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Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defects in bile secretion and presentation with intrahepatic cholestasis in infancy or childhood. The most common types include PFIC 1 (deficiency of FIC1 protein, ATP8B1 gene mutation), PFIC 2 (bile salt export pump deficiency, ABCB11 gene mutation), and PFIC 3 (multidrug resistance protein-3 deficiency, ABCB4 gene mutation). Mutational analysis of subjects with normal gamma-glutamyl transferase cholestasis of unknown etiology has led to the identification of newer variants of PFIC, known as PFIC 4, 5, and MYO5B related (sometimes known as PFIC 6). PFIC 4 is caused by the loss of function of tight junction protein 2 (TJP2) and PFIC 5 is due to NR1H4 mutation causing Farnesoid X receptor deficiency. MYO5B gene mutation causes microvillous inclusion disease (MVID) and is also associated with isolated cholestasis. Children with TJP2 related cholestasis (PFIC-4) have a variable spectrum of presentation. Some have a self-limiting disease, while others have progressive liver disease with an increased risk of hepatocellular carcinoma. Hence, frequent surveillance for hepatocellular carcinoma is recommended from infancy. PFIC-5 patients usually have rapidly progressive liver disease with early onset coagulopathy, high alpha-fetoprotein and ultimately require a liver transplant. Subjects with MYO5 B-related disease can present with isolated cholestasis or cholestasis with intractable diarrhea (MVID). These children are at risk of worsening cholestasis post intestinal transplant (IT) for MVID, hence combined intestinal and liver transplant or IT with biliary diversion is preferred. Immunohistochemistry can differentiate most of the variants of PFIC but confirmation requires genetic analysis.

Congenital diarrheal disorders are heterogeneous conditions characterized by diarrhea with onset in the first years of life. They range from simple temporary conditions, such as cow's milk protein intolerance to irreversible complications, such as microvillous inclusion disease with significant morbidity and mortality. Advances in genomic medicine have improved our understanding of these disorders, leading to an ever-increasing list of identified causative genes. The diagnostic approach to these conditions consists of establishing the presence of diarrhea by detailed review of the history, followed by characterizing the composition of the diarrhea, the response to fasting, and with further specialized testing.

International audience; Objectives: Congenital diarrhea and enteropathies linked to epithelial structural abnormalities constitute 3 different rare diseases: the tufting enteropathies (TE; EPCAM and SPINT2 mutations), microvillous inclusion disease (MVID; MYO5B and STX3 mutations), and tricho-hepato-enteric syndrome (THE; TTC37 and SKIV2L mutations). Moreover, enteroendocrine deficiencies (ED; PCSK1 and NEUROG3 mutations) share common clinical characteristics with TE, THE, and MVID in that the treatment requires, in most cases, long-term parenteral nutrition. Although numerous cases have been reported in the literature, aggregated data on morbidity and mortality are missing owing to the rarity of the diseases.Methods: We performed a systematic review of all published cases and retrieved 86 articles describing 323 patients (164 boys and 135 girls).Results: The mortality rate was 20.28%, with a median age at death of 13.5 months (range 0–228 months); the mortality risk was 30.8/1000 person-year; in half of the cases, death was caused by infections. Parenteral nutrition was required in 95.4% of patients and weaning off from parenteral nutrition was achieved in 29.35% at a median age of 23 months (range 3.3–276 months). The patients with ED linked to PCSK1 were nearly all weaned at a median age of 14 months, but most of the patients became overweight. MVID patients with MYO5B mutations were most often born preterm. ED linked to NEUROG3 mutation and THE patients usually presented with intrauterine growth retardation.Conclusions: This review presents data from 323 patients with congenital diarrhea linked to EPCAM TE, SPINT2 TE, TTC37 THE, SKIV2L THE, MYO5B MVID, STX3 MVID, NEUROG3 ED, and PCSK1 ED mutations.

