos clínicos, diagnósticos y terapéuticos abordados. Conclusiones: La enteropatía en penachos supone un reto diagnóstico al no exhibir un cortejo clínico patognomónico. La concomitancia de diarrea crónica con los trastornos malformativos debe hacer saltar las alarmas y orientar el pensamiento clínico y la metodología diagnóstica hacia posibles trastornos genéticos(AU)

Introduction: Tufting enteropathy, also known as intestinal epithelial dysplasia, is a very infrequent congenital disorder presenting as refractory diarrhea in infants. Objective: Describe the first report of congenital tufting enteropathy in Cuba. Case presentation: A presentation is provided of the first case of the disease in Cuba based on histopathological findings and accompanied by a description of the clinical, diagnostic and therapeutic aspects addressed. Conclusions: Tufted enteropathy poses a diagnostic challenge as it does not exhibit a pathognomonic clinical courtship. The concomitance of chronic diarrhea with malformation disorders should set off alarms and guide clinical thinking and diagnostic methodology towards possible genetic disorders(AU)

Combined pancreatic and gastric heterotopia in small intestine presenting as intussusception-A rare congenital anomaly.

Pancreatic and gastric heterotopias are rare congenital anomalies which have been reported throughout the length of the gastrointestinal tract. Combined gastric and pancreatic heterotopias, although very rare, have been described mainly in the duodenum followed by jejunum with ileum being a rare site. The reported incidence of this combined heterotopias is low, ranging from <1% to 13%. Extensive literature search has revealed that only Four cases of combined pancreatic and gastric heterotopias have been reported in the small intestine till date. Hence, we report this case for its rarity and unusual presentation as intussusception in a young male.

Updates in Pediatric Congenital Enteropathies: Differential Diagnosis, Testing, and Genetics.

Congenital enteropathies comprise a heterogeneous group of disorders typically resulting in severe diarrhea and intestinal failure. Recent advances in and more widespread application of genetic testing have allowed more accurate diagnosis of these entities as well as identification of new disorders, provided a deeper understanding of intestinal pathophysiology through genotype-phenotype correlations, and permitted the exploration of more specific therapies to diseases that have heretofore been resistant to conventional treatments. The therapeutic armamentarium for these disorders now includes intestinal and hematopoietic stem cell transplantation, specific targeted therapy, such as the use of interleukin-1 receptor antagonists and, in some cases, gene therapy. These considerations are particularly applicable to the group of disorders identified as "very-early onset inflammatory bowel disease" (VEO-IBD), for which a veritable explosion of knowledge has occurred in the last decade. The pathologist plays a crucial role in assisting in the diagnosis of these entities and in ruling out other disorders that enter into the differential diagnosis.

Duplication cyst with midgut volvulus in a neonate: an unusual presentation.

Incomplete intestinal fixation or malrotation of gut with midgut volvulus is one of the important causes of bilious vomiting in neonates. The incidence of malrotation of gut in population is 4% and that of duplication cyst is 1:4500. Patients with malrotation are prone to develop midgut volvulus due to their narrow mesenteric base demanding urgent surgical intervention. Common associated anomalies are intrinsic duodenal obstruction, internal hernias, caecal volvulus, anorectal malformations and Hirschsprung's disease. The present case refers to a 4-day-old neonate who presented with malrotation of gut with reverse volvulus and an associated gastrointestinal duplication cyst, which is a rare association with only few reported case reports. After imaging with ultrasound and contrast radiograph, the baby underwent prompt surgical intervention in the form of Ladd's procedure with resection and anastomosis of jejunal duplication cyst.

Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD.

