Wolfram Syndrome-2, a Cause of Severe Gastrointestinal Bleeding: A Case Series and a Literature Review.

Background: There are very few reports of Wolfram syndrome-2 (WFS2) in the literature, and understanding of involvement of the gastrointestinal (GI) tract in the syndrome is limited. Objectives: This study aims to describe the clinical presentations of a large number of WFS2 patients with specific focus on their GI manifestations. Methods: This is a retrospective case series study. Patients who were homozygous for the CISD2 gene mutation were identified through the genetic department of Al-Makassed hospital. Their medical records were reviewed, and biometric data have been obtained. The data were collected and arranged on a data sheet, and descriptive analysis was done using SPSS. Results: Thirteen patients from 9 families were identified; diabetes mellitus was present in 6 of them, optic atrophy in 5, diabetes insipidus (DI) in 5, and deafness in 2. All of the patients had GI manifestations with abnormal findings on upper endoscopy. Dysmorphic facial features and abnormal findings on brain MRI were present in 3 of our patients. The GI manifestations including GI bleeding and severe ulcerations were the first to appear in 9 of them, while anemia in the remaining 4. Conclusion: This is the largest study to date describing patients with WFS2. This study's evidence shows the prominent presence of GI involvement, and the severe findings on endoscopy, including duodenal, gastric, and esophageal ulcerations and strictures. Unlike in the Jordanian report, some of the patients in our report also have DI.

RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features.

Purpose: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of necroptosis and inflammatory responses. We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from RIPK1 mutations. Methods: Whole exome and Sanger sequencing was performed in two IBD patients. Mass cytometry time of flight (CyTOF) was conducted for in-depth immunophenotyping on one of the patient's peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn's disease. Results: The patients presented with severe colitis and perianal fistulas in the first months of life, without severe/atypical infections. Genetic studies identified pathogenic genetic variants in RIPK1 (Patient 1, A c.1934C>T missense mutation in Exon 11; Patient 2, c.580G>A missense mutation residing in Exon 4). Protein modeling demonstrated that the mutation in Patient 1 displaces a water molecule, potentially disrupting the local environment, and the mutation in Patient 2 may lead to disruption of the packing and conformation of the kinase domain. Immunofluorescence RIPK1 staining in rectal biopsies demonstrated no expression for Patient 1 and minimal expression for Patient 2, compared to controls and patients with active Crohn's disease. Using CyTOF unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8+ T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient's immune cells exhibited decreased IL-6 production in response to lipopolysaccharide (LPS) across multiple cell types including T cells, B cells and innate immune cells. Conclusions: Mutations in RIPK1 should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1's role in inflammasome activation, but also in epithelial cells, it is unclear whether IL1 blockade or allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency.

Homozygous variant in MADD, encoding a Rab guanine nucleotide exchange factor, results in pleiotropic effects and a multisystemic disorder.

Rab proteins coordinate inter-organellar vesicle-mediated transport, facilitating intracellular communication, protein recycling, and signaling processes. Dysfunction of Rab proteins or their direct interactors leads to a wide range of diseases with diverse manifestations. We describe seven individuals from four consanguineous Arab Muslim families with an infantile-lethal syndrome, including failure to thrive (FTT), chronic diarrhea, neonatal respiratory distress, variable pituitary dysfunction, and distal arthrogryposis. Exome sequencing analysis in the independent families, followed by an internal gene-matching process using a local exome database, identified a homozygous splice-site variant in MADD (c.2816 + 1 G > A) on a common haplotype. The variant segregated with the disease in all available family members. Determination of cDNA sequence verified single exon skipping, resulting in an out-of-frame deletion. MADD encodes a Rab guanine nucleotide exchange factor (GEF), which activates RAB3 and RAB27A/27B and is thus a crucial regulator of neuromuscular junctions and endocrine secretory granule release. Moreover, MADD protects cells from caspase-mediated TNF-α-induced apoptosis. The combined roles of MADD and its downstream effectors correlate with the phenotypic spectrum of disease, and call for additional studies to confirm the pathogenic mechanism and to investigate possible therapeutic avenues through modulation of TNF-α signaling.

Palestinian doctors' views on patient-centered care in hospitals.