BACKGROUND & AIM: Myosin VB (MYO5B) is an essential trafficking protein for membrane recycling in gastrointestinal epithelial cells. The inactivating mutations of MYO5B cause the congenital diarrheal disease, microvillus inclusion disease (MVID). MYO5B deficiency in mice causes mislocalization of SGLT1 and NHE3, but retained apical function of CFTR, resulting in malabsorption and secretory diarrhea. Activation of lysophosphatidic acid (LPA) receptors can improve diarrhea, but the effect of LPA on MVID symptoms is unclear. We investigated whether LPA administration can reduce the epithelial deficits in MYO5B-knockout mice. METHODS: Studies were conducted with tamoxifen-induced, intestine-specific knockout of MYO5B (VilCre(ERT2);Myo5b(flox/flox)) and littermate controls. Mice were given LPA, an LPAR2 agonist (GRI977143), or vehicle for 4 days after a single injection of tamoxifen. Apical SGLT1 and CFTR activities were measured in Üssing chambers. Intestinal tissues were collected, and localization of membrane transporters was evaluated by immunofluorescence analysis in tissue sections and enteroids. RNA sequencing and enrichment analysis were performed with isolated jejunal epithelial cells. RESULTS: Daily administration of LPA reduced villus blunting, frequency of multivesicular bodies and levels of cathepsins in intestinal tissues of MYO5B-knockout mice compared to vehicle administration. LPA partially restored the brush border height and the localization of SGLT1 and NHE3 in small intestine of MYO5B-knockout mice and enteroids. The SGLT1-dependent short-circuit current was increased and abnormal CFTR activities were decreased in jejunum from MYO5B-knockout mice given LPA compared with vehicle. CONCLUSIONS: LPA may regulate a MYO5B-independent trafficking mechanism and brush border maturation, and therefore be developed for treatment of MVID.

Microvillous inclusion disease (MVID), also known as congenital microvillus atrophy remains an important differential diagnosis of intractable secretory diarrhea in neonatal period. The condition is inherited as an autosomal recessive disorder with no sex predilection and more commonly reported in those tribes with consanguineous marriages. The pathognomonic electron microscopic findings includes villous atrophy with the formation of intracellular microvillous inclusions. Definite treatment includes either isolated small bowel or combined small bowel and liver transplantation. Herein, we are describing a case of intractable diarrhea in a preterm neonate with MVID phenotype presented on second day of life with intractable diarrhea. The diagnosis was established by classical electron microscopic findings in the intestinal biopsy sample.

Intestinal transplantation is a complex procedure both in terms of anesthesia and surgery. In particular, pediatric anesthesia management during intestinal transplant surgery can become even more complicated. It has been stated that propofol, remifentanil, and sevoflurane reduce patient mortality by reducing the incidence of intestinal ischemia-reperfusion injury. Although studies of these agents continue to be conducted in vivo or in vitro, these anesthetics are currently used for specific procedures that have a high risk of incurring ischemia-reperfusion injury. Herein, we present the case of a male child, aged 20 months, who was dependent on total parenteral nutrition and was found to have intestinal failure associated with liver disease type 1. Hematologic tests showed findings of anemia and metabolic acidosis. Propofol was administered for induction of anesthesia. Anesthesia maintenance was achieved using sevoflurane with remifentanil infusion. We ensured safe and adequate vascular access in the patient and performed hematologic and biochemical tests with detailed system controls. Before the procedure, we prepared a leukocyte-poor erythrocyte suspension, leukocyte-poor random or apheresis platelets, and ABO- and Rh-compatible fresh frozen plasma. We monitored for signs of acidosis, hypotension, coagulation disorders, and hyperkalemia during the reperfusion period. We maintained patient normothermia. In this case report on the anesthetic management of a pediatric patient aged 20 months who received a small bowel transplant due to microvillous inclusion disease, we found that the selection of anesthetic agents may affect the prognosis of future surgical procedures.

Congenital diarrhea and enteropathies (CODEs) are monogenic disorders causing early onset of intractable diarrhea. Their diagnosis and management are challenging. With the availability of commercial next generation genetic testing, we are now better able to classify and manage these disorders. The authors present their experience with 4 cases. Two patients had congenital tufting enteropathy (CTE) and 1 case each of microvillous inclusion disease (MVID) and trichohepatoenteric syndrome (THES). Age at onset varied from 3 to 38 d of life. Light microscopy and electron microscopy of duodenal and rectal endoscopic biopsies were consistent with the diagnosis. Genetic evaluation was possible in 3 cases indicating causative mutations. Two children (CTE and MVID) were alive at last follow-up. The authors suggest a stepwise approach to the diagnosis and management of these disorders in the Indian context.