Childhood enteropathies are a group of diseases causing severe chronic (>2-3 weeks) diarrhoea often starting in the first week of life with the potential for fatal complications for the affected infant. Early identification and accurate classification of childhood enteropathies are, therefore, crucial for making treatment decisions to prevent life-threatening complications. Childhood enteropathies are classified into four groups based on the underlying pathology: (i) conditions related to defective digestion, absorption and transport of nutrients and electrolytes; (ii) disorders related to enterocyte differentiation and polarization; (iii) defects of enteroendocrine cell differentiation; and (iv) disorders associated with defective modulation of intestinal immune response. While the intestinal mucosa is usually normal in enteropathies related to congenital transport or enzyme deficiencies, the intestinal biopsy in other disorders may reveal a wide range of abnormalities varying from normal villous architecture to villous atrophy and/or inflammation, or features specific to the underlying disorder including epithelial abnormalities, lipid vacuolization in the enterocytes, absence of plasma cells, lymphangiectasia, microorganisms, and mucosal eosinophilic or histiocytic infiltration. This review intends to provide an update on small intestinal biopsy findings in childhood enteropathies, the "newcomers", including very early onset monogenic inflammatory bowel disease (IBD), in particular, for the practicing pathologist.

Parenteral nutrition-associated liver disease in extremely low-birthweight infants with intestinal disease.

BACKGROUND: The aim of this study was to investigate factors associated with the development of parenteral nutrition-associated liver disease (PNALD) and to examine the clinicopathological relationship of PNALD in extremely low-birthweight infants (ELBWI). METHODS: The subjects were 13 ELBWI who had received PN because of intestinal perforation or functional ileus between 2000 and 2013. We measured the serum levels of biochemical parameters, including aspartate aminotransferase, alanine aminotransferase, and direct bilirubin. Liver histopathology was examined in relation to outcome. The subjects were categorized into two groups on liver histopathology: F(+), development of hepatic fibrosis and necrosis with/without cholestasis; and F(-), no hepatic fibrosis. RESULTS: Of 13 ELBWI, five died of hepatic failure, five died of sepsis, and the other three were alive at the time of the study. Of the five infants who died of hepatic failure, two developed fulminant hepatitis without cholestasis, and the other three developed chronic cholestasis and finally hepatic failure. Postmortem histopathology in F(+) indicated not only massive hepatic necrosis, but also massive hepatic fibrosis. These histopathological findings explained the clinical presentation of portal hypertension. There were significant differences in the fasting period after intestinal disease onset between the two groups. CONCLUSION: The prolonged fasting with PN is responsible for severe hepatocellular necrosis with fibrosis and consequent lethal portal hypertension.

Esophageal atresia and malrotation: what association?

INTRODUCTION: Esophageal atresia/tracheo-esophageal fistula (EA/TEF) has an incidence of approximately 1:3,500. The incidence of malrotation is thought to be 1:200-500. We attempted to define the incidence of a combination and discuss the implications. METHODS: This was a retrospective review of all patients admitted to a single institution with a diagnosis of EA or EA/TEF or TEF between April 1981 and January 2013. Patients were included if the position of the duodeno-jejunal flexure (DJF) was determined by upper GI contrast study (UGIS), surgery or post-mortem. RESULTS: Case notes were reviewed for 235 patients. In the EA type A group, 3/28 (11 %; 95 % CI 3.7-27.2 %) had malrotation, significantly higher than the reported incidence of malrotation in the general population (p = 0.0008). All three patients in this group were symptomatic with one patient found to have a volvulus at emergency surgery. In the type C group, 6/196 (3 %, 95 % CI 1.4-6.5 %) had malrotation, significantly higher than the incidence reported for the general population (p = 0.0033) but not significantly different to that of the type A group (p = 0.0878). There were no patients with malrotation identified in any other EA/TEF type. In total, 9/235 (3.8 %; 95 % CI 2.0-7.2 %) patients with EA had malrotation, significantly higher than the 5/1,050 (0.48 %) reported for the general population (p = 0.0002). CONCLUSION: There is a high incidence of malrotation in patients with pure EA. In the type A group an attempt to identify the DJF position at gastrostomy siting and/or performance of UGIS in the neonatal period should be undertaken. There should also be a low threshold for UGIS in all EA/TEF patients.

Evaluation of intestinal biopsies for pediatric enteropathy: a proposed immunohistochemical panel approach.