BACKGROUND: Understanding the perceived importance of Patient-Centered Care (PCC) among Palestinian doctors and how the provider and other clinical characteristics may impact their views on PCC is essential to determine the extent to which PCC can be implemented. This study investigates the provision of PCC among hospital doctors in a developing and unstable country, namely, Palestine. METHODS: This descriptive, cross-sectional research employed self-report survey among 369 Palestinian doctors working in hospitals in 2016. Respondents completed the Provider-Patient Relationship Questionnaire (PPRQ) and were asked to rate the importance of 16 PCC subjects in a context-free manner. Then they scored the existence of eight contextual attributes in their workplace. RESULTS: Although 71.4% of the participants got training in communication, only 45% of the participants knew about PCC. 48.8% of doctors considered the "exchange of information" with patients most important PCC component. Clustering identified three groups of doctors: 32.4% of doctors reported good perceptions of PCC, 47.5% moderate; and 20.1% poor. Older, married, and specialist doctors and those familiar with PCC are more likely classified in the "good" cluster. Results revealed a significant difference between doctors' views based on their gender, experience, marital status, previous knowledge about PCC, and type of hospital in favor of males, experienced, married, familiar with PCC, and doctors in private hospital respectively. The level of job interest, nurses' cooperation, the tendency of patients to hide information, and doctor's friendly style were positively related with more perceived importance of PCC. CONCLUSION: We identified benchmark doctors who perceive the high relative importance of PCC. Our results highlighted knowledge gaps and training weaknesses among doctors in public and private hospitals in respect to their views on PCC. Decision makers may invest in the determined contextual predictors to enhance attitudes towards PCC. This work doesn't address patients' views on PCC.

Organic solute transporter-ß (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis.

Primary bile acid malabsorption is associated with congenital diarrhea, steatorrhea, and a block in the intestinal return of bile acids in the enterohepatic circulation. Mutations in the ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2) can cause primary bile acid malabsorption but do not appear to account for most familial cases. Another major transporter involved in the intestinal reclamation of bile acids is the heteromeric organic solute transporter alpha-beta (OSTα-OSTß; SLC51A-SLC51B), which exports bile acid across the basolateral membrane. Here we report the first patients with OSTß deficiency, clinically characterized by chronic diarrhea, severe fat soluble vitamin deficiency, and features of cholestatic liver disease including elevated serum gamma-glutamyltransferase activity. Whole exome sequencing revealed a homozygous single nucleotide deletion in codon 27 of SLC51B, resulting in a frameshift and premature termination at codon 50. Functional studies in transfected cells showed that the SLC51B mutation resulted in markedly reduced taurocholic acid uptake activity and reduced expression of the OSTα partner protein. CONCLUSION: The findings identify OSTß deficiency as a cause of congenital chronic diarrhea with features of cholestatic liver disease. These studies underscore OSTα-OSTß's key role in the enterohepatic circulation of bile acids in humans. (Hepatology 2017).

Fanconi-Bickel syndrome in two Palestinian children: marked phenotypic variability with identical mutation.

BACKGROUND: Fanconi-Bickel syndrome (FBS, OMIM 227810) is a rare autosomal recessive disease caused by a deficiency of glucose transporter 2 (GLUT2), a member of the facilitative glucose transporter family (Santer et al. J Inherit Metab Dis 21:191-194, 1998). The typical clinical picture is characterized by hepatorenal glycogen accumulation resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal renal tubular dysfunction, rickets and severe short stature. CASE PRESENTATION: We report 2 Palestinian patients from 2 families who were homozygous for the mutation p.R301X (C>T) in exon 7of GLUT2 gene. Patient 1 showed clinical and laboratory improvement with age characterized by normal growth and resolution of rickets. Patient 2 had severe phenotype characterized by progressive weight loss, persistent metabolic acidosis, marked polyuria and clinical and laboratory findings of rickets progressing to death at age 10 months. CONCLUSION: This report further expands the clinical spectrum of FBS even with identical mutations. Other yet unknown genetic, environmental or stochastic factors may be responsible for phenotypic variability.

Severe persistent unremitting dermatitis, chronic diarrhea and hypoalbuminemia in a child; Hartnup disease in setting of celiac disease.

BACKGROUND: Celiac disease (CD) is a complex autoimmune disorder that can lead to an inflammatory small intestinal villous atrophy and malabsorption. Hartnup disease is an autosomal recessive disorder caused by increased urinary excretion of neutral amino acids. Co-occurrence of Hartnup disease and CD is extremely rare with only a single case reported. CASE PRESENTATION: We report a 3-year girl with chronic diarrhea, Hypoalbuminemia and exfoliative erythema. She was diagnosed with celiac disease, which did not improve on gluten free diet. Hartnup disease was suspected and was confirmed by neutral aminoaciduria. Niacin was started and followed by dramatic improvement. CONCLUSION: Presence of Celiac and Hartnup disease in single individual is very rare. Complete nutritional assessment of refractory celiac patient can reveal underlying nutritional deficiency.

Calprotectin in cystic fibrosis.