AIHA is rare in the general population and associated with a mortality of 8%. In contrast, AIHA occurs in up to 12.2% of cases after intestinal transplantation and is associated with mortality up to 50%. Treatment entails a "step-up" approach including corticosteroids, IvIg, plasmapheresis, and rituximab. However, AIHA after transplantation often is refractory to this strategy, contributing to a poor outcome. We describe a child with microvillous inclusion disease who developed AIHA 1 year after multivisceral transplantation that was refractory to standard therapy and was subsequently treated with bortezomib.We observed remission of AIHA within 1 week after the start of bortezomib. Bortezomib was associated with transient diarrhea, leucopenia, and elevated liver enzymes. Three years later, he remains in remission without important complications. Published data on bortezomib for autoimmune cytopenias outside SOT are discussed. This is the first report to support bortezomib as an important therapeutic alternative for AIHA after SOT. The occurrence and treatment of AIHA after SOT, and specifically intestinal transplantation, should be the subject of future registry studies to collect additional experience and explore the optimal therapeutic approach. ispartof: PEDIATRIC TRANSPLANTATION vol:24 issue:4 ispartof: location:Denmark status: published

OBJECTIVES Mutations in Myosin 5B (MYO5B) are known to be associated with microvillous inclusion disease (MVID) a genetic cause of neonatal intractable diarrhoea. More recently, they have been reported in children with cholestasis but without typical gastrointestinal symptoms of MVID. We describe our series of children with cholestasis and mutations in MYO5B. METHODS Clinical, laboratory, and histological data were collected from patients with cholestasis and pathogenic mutations in MYO5B, found by next generation sequencing (NGS) but with minimal gastrointestinal disease. RESULTS Six patients (3 boys) were identified. Median age at presentation was 19 months (range, 3-92). Presenting features were jaundice, pale stools, pruritus, and failure to thrive. Patients 5 and 6 had intractable diarrhoea until the age of 3 and 7 years, respectively, but currently are on full enteral diet with no intestinal symptoms. Median values for serum total bilirubin were 55 μmol/L (2-500), alanine aminotransferase 73I IU/L (32-114), γ-glutamyltransferase 7 IU/L (7-10), and serum bile acids 134 μmol/L (18-274). Three patients underwent 1 or more types of biliary diversion for symptom control. Median follow-up was 5 years (2-22). At most recent follow-up, they all reported pruritus while on antipruritics. Patient 1 had a liver transplant. CONCLUSIONS We identified 6 patients, with mutations in MYO5B, early-onset cholestasis and pruritus, with variable response to biliary diversion without typical MVID.

Key Clinical Message Microvillous inclusion disease (MVID) typically appears with severe chronic diarrhea in the few days after birth and rapidly causes dehydration and metabolic acidosis. In this context, presenting two novel cases, we underline the crucial importance of mutation analysis for the diagnosis of this disease that may be easily misdiagnosed.

Microvillous inclusion disease (MVID), also known as congenital microvillus atrophy, was first described by Davidson et al. in 1978. Till date, only a handful of cases with MVID have been described in English literature. It is an autosomal recessive disorder with no sex predisposition and more commonly noted in countries with prevalent consanguineous marriages. These patients usually present with intractable secretory diarrhea in early days of life. The pathognomonic findings of MVID are villous atrophy along with the formation of intracellular microvillous inclusions on electron microscopy. Till date, no curative therapy exists, and prognosis mainly depends upon parenteral nutrition. Small bowel transplantation is one of the treatment options. Clinician and pathologist should consider the possibility of MVID in the differential diagnosis of chronic intractable diarrhea in an infant. Herein, authors are describing a case of intractable diarrhea with MVID phenotype diagnosed in a 3-mo-old male child who presented with intractable diarrhea in an outside hospital, and the diagnostic workup was performed by the authors on endoscopic biopsy sample.

Microvillus inclusion disease (MVID, MIM♯ 251850), also known as congenital microvil-lus atrophy, was first described by Davidson et al. in 1978. It is a rare au-tosomal recessive disease that presents with an intractable life-threatening watery diarrhea either within the first days of life (early-onset form) or at several months of life (late-onset form) . The hallmarks of MVID are a lack of microvilli on the surface of villous enterocytes, occurrence of microvillous inclusions and the cytoplasmic accumulation of periodic acid-schiff-positive vesicles. In 2008, Muller et al showed that mutations in MYO5B (MIM ♯ 606540), en-coding the unconventional type Vb myosin motor protein, were associated with MVID in an ex-tended Turkish kindred. Since then, more mutations were described in different populations . In this report we describe a novel mutation in two unrelated Syrian patients with MVID.

Background: Microvillous inclusion disease (MVID) is one of the most severe congenital diarrhea disorders, caused by a genetic defect in enterocyte differentiation and polarization. Case report: We describe a neonate who presented with severe weight loss, hypernatremic dehydration and metabolic acidosis due to intractable diarrhea due to MVID, confirmed by electron microscopy Conclusion: MVID can present with severe weight loss, hypernatremic dehydration and metabolic acidosis that is life threatening. The diagnosis is made by typical findings on light microscopy and electron microscope of small bowel biopsies. The only therapeutic options at this time are total parenteral nutrition and bowel rest and intestinal transplantation.