Congenital enteropathies are rare disorders with significant clinical consequences; however, definitive diagnosis based on morphologic assessment of duodenal biopsies with routine stains alone is often impossible. To determine the role of immunohistochemistry (IHC) in the evaluation for microvillous inclusion disease, congenital tufting enteropathy (intestinal epithelial dysplasia), and enteroendocrine cell dysgenesis, a series of duodenal biopsies from 26 pediatric patients with chronic/intractable diarrhea was retrospectively reviewed. IHC stains for CD10, EpCAM, chromogranin, and villin were performed on all biopsies, and the results were correlated with hematoxylin and eosin and ultrastructural findings using electron microscopy, when available. Biopsies from 2 patients diagnosed with microvillous inclusion disease at the time of original biopsy demonstrated diffuse CD10-positive cytoplasmic inclusions within enterocytes and normal expression of EpCAM and chromogranin. Biopsies from 3 patients, including 2 siblings with confirmed EPCAM mutations, demonstrated complete loss of EpCAM expression and normal expression of CD10 and chromogranin; electron microscopic evaluation revealed characteristic ultrastructural findings of tufting enteropathy. Biopsies from 1 patient with a confirmed NEUROG3 mutation demonstrated an absence of intestinal enteroendocrine cells by chromogranin staining, consistent with enteroendocrine cell dysgenesis. Four patients' biopsies displayed nonspecific staining patterns for CD10 and/or EpCAM with normal expression of chromogranin, and 16 patients' biopsies exhibited normal expression for all 3 markers. Villin stains demonstrated heterogenous brush border labeling with nonspecific cytoplasmic reactivity, a pattern variably present throughout the biopsy series. In conclusion, the routine use of an IHC panel of CD10, EpCAM, and chromogranin is warranted in patients meeting specific age and/or clinical criteria, as the morphologic findings of congenital enteropathies may be subtle, focal, or inapparent on routine stains.

A novel nonsense mutation in the EpCAM gene in a patient with congenital tufting enteropathy.

OBJECTIVES: Tufting enteropathy (TE) is a classical congenital disorder of the intestinal mucosa causing protracted diarrhea in infancy as a result of a dysfunctional epithelial cell barrier, which is mainly caused by mutations in the EpCAM gene and expression of a nonfunctional epithelial cell adhesion molecule in the intestine. We report here a novel nonsense mutation in a patient suspected of having TE, resulting in a complete absence of EpCAM in duodenal enterocytes. METHODS: A patient presenting with congenital diarrhea and suspected of having TE was screened for EpCAM mutations, and duodenal biopsies were stained for EpCAM using immunohistochemistry analysis. RESULTS: We identified a novel homozygous nonsense mutation in the EpCAM gene in a patient suspected of having TE, causing a complete loss of EpCAM expression in duodenal enterocytes. CONCLUSIONS: With screening analysis for EpCAM mutations and immunohistochemistry for EpCAM expression in duodenal enterocytes, we found a novel homozygous mutation in a patient with classical protracted diarrhea in infancy finally diagnosed as TE, which results in a complete absence of EpCAM and in dysfunctional barrier formation in duodenal enterocytes.

A newborn with caudal duplication and duplex imperforate anus.

There are case reports of duplication of the colon, rectum, anus, urinary system, lower genital tract, and external genitalia, spinal anomalies, and abdominal wall defects. However, it is rare to encounter a single newborn with all of the mentioned abnormalities, which have been defined as the caudal duplication syndrome (CDS). Herein, we present a newborn with an omphalocele, duplex external genitalia (with duplex labia minora and labia majora), duplex urethral orifices, duplex vaginal orifices, and duplex anal dimple with imperforate anus and rectovestibular fistula on both sides. Exploration revealed duplex appendix, colon duplication, duplex uterus (continuing with tuba and ovaries on both sides), duplex rectum, malrotation of the intestines, with the cecum located in the middle of the abdomen, defect in the intestinal mesentery, and internal herniation of the small intestines through this defect. The intestines were operatively reduced and the defect repaired.

Multiple duplication cysts diagnosed prenatally: case report and review of the literature.

Enteric duplication cysts (EDC) are typically solitary lesions that occur throughout the alimentary tract. Postnatal diagnosis is often prompted when complications occur from bleeding, obstruction, or infection. We present a case of multiple EDC diagnosed prenatally, managed with prenatal and neonatal follow-up and resection in infancy. Prenatal detection allowed for optimal management prior to the development of symptoms or complications.

Hepatic fibrosis persists and progresses despite biochemical improvement in children treated with intravenous fish oil emulsion.