BACKGROUND: There is increasing evidence that intestinal inflammation plays a major role in gastrointestinal symptoms in cystic fibrosis (CF). Fecal calprotectin is a marker that is elevated in several gastrointestinal inflammatory diseases, but little is known about its value in CF. We aimed to look for associations of elevated fecal calprotectin among CF patients and whether its level correlates with the clinical manifestations of CF. METHODS: A single stool specimen was collected from 62 patients with CF. Fecal calprotectin was measured using the commercially available ELISA kits (PhiCal™ test). Clinical data were collected from patients' records and CF registry. RESULTS: There were no significant differences between CF patients with normal and abnormal fecal calprotectin levels. However, patients who were not receiving inhaled antibiotics had higher fecal calprotectin levels than those who were. CONCLUSION: Elevated fecal calprotectin may not accurately predict intestinal inflammation in CF. However, the fact that it was elevated in both pancreatic sufficient and insufficient groups supports the concept of "cystic fibrosis enteropathy" regardless of the pancreatic status.

Subjective global nutritional assessment in critically ill children.

BACKGROUND: Underweight children admitted to the pediatric intensive care unit (PICU) have a higher risk of mortality than normal-weight children. The authors hypothesized that subjective global nutrition assessment (SGNA) could identify malnutrition in the PICU and predict nutrition-associated morbidities. METHODS: The authors prospectively evaluated the nutrition status of 150 children (aged 31 days to 5 years) admitted to the PICU with the use of SGNA and commonly used objective anthropometric and laboratory measurements. Each child was administered the SGNA by a dietitian while anthropometric measurements were performed by an independent assessor. To test interrater reproducibility, 76 children had SGNA performed by another dietitian. Occurrence of nutrition-associated complications was documented for 30 days after admission. RESULTS: SGNA ratings of well nourished, moderately malnourished, or severely malnourished demonstrated moderate to strong correlation with several standard anthropometric measurements (P < .05). The laboratory markers did not demonstrate any correlation with SGNA. Interrater agreement showed moderate reliability (κ = 0.671). Length of stay, pediatric logistic organ dysfunction, and Pediatric Risk of Mortality III were not significantly different across the groups and did not correlate with SGNA.

Endoscopic diagnosis of pediatric acute gastrointestinal graft-versus-host disease.

BACKGROUND AND OBJECTIVES: Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in the first 100 days following allogeneic hematopoietic progenitor stem cell transplant. The best diagnostic endoscopic strategy for gastrointestinal (GI) GVHD is a matter of debate. Our aim in the present study was to compare the relative contribution of the endoscopic appearance and biopsies from upper endoscopy and flexible sigmoidoscopy in children with suspected acute GVHD. METHODS: The present study was designed as single-center retrospective chart review cohort study. We reviewed the charts of all of the patients younger than 18 years with suspected acute GI GVHD who had endoscopic evaluation within the first 100 days after stem cell transplant between 1999 and 2009. RESULTS: A total of 48 patients were included. The most common symptoms prompting endoscopic evaluation were diarrhea (70%) and a combination of nausea and vomiting (67%). GVHD was diagnosed in at least 1 biopsy site in 40 of 48 patients (83%). Twenty-two of 40 (55%) patients with GVHD had simultaneous upper and lower endoscopic biopsies, 11 patients had only upper endoscopy, and 7 had only lower endoscopy. The most common endoscopic finding was normal mucosa. The sensitivity for diagnosing GVHD was 77% for both rectosigmoid and upper endoscopic biopsies. Thirty-three of 40 patients had upper endoscopy with biopsies; 28 (85%) had GVHD. The sensitivities and negative predictive value of gastric biopsies were 85% and 63%, whereas for duodenal biopsies they were 50% and 57%, respectively. CONCLUSIONS: Rectosigmoid and combined upper endoscopic biopsies are equally sensitive for the diagnosis of acute GI GVHD in children. Flexible sigmoidoscopy can be done unsedated in appropriate patients at the bedside without anesthesia; it can be performed first to identify GI GVHD.

Genetic prevalence and characteristics in children with recurrent pancreatitis.