Indexación: Scopus; Scielo. Introducción: Las diarreas congénitas son patologías graves de baja frecuencia y alta mortalidad. Se manifiestan durante los primeros días o meses de vida con severa diarrea, generando insuficiencia intestinal y dependencia de nutrición parenteral. Se debe sospechar ante un recién nacido o lactante con pérdidas masivas hidroelectrolíticas, y se diagnostican utilizando parámetros clínicos, endoscópicos, histológicos y eventualmente genéticos. El tratamiento es de soporte, con reposición hidroelectrolítica intensa y nutricional. Objetivo: Presentar un caso de diarrea congénita, identificada como Enfermedad por Inclusión Microvellositaria, de presentación neonatal. Caso clínico: Paciente varón edad actual 3 años, hijo de padres consanguíneos, quien debutó a los 10 días de vida con diarrea secretora severa, requiriendo ingreso a unidad de paciente crítico y nutrición parenteral permanente. Inicialmente además con síndrome de Fanconi, que luego se recupera. Se confirmó la sospecha de Enfermedad de Inclusión Microvellositaria utilizando microscopia óptica, electrónica e inmunohistoquímica. Se obtuvo una favorable evolución utilizando nutrición parenteral total (NPT) a domicilio. Conclusiones: Se presenta el primer caso conocido en Chile de un paciente con diarrea congénita por inclusión microvellositaria manejado y su evolución. https://scielo.conicyt.cl/scielo.php?script=sci_arttext&pid=S0370-41062017000500015&lng=en&nrm=iso&tlng=es&ORIGINALLANG=es

Emergency splenectomy is rarely performed since a widespread consensus exists towards conservative management of splenic injury. However, in selected conditions, mainly hematological, there is a role for emergency or urgent splenectomy. This study aims to retrospectively review these cases and discuss outcome in relation to the pre-existing splenic pathologies. Between 2000 and 2015, 12 patients, five girls, and seven boys, with a median age of six years (3 months-13.11 years), underwent emergency or urgent splenectomy for non-traumatic conditions. All patients had major associated disorders; mainly hematological (11 cases) including hemolytic anemia with pancytopenia (1), sickle cell anemia (1), AML (1), ALL (2), CML (1), T cell lymphoma (1), Burkitt lymphoma (1), and ITP (3). One patient had a microvillous inclusion disease. Indications for splenectomy included diffuse resistant splenic abscesses (4), intracranial hemorrhage (4) or hypersplenism (3) with refractory thrombocytopenia, and spontaneous splenic rapture (1). Nine patients improved following surgery but three died, owing to massive intracranial hemorrhage (1) and severe respiratory failure (2) despite aggressive management.Conclusions: Rarely, an emergency splenectomy is required in complex settings, mostly refractory hematological conditions, in a deteriorating patient when all other measurements have failed. A multidisciplinary team approach is mandatory in the treatment of these complex cases. What is known • Conservative treatment is advised for splenic injury. • Many hematological disorders are responsible of splenic pathology. What is new • Emergency splenectomy in children for reasons other than trauma is a treatment of last resort that should be performed in a multidisciplinary context. • The outcome of emergency splenectomy in children for reasons other than trauma depends on the underlying medical condition.

Congenital diarrheal disorders (CDDs) are early-onset enteropathies generally inherited as autosomal recessive traits. Most patients with CDDs require rapid diagnosis as they need immediate and specific therapy to avoid a poor prognosis, but their clinical picture is often overlapping with a myriad of nongenetic diarrheal diseases. We developed a next-generation sequencing (NGS) panel for the analysis of 92 CDD-related genes, by which we analyzed patients suspect for CDD, among which were (i) three patients with sucrose-isomaltase deficiency, (ii) four patients with microvillous inclusion disease, (iii) five patients with congenital tufting enteropathy, (iv) eight patients with glucose-galactose malabsorption, (v) five patients with congenital chloride diarrhea. In all cases, we identified the mutations in the disease-gene, among which were several novel mutations for which we defined pathogenicity using a combination of bioinformatic tools. Although CDDs are rare, all together, they have an incidence of about 1%. Considering that the clinical picture of these disorders is often confusing, a CDD-related multigene NGS panel contributes to unequivocal and rapid diagnosis, which also reduces the need for invasive procedures.