OBJECTIVES: Intestinal failure-associated liver disease (IFALD) is a multifactorial process, which can culminate in cirrhosis and need for transplantation. Fish oil-based lipid emulsions (FOE) reportedly reverse hyperbilirubinemia, but there are little data on their effect on the histopathology of IFALD. METHODS: We blindly examined sequential liver biopsy data on 6 children receiving FOE, with scoring of cholestasis, inflammation, fibrosis, and ductal proliferation based on standardized systems. This information was correlated with biochemical and clinical data to determine any possible relations between biologic and histologic improvement. RESULTS: The median gestational age was 35 weeks, median birth weight 2064 g, and common most reason for intestinal loss was gastroschisis (5/6 children). Median intestinal length was 26 cm beyond the ligament of Treitz and most children had roughly 2 of 3 of their colonic length. It was observed that although hyperbilirubinemia reversed and hepatic synthetic function was preserved across timepoints, fibrosis was persistent in 2 cases, progressive in 3 cases, and regressed in only 1. It remained severe (grade 2 or higher) in 5 of 6 children at last biopsy. Histologic findings of cholestasis improved in all patients and inflammation improved in 5 of 6 children. There were mixed effects on ductal proliferation and steatosis. CONCLUSIONS: In children treated with FOE, reversal of hyperbilirubinemia is not reflected by a similar histologic regression of fibrosis at the timepoints studied. Children with IFALD should have active ongoing treatment and be considered for early referral to an Intestinal Failure Program even with a normalized bilirubin.

Reversed intestinal malrotation with concurrent cecal carcinoma.

A 57-year-old man was admitted with a type 2 (ulcerated with clear margin) cancer in the cecum. Contrast-enhanced CT showed that the superior mesenteric vein was anterior to the superior mesenteric artery, and the patient was suspected of having intestinal malrotation. A laparoscopic-assisted ileocecal resection was performed. At operation, the cecum and the transverse colon passed through the root of the mesentery behind the superior mesenteric artery with the duodenum. Therefore, this was thought to be a reversed-type intestinal malrotation. After the operation, 3D-CT colonography with duodenography images were reconstructed to retrospectively confirm the diagnosis of a reversed malrotation. These images clearly demonstrated the abnormal anatomy and overall orientation of the intestine. Patients with a reversed intestinal malrotation and concurrent cecal cancer are extremely rare. Herein, we present a patient who underwent a laparoscopic-assisted ileocecal resection for cecal cancer that presented concurrently with a reversed intestinal malrotation.

Perinatal outcomes of fetal echogenic bowel.

OBJECTIVE: To investigate perinatal outcomes of fetal echogenic bowel (FEB). METHOD: This is a retrospective observational study of FEB cases from Jan 2005-Dec 2010. Data from ultrasound and fetal medicine investigations, uterine artery Doppler (UAD), intra-partum care and neonatal outcome were obtained from Fetal Medicine, Obstetric and Neonatal Databases. RESULTS: There were 139 cases presenting at 21(+5) (15(+1) -35(+5) ) weeks gestation. Overall, 106/139 (76.2%) were live born (LB), 8/139 (5.8%) were complicated by intra-uterine deaths (IUD), 11/139 (7.9%) had termination of pregnancy (TOP) and 14/139 (10.1%) were lost to follow-up after 28 weeks gestation. Six had chromosomal/genetic abnormalities, two had congenital cytomegalovirus, none had cystic fibrosis.Uterine artery Doppler was normal in 106/130 (81.5%) cases. In this group, there were no cases of fetal growth restriction (FGR), 95/106 (89.6%) were LB, 1/106 (0.94%) had an IUD. In the abnormal UAD group, 17/24 (70.1%) developed FGR, 11/24 (45.8%) were LB, 4/24 (16.7%) had TOP, 7/24 (29.2%) had IUD.In total, 20/106 (18.9%) live births were admitted for specialist neonatal care, 12/20 (60%) for prematurity. Only one had primary bowel pathology. CONCLUSION: Pregnancies with FEB and screen positive UAD are at risk of adverse perinatal outcome. Primary bowel pathology is rare following the finding of FEB.