AIMS: The causes of chronic (CP) and recurrent acute pancreatitis (RAP) in children include anatomic abnormalities and hereditary, metabolic, and autoimmune disorders, with a significant proportion of cases being labeled as idiopathic. Genetic pancreatitis (GP) is associated with mutations of cystic fibrosis transmembrane conductor regulator gene (CFTR), cationic trypsinogen (PRSS1) gene, and serine protease inhibitor Kazal type 1 (SPINK1). There literature is sparse regarding the clinical profile of GP in children. The aim of the present study was to estimate the prevalence and describe the clinical characteristics and outcome of genetic pancreatitis. METHODS: We reviewed the charts of children ages 18 years or younger with RAP or CP diagnosed from 2000 to 2009 at the Children's Hospital of Wisconsin, Milwaukee. Twenty-nine patients with RAP or CP were identified, of whom 23 (79%) were positive for mutations in ≥1 of the above-mentioned genes, and were included for review. RESULTS: The median age of symptom onset was 5 years (range 9 months-15 years) with diagnosis at 6.5 years (range 1-16 years). Twenty-one were white; 14 were girls. The most common presenting symptoms were abdominal pain and vomiting. Patients with RAP had 2 to 8 episodes of pancreatitis during 3.6-year average follow-up. Family history was positive in 5 of 29 of gene-tested patients. CFTR, SPINK1, or PRSS1 mutations were seen in 14 (48%), 8 (27%), and 7 (24%) patients, respectively. Two patients were homozygous for CFTR mutations, 6 heterozygote and 4 patients had 5 T variants. Two other patients had double heterozygous mutations in F508 del/2789 + 5G > A and F508 del/5T variant. Six patients with CP had a combination of CFTR and SPINK1 or PRSS1 mutations. Eleven of 29 (38%) patients met radiological criteria for CP. All of the heterozygote patients with a combination of CFTR and SPINK1 or PRSS1 mutations had CP. Eight patients developed a chronic pain syndrome and 2 developed exocrine pancreatic insufficiency during follow-up. CONCLUSIONS: We found a high prevalence of genetic mutations in patients without anatomic or metabolic abnormalities known to be associated with pancreatitis. Studies are needed to ascertain the genetic causes of RAP and CP and examine the relation between single CFTR mutations and single mutations in the PRSS1 and SPINK1 genes.

Role of nutrition in pediatric chronic liver disease.

The liver plays a central role in energy and nutrient metabolism. Malnutrition is highly prevalent among patients with chronic liver disease and leads to increased morbidity and mortality rates. This review addresses the causes of malnutrition, methods used to assess nutrition status, and appropriate treatment strategies in pediatric patients with chronic liver disease.

One-day bowel preparation with polyethylene glycol 3350: an effective regimen for colonoscopy in children.

BACKGROUND: Polyethylene glycol (PEG) 3350 is commonly used and has been proven safe and effective for the treatment of chronic constipation and as a 4-day bowel preparation in children. A 1-day PEG 3350 bowel preparation regimen has been recently developed for adults; however, data regarding its use in children are lacking. OBJECTIVE: To evaluate the safety and effectiveness of a 1-day PEG 3350 regimen for bowel preparation in children before colonoscopy. DESIGN: Retrospective review. SETTING: Tertiary-care center. PATIENTS: This study involved all children prescribed a 1-day PEG 3350 bowel preparation regimen before colonoscopy at our center in 2008. INTERVENTION: We reviewed medical records of patients (< or = 18 years of age) who underwent colonoscopy during 2008 and received the 1-day bowel preparation regimen. MAIN OUTCOME MEASUREMENTS: Adequate preparation for colonoscopy, success of colonoscopy, and factors associated with inadequate bowel preparation. RESULTS: Inclusion criteria were met by 272 patients. The median age of the children receiving the 1-day PEG 3350 preparation regimen was 13.7 years (range 1.08-17.92 years). Fifty-two percent were male; 48% were female. The most common indications for colonoscopy included abdominal pain (65%), bloody stools (29%), diarrhea (21%), and weight loss (18%). The 1-day bowel preparation regimen was effective in 253 patients (93%). The indication for colonoscopy, the age of the child, or a history of constipation did not significantly alter the success rate of colonoscopy. LIMITATIONS: A retrospective study at one tertiary-care center. CONCLUSION: The 1-day PEG 3350 bowel preparation regimen is safe and effective and should be considered for use as preparation for colonoscopy in children.

H syndrome: recently defined genodermatosis with distinct histologic features. A morphological, histochemical, immunohistochemical, and ultrastructural study of 10 cases.

This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68 histiocytes and CD34 and FXIIIa dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68 small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.

Tricho-hepato-enteric syndrome: a case of hemochromatosis with intractable diarrhea, dysmorphic features, and hair abnormality.

We report on a female infant with congenital iron storage disease, facial dysmorphism, intractable diarrhea, and hair abnormalities. The intractable diarrhea failed to resolve despite total parenteral nutrition and complete bowel rest for more than 3 weeks. The patient also had elevated liver enzymes and failure to thrive. Histopathologic examination of the liver revealed marked iron deposits in hepatocytes with portal edema, fibrosis, and septal formation. No metabolic abnormalities could be detected. She died at the age of 10 months. We suggest that this case could have a specific iron storage syndrome that is similar to the two sibs reported by Stankler et al. [1982; Arch Dis Child 57:212-216] and Verloes et al. [1997; Am J Med Genet 68:391-395]. The condition was called the tricho-hepato-enteric (THE) syndrome.