All over the causes of intractable diarrhea of infancy, microvillous inclusion disease is a rare congenital defect of intestinal brush border of unknown aetiology. An autosomal recessive inheritance is suggested by cases occurring in siblings and high incidence of consanguinity. The prognosis of the disease is extremely poor, as life can be sustained only by total parenteral nutrition. The authors report a preterm male newborn of 35 weeks gestation presenting severe hypernatremic dehydration on day 4 after birth caused by a secretory profuse diarrhea and discuss the tools allowing the light microscopic and genetic diagnosis. The final diagnosis of microvillus intestinal disease (MVID) was made on the third month after extensive investigations using electron microscopic examination of intestinal biopsy and genetic confirmation, finding a mutation at the homozygous status of MYO5B gene. The infant died on the fourth month in spite of optimal electrolytic support and parenteral prolonged nutrition. Although MVID is extremely rare, it remains a possible cause of intractable secretory diarrhea leading to severe hypernatremic dehydration and metabolic acidosis in neonates.

Resumen: Introducción: La enfermedad por inclusiones microvellositarias es una entidad rara, de herencia autosómica recesiva y caracterizada por una diarrea grave de carácter secretor que produce un fracaso intestinal permanente dependiente de nutrición parenteral. Habitualmente se inicia en el período neonatal y el único tratamiento posible en el momento actual es el trasplante intestinal. Pacientes y métodos: Se revisa, de forma retrospectiva, a 6 pacientes (3 varones y 3 mujeres), diagnosticados entre 1998 y 2013 de enfermedad por inclusiones microvellositarias. Resultados: Todos comenzaron en el primer mes de vida, con una mediana de edad de tres días (rango: 3-30 días) y presentaron diarrea secretora dependiente de nutrición parenteral, con un volumen fecal en ayunas de 150-200 ml/kg/día. La microscopia óptica de muestras biópsicas duodenales mostró grados variables de atrofia vellositaria sin hiperplasia críptica, con acumulación de material PAS positivo en el citoplasma de los enterocitos del borde en cepillo y la inmunotinción anti-CD10 fue indicativa de inclusiones intracitoplasmáticas. La confirmación diagnóstica se realizó con microscopia electrónica. En 2 de ellos se realizó estudio genético que demostró mutaciones en el gen MYO5B. Evolutivamente, 3 fallecieron y 3 se encuentran vivos; 2 de ellos portadores de trasplante intestinal y el tercero en espera de trasplante multivisceral. Abstract: Introduction: Microvillous inclusion disease is a rare autosomal recessive condition, characterized by severe secretory diarrhea that produces a permanent intestinal failure and dependency on parenteral nutrition. It usually begins in the neonatal period, and the only treatment at present is intestinal transplantation. Patients and methods: A retrospective review was conducted on 6 patients (three males and three females) diagnosed with microvillous inclusion disease between 1998 and 2013. Results: All debuted in the first month of life, with a median age of three days (range, 3-30 days), and had secretory diarrhea dependent on parenteral nutrition, with fasting fecal volume of 150-200 ml/kg/day. Light microscopy of duodenal biopsy samples showed varying degrees of villous atrophy without cryptic hyperplasia, accumulation of PAS positive material in the cytoplasm of enterocytes brush border, and anti-CD10 immunostaining was suggestive of intracytoplasmic inclusions. Diagnostic confirmation was performed with electron microscopy. Two of them had a genetic study, and showed mutations in MYO5B gene. Three died and three are alive; two of them with an intestinal transplantation and the third waiting for a multivisceral transplantation.