Antenatal diagnosis of bowel dilatation in gastroschisis is predictive of poor postnatal outcome.

PURPOSE: Although gastroschisis infants usually have a good outcome, there remains a cohort of babies who fare poorly. We inquired whether the presence of bowel dilatation in utero is predictive of postnatal course in infants with gastroschisis. METHODS: We compared the clinical course of infants who had bowel dilatation with those who did not. Bowel dilatation was defined as more than 20 mm in cross-sectional diameter on ultrasound at any gestational age. Outcome measures used were length of time of parenteral nutrition, death, and surgery for intestinal failure. RESULTS: A review of 170 infants with gastroschisis identified 74 who had dilatation of more than 20 mm (43.5%). There was no significant difference in the incidence of intestinal atresia in those with bowel dilatation and those without (P = .07). Those with bowel dilatation spent a longer period on parenteral nutrition. There were significantly more deaths in the group with bowel dilatation (P = .01). There was no significant difference in the number of infants requiring surgery for intestinal failure between the 2 groups (P = .47). CONCLUSIONS: We found that sonographically detected bowel dilatation more than 20 mm in utero in fetuses with gastroschisis may have value in predicting clinically significant adverse postnatal outcomes.

A founder effect at the EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf.

Mutations of the EPCAM gene have been recently identified in Congenital Tufting Enteropathy (CTE), a severe autosomal recessive gastrointestinal insufficiency of childhood requiring parenteral nutrition and occasionally intestinal transplantation. Studying seven multiplex consanguineous families from the Arabic peninsula (Kuwait and Qatar) we found that most patients were homozygote for a c.498insC mutation in exon 5. The others carried a novel mutation IVS4-2A→G. Both mutations were predicted to truncate the C-terminal domain necessary to anchorage of EPCAM at the intercellular membrane. Consistently, immunohistochemistry of intestinal biopsies failed to detect the EPCAM protein at the intercellular membrane level. The c.498insC mutation was found on the background of a minimal common haplotype of 473kb suggesting a very old founder effect (5000-6000 yrs).

Colonic cancer in a patient with intestinal malrotation: a case report.

We present a case of a 76-year-old patient with intestinal malrotation, with incomplete rotation of the small intestine and abnormal positioning of the duodenum and superior mesenteric vessels over the transverse colon. Furthermore, the patient suffered of a concomitant cancer of the ascending colon.

Superficial punctate keratitis and conjunctival erosions associated with congenital tufting enteropathy.

PURPOSE: To study the value of conjunctival biopsy in congenital tufting enteropathy diagnosis. DESIGN: Case-comparative study. METHODS: Between January 2000 and June 2007, all children seeking treatment with an early onset of intractable diarrhea were examined in the ophthalmology department of Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, France. Children underwent complete ophthalmologic examination with concurrent conjunctival and intestinal biopsies. Main outcome measures were age at diagnosis, associated disorders, parenteral nutrition, and ophthalmologic symptoms. Conjunctival biopsies support diagnosis in the presence of specific alteration. RESULTS: Twenty patients were included. The mean age of the population was 30.2 months. Congenital tufting enteropathy was diagnosed in 15 cases. In the congenital tufting enteropathy group, 10 children exhibited ophthalmic functional disorders since the first months of life, with superficial punctate keratitis and conjunctivitis and in addition alacrima and cataract in 1 case, respectively, whereas 5 children had asymptomatic conjunctival hyperemia at presentation. Conjunctival biopsies showed epithelial parakeratosis, hyperplasia, basal cells hyperplasia, and tufts. In some cases, the lamina propria contained inflammatory cells or fibrosis, and the density of goblet cells then was abnormal. In the comparison group of 5 children with early-onset intractable diarrhea but without congenital tufting enteropathy diagnosis, no tuft occurrence was observed. CONCLUSIONS: In cases of intractable diarrhea in infancy, even without ocular symptoms, a systematic ophthalmologic examination should be performed. It also should be associated with the pathologic examination of both the conjunctival and the intestine mucosae, which helps to diagnose congenital tufting enteropathy (adhesion molecules disease). Specific conjunctival findings allow affirmation of congenital tufting enteropathy before the genetic confirmation of an EpCAM gene mutation.