Background & Aims Crohn disease (CD) presents as chronic and often progressive intestinal inflammation, but the contributing pathogenic mechanisms are unclear. We aimed to identify alterations in intestinal cells that could contribute to the chronic and progressive course of CD. Methods We took an unbiased system-wide approach by performing sequence analysis of RNA extracted from formalin-fixed paraffin-embedded ileal tissue sections from patients with CD (n = 36) and without CD (controls; n = 32). We selected relatively uninflamed samples, based on histology, before gene expression profiling; validation studies were performed using adjacent serial tissue sections. A separate set of samples (3 control and 4 CD samples) was analyzed by transmission electron microscopy. We developed methods to visualize an overlapping modular network of genes dysregulated in the CD samples. We validated our findings using biopsy samples (110 CD samples for gene expression analysis and 54 for histologic analysis) from the UNITI-2 phase 3 trial of ustekinumab for patients with CD and healthy individuals (26 samples used in gene expression analysis). Results We identified gene clusters that were altered in nearly all CD samples. One cluster encoded genes associated with the enterocyte brush border, leading us to investigate microvilli. In ileal tissues from patients with CD, the microvilli were of decreased length and had ultrastructural defects compared with tissues from controls. Microvilli length correlated with expression of genes that regulate microvilli structure and function. Network analysis linked the microvilli cluster to several other down-regulated clusters associated with altered intracellular trafficking and cellular metabolism. Enrichment of a core microvilli gene set also was lower in the UNITI-2 trial CD samples compared with controls; expression of microvilli genes was correlated with microvilli length and endoscopy score and was associated with response to treatment. Conclusions In a transcriptome analysis of formalin-fixed and paraffin-embedded ileal tissues from patients with CD and controls, we associated transcriptional alterations with histologic alterations, such as differences in microvilli length. Decreased microvilli length and decreased expression of the microvilli gene set might contribute to epithelial malfunction and the chronic and progressive disease course in patients with CD.

Las diarreas congénitas son patologías graves de baja frecuencia y alta mortalidad. Se manifiestan durante los primeros días o meses de vida con severa diarrea, generando insuficiencia intestinal y dependencia de nutrición parenteral. Se debe sospechar ante un recién nacido o lactante con pérdidas masivas hidroelectrolíticas, y se diagnostican utilizando parámetros clínicos, endoscópicos, histológicos y eventualmente genéticos. El tratamiento es de soporte, con reposición hidroelectrolítica intensa y nutricional. Objetivo: Presentar un caso de diarrea congénita, identificada como Enfermedad por Inclusión Microvellositaria, de presentación neonatal. Caso clínico: Paciente varón edad actual 3 años, hijo de padres consanguíneos, quien debutó a los 10 días de vida con diarrea secretora severa, requiriendo ingreso a unidad de paciente crítico y nutrición parenteral permanente. Inicialmente además con síndrome de Fanconi, que luego se recupera. Se confirmó la sospecha de Enfermedad de Inclusión Microvellositaria utilizando microscopia óptica, electrónica e inmunohistoquímica. Se obtuvo una favorable evolución utilizando nutrición parenteral total (NPT) a domicilio. Conclusiones: Se presenta el primer caso conocido en Chile de un paciente con diarrea congénita por inclusión microvellositaria manejado y su evolución. Congenital diarrheas correspond to a severe and low frequency digestive disease, with a high mortality. They start a few days or months after birth, leading to intestinal insufficiency and dependence on parenteral nutrition. It must be highly suspected in newborns or infants with diarrhea and severe electrolyte disorders. The diagnosis is based on clinical, endoscopic, histologic and eventually genetic findings. Treatment is supportive with intensive correction of electrolyte imbalances as well as parenteral nutrition. Objective: To present a case report of congenital diarrhea identified as microvillous inclusion disease presenting in the neonatal period. Case report: Male patient currently 3 years of age, son of consanguineous parents. At 10 days of age presents a severe secretory diarrhea, requiring treatment in a critical care unit and parenteral nutrition. Initially he also presented with Fanconi syndrome, which improved afterwards. The suspicion of congenital microvillous inclusion was confirmed later by optic and electronic microscopy, and inmunohistochemistry. A succesful evolution was later achieved maintaining home parenteral nutrition after discharge. Conclusion: We present the first known case in Chile of congenital diarrhea due to microvillous inclusión disease and his evolution.

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.

In the clinical context of pediatric diarrheal illness, the interpretation of endoscopic mucosal biopsies varies significantly from that in adults. This review outlines these differences by first describing a host of diarrheal illnesses that are nearly exclusive to the pediatric age group. The final portion of this article describes salient pathologic differences between adult and pediatric idiopathic inflammatory bowel disease. The goal of this review is to provide a brief description of each disease process and focus on practical aspects of diagnosis that are applicable for pathologists working in general practice settings.

The patient, who was born full term to non-consanguineous parents following a pregnancy complicated only by polyhydramnios, was admitted with severe dehydration, weight loss and diarrhea on the sixth day of life. His electrolytes were significant for sodium 149 mmol/L, potassium 5 mmol/L, chloride 130 mmol/L, and bicarbonate 4.5 mmol/L. For the next 2 months, he suffered recurrent episodes of sepsis and suspected necrotizing enterocolitis. His stool output was secretory and large volume, ranging from 100 to 200 ml/kg/ day, and did not change with cessation of enteral feeds. Workup included stool cultures and serum titers negative for enteric bacteria, viral and parasitic infections, normal inflammatory markers, normal immunoglobulins and complement, normal gastrin and urine catecholamines. An endoscopic biopsy at 3 months of life showed total atrophy of the intestinal villi. Periodic acid-Schiff staining revealed targetoid structures in the cytoplasm of absorptive epithelial cells. Electron microscopy revealed spherical inclusions lined by microvilli within enterocytes. Surface microvilli were markedly decreased in number (Fig. 1). These EM findings were diagnostic of microvillous inclusion disease. He continued to receive total parenteral nutrition (TPN) as his sole nutrition and fluid source. By age 3 years, his TPN was adjusted to a regimen of 3–4 l of 15 % dextrose containing fluid infused over 12 h at night with a peak rate of 12–15 mg/kg/min of glucose. He fasted for 12 h during the day. His stool output continued to be between 3 and 4 l per day (100–200 ml/kg/day). After age 2 years, monthly laboratory monitoring showed electrolytes, serum aminotransferases and total bilirubin levels consistently less than two times the upper limit of normal. Serum triglyceride and cholesterol levels were always within normal limits. He was seen by endocrinology at 10 years of age due to decreased height velocity, not improved by an increase in the protein and caloric density of his TPN. He was diagnosed with mild compensated hypothyroidism with a normal free T4 and TSH 11 mcu/ml (normal 0.49–4.67 mcu/ ml) and was placed on intravenous levothyroxine. Given waxing and waning abdominal pain, an abdominal ultrasound at age 12 years revealed a diffuse increase in liver echogenicity without any focal lesions. The gallbladder appeared normal, without cholelithiasis. No interventions were done at that time. Labs were consistent with his normal baseline values with total bilirubin 0.8 mg/dl, AST 29 mg/dl, ALT 26 mg/dl, alkaline phosphatase 187 units/l, gamma-glutamyl transferase 33 units/l, albumin 3.3 g/dl and triglycerides 36 mg/dl. At age 14 years, he presented with a recurrence of right upper quadrant abdominal pain associated with vomiting and scleral icterus. Laboratory evaluation revealed total bilirubin 2.4 mg/dl, direct bilirubin 1.4 mg/dl, AST 19 mg/ dl, ALT 28 mg/dl, alkaline phosphatase 238 units/l, and gamma-glutamyl transferase 94 units/L. An abdominal ultrasound demonstrated multiple foci of shadowing echogenic material within the gallbladder, consistent with cholelithiasis. In addition, three round discrete lesions J. C. Burgis C. A. Pratt J. A. Kerner (&) Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Lucile Packard Children’s Hospital at Stanford, Stanford University Medical Center, 750 Welch Road Suite 116, Palo Alto, CA 94304-0126, USA e-mail: jkerner@stanfordmed.org

Growing evidence from several clinical and experimental studies indicates that arginine and nitric oxide are critical to the normal physiology of the gastrointestinal tract and maintain the mucosal integrity of the intestine in various intestinal disorders such as inflammatory bowel disease, rheumatoid arthritis, and hepatitis. In this report, we discuss the use of a dietary arginine supplementation in the treatment of different gastrointestinal disorders including intestinal ischemia-reperfusion, short bowel syndrome, chemotherapy-induced mucositis, microvillous inclusion disease, etc. The mechanisms of action of arginine and nitric oxide on intestinal cell turnover (proliferation and apoptosis) as well as the effects of this agent on intestinal regrowth after bowel resection and intestinal recovery following intestinal ischemia or chemotherapy-induced damage in rodent models are discussed. Such knowledge may allow us to exploit arginine that acts as gut-trophic agent for the bowel mucosa and suggest new therapeutic strategies to maintain gut integrity after massive bowel resection or intestinal injury, eliminating the dependence on total parenteral nutrition.

Some patients with microvillus inclusion disease due to myosin 5B (MYO5B) mutations may develop cholestasis characterized by a progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity. So far MYO5B deficiency has not been reported in patients with such a cholestasis phenotype in the absence of intestinal disease. Using a new-generation sequencing approach, we identified MYO5B mutations in five patients with progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity without intestinal disease. Conclusion: These data show that MYO5B deficiency may lead to isolated cholestasis and that MYO5B should be considered as an additional progressive familial intrahepatic cholestasis gene. (Hepatology 2017;65:164-173).

Microvillous Inclusion Disease (MVID) is one of the congenital diarrheal disorders (CDD) caused by genetic defects in enterocyte differentiation and polarization. Its prevalence is higher in countries with a high degree of consanguinity. It causes severe, intractable secretory diarrhea leading to permanent and definitive intestinal failure with resultant dependency on parenteral nutrition (PN). Small bowel transplantation is the only curative treatment. The gold standard for diagnosis are the typical morphological abnormalities in small bowel biopsies on light and electron microscopy (EM). In recent times, histochemistry and immunohistochemistry have shown sufficient diagnostic accuracy replacing EM if the facility is unavailable or EM findings are inconclusive. We describe a neonate with CDD who was diagnosed to have MVID on the duodenal biopsy by morphohistochemical and immunophenotypic methods used for the first time in Oman. By utilizing such easy and accessible diagnostic methods, a rare genetic disorder could be diagnosed with certainty and the family could be counseled accordingly. With a high degree of consanguinity in the region, the prevalence of MVID in Oman needs to be identified once these patients are diagnosed by utilizing appropriate investigations. Care of such patients necessitates improving current parenteral nutrition services and addressing the future need for small bowel transplantation (SBTx), in Oman.

Microvillous inclusion disease (MVID) is a rare congenital disease producing intractable secretory diarrhea in early infancy. It is characterized by diffuse intestinal villous atrophy with no inflammatory reaction. Ultrastructural identification of apical microvillous inclusions in the surface enterocytes is diagnostic. However, there is difficulty in the diagnosis of MVID due to the existence of variants (e.g., microvillous dystrophy), possible disease resolution, and tissue orientation for electron microscopy (EM). The authors analyzed materials from 4 patients with MVID from a single institution. The morphologic features, distribution of lesions, biomarkers, and complementary ultrastructural characteristics were studied.Materials of MVID cases were collected from 6 different hospitals in the United Kingdom between 1990 and 2008. Epidemiological data, including age range, median, mode, sex ratios, and follow-up, were retrieved. All intestinal biopsy specimens were analyzed histologically, histochemically (for PAS, n = 17), immunohistochemically (for CD10, n = 2 and polyclonal CEA, n = 4), and ultrastructurally (n = 9).Ultrastructurally, apical microvillous inclusions in surface enterocytes in duodenal biopsies were identified in all cases, while 1 case had variant morphology (microvillous dystrophy and very occasionally atypical microvillous inclusions). Tissue orientation for EM was supportive for identification of inclusions in apical enterocytes. Morphologically, a bubbly vacuolated appearance of the apical cytoplasm with extensive or patchy absence of the brush border with occasional cytoplasm inclusions was observed in the enterocytes. Some of these changes vaguely resembled gastric mucin cell metaplasia. Architecturally, villous blunting with either crypt hypoplasia or hyperplasia and absence of inflammation were common findings. The epithelial changes were also found in colon biopsies. PAS, CD10, and p-CEA showed a bright apical cytoplasmic blush/staining, which correlated ultrastructurally with apical granules with inclusions of variable electron density in all cases. These stains also highlighted the targetoid inclusions.Besides electron microscopy identification of inclusions, the light microscopic morphological features together with the biomarker studies highlighting the apical cytoplasmic blush are quite unique and diagnostic of MVID. Furthermore, it is the opinion of the authors that a diagnosis of MVID can be made without electron microscopy.

Autosomal recessive microvillus inclusion disease (MVID) is characterized by an intractable diarrhea starting within the first few weeks of life. The hallmarks of MVID are a lack of microvilli on the surface of villous enterocytes, occurrence of intracellular vacuoles lined by microvilli (microvillus inclusions), and the cytoplasmic accumulation of periodic acid-Schiff (PAS)-positive vesicles in enterocytes. Recently, we identified mutations in MYO5B, encoding the unconventional type Vb myosin motor protein, in a first cohort of nine MVID patients. In this study, we identified 15 novel nonsense and missense mutations in MYO5B in 11 unrelated MVID patients. Fluorescence microscopy, Western blotting, and electron microscopy were applied to analyze the effects of MYO5B siRNA knock-down in polarized, brush border possessing CaCo-2 cells. Loss of surface microvilli, increased formation of microvillus inclusions, and subapical enrichment of PAS-positive endomembrane compartments were induced in polarized, filter-grown CaCo-2 cells, following MYO5B knock-down. Our data indicate that MYO5B mutations are a major cause of microvillus inclusion disease and that MYO5B knock-down recapitulates most of the cellular phenotype in vitro, thus independently showing loss of MYO5B function as the cause of microvillus inclusion disease.