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Ocular Manifestations of Gastrointestinal Disease
Abstract
Many pediatric gastrointestinal disorders have ophthalmic manifestations. The detection of these ophthalmic features may help establish the underlying diagnosis. Pediatric liver, intestinal and pancreatic diseases with ophthalmic manifestations are discussed with extensive review of the relevant literature. Where relevant the pathologic mechanisms underlying these manifestations are discussed.
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There have been substantial improvements in the management of acute pancreatitis since the publication of the International Association of Pancreatology (IAP) treatment guidelines in 2002. A collaboration of the IAP and the American Pancreatic Association (APA) was undertaken to revise these guidelines using an evidence-based approach.
Purpose
To determine the prevalence of eye disorders in children with celiac disease (CD).
Methods
A total of 67 patients with CD aged from 1 to 16 years and 38 age- and sex-matched healthy children were screened for decreased visual acuity, cataract, uveitis, and diabetic retinopathy at diagnosis and during follow‐up.
Results
None of the patients had eye disorders at diagnosis. Only 2 of the patients had accommodative dysfunction and the others had no change in visual function during the follow-up. One of the controls had accommodative dysfunction.
Conclusions
No significant association was found between CD and eye disorders such as visual acuity, cataract, and uveitis among children.
We report the first genetically proven case of COACH syndrome from the Indian subcontinent in a 6-year-old girl who presented with typical features of Joubert syndrome along with hepatic involvement. Mutation analysis revealed compound heterozygous missense mutation in the known gene TMEM67 (also called MKS3).
Exclusive enteral nutrition involves the use of a complete liquid diet, with the exclusion of normal dietary components for a defined period of time, as a therapeutic measure to induce remission in active Crohn's disease (CD). This very efficacious approach leads to high rates of remission, especially in children and adolescents newly diagnosed with CD. This intervention also results in mucosal healing, nutritional improvements and enhanced bone health. Whilst several recent studies have provided further elaboration of the roles of exclusive enteral nutrition in the management of CD, other reports have provided new understanding of the mechanisms by which this intervention acts.
Though inflammatory bowel disease (IBD) has a specific predilection for the intestinal tract, it is a systemic inflammatory disorder affecting multiple organs, including the eye. Ocular complications directly related to IBD are categorized as primary and secondary. Primary complications are usually temporally associated with IBD exacerbations and tend to resolve with systemic treatment of the intestinal inflammation. These include keratopathy, episcleritis, and scleritis. Secondary complications arise from primary complications. Examples include cataract formation due to treatment with corticosteroids, scleromalacia due to scleritis, and dry eye due to hypovitaminosis A following gut resection. Some ocular manifestations of IBD can lead to significant visual morbidity and temporally associated complications can also be a herald of disease control. Furthermore, ocular manifestations of IBD can occasionally manifest before
the usual intestinal manifestations, leading to an earlier diagnosis. Thus, it is important to understand the clinical presentation of possible ocular manifestations in order to initiate appropriate treatment and to help prevent significant visual morbidity.
Familial adenomatous polyposis (FAP) is an inherited disorder that represents the most common gastrointestinal polyposis syndrome. Germline mutations in the APC gene were initially identified as responsible for FAP, and later, several studies have also implicated the MUTYH gene as responsible for this disease, usually referred to as MUTYH-associated polyposis (MAP). FAP and MAP are characterized by the early onset of multiple adenomatous colorectal polyps, a high lifetime risk of colorectal cancer (CRC), and in some patients the development of extracolonic manifestations. The goal of colorectal management in these patients is to prevent CRC mortality through endoscopic and surgical approaches. Individuals with FAP and their relatives should receive appropriate genetic counseling and join surveillance programs when indicated. This review is focused on the description of the main clinical and genetic aspects of FAP associated with germline APC mutations and MAP.
Celiac disease is a lifelong disorder for which there is currently only one known, effective treatment: a gluten-free diet. New treatment approaches have recently emerged; several drugs are in Phase 2 trials and results appear promising; however, discussion around regulatory endpoints is in its infancy. We will briefly discuss the drugs that are under development and then shift our attention to potential trial endpoints, such as patient-reported outcomes, histology, serology, gene expression analysis and other tests. We will outline the differing requirements for proof-of-concept Phase 2 trials and Phase 3 registration trials, with a particular emphasis on current thinking in regulatory agencies. We conclude our paper with recommendations and a glossary of regulatory terms, to enable readers who are less familiar with regulatory language to take maximum advantage of this review.
© The Author(s) 2015. Published by Oxford University Press and the Digestive Science Publishing Co. Limited.
To investigate prevalence, type and time of onset of extraintestinal manifestations (EIMs) in a series of Italian inflammatory bowel disease (IBD) patients.
Data of 811 IBD consecutive patients, first referred to our Centre from 2000 to 2011, were retrospectively evaluated.
Eight hundred and eleven IBD patients (437 M, 374 F) were studied: 595 ulcerative colitis (UC) (73.4%) and 216 Crohn's disease (CD) (26.6%). Among these, 329 (40.6%) showed EIMs: 210 UC (35.3%) and 119 CD (55.1%) (P < 0.0001). Considering the time of the diagnosis of IBD, 37 EIMs (11.2%) were developed before, 229 (69.6%) after and 63 (19.2%) were simultaneous. The type of EIM were as follows: 240 musculoskeletal (29.6%), in 72 CD patients and in 168 UC (P < 0.0001); 47 mucocutaneous (5.8%), in 26 CD and in 21 UC (P = 0.0049); 26 ocular (3.2%), in 16 CD and in 10 UC (CD 7.4% vs UC 1.7%, P = 0.0093); 6 hepatobiliary (0.8%); 10 endocrinological (1.2%). In particular, with regards to the involvement of the musculoskeletal system, arthritis Type 1 was found in 41 CD (19%) and in 61 UC (10.2%) (P = 0.0012) and Type 2 in 25 CD (11.6%) and in 100 UC (16.8%) (P = 0.0012).
Mucocutaneous manifestations, arthritis Type 1 and uveitis were significantly more frequent in CD than UC. The complications of the musculoskeletal system were the mostly observed ones, often with symptoms more severe than intestinal ones, confirming the need for close cooperation with rheumatologists.
Importance
Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler therapeutics using direct-acting antivirals that target various stages of the HCV life cycle are in development to eradicate HCV without concomitant interferon.Objectives
To summarize published evidence on safety, efficacy (measured by a sustained virologic response [SVR], which is the treatment goal of undetectable plasma HCV RNA 12 or 24 weeks after therapy completion), and tolerability of current US Food and Drug Administration–approved interferon-based regimens and oral interferon-free regimens used for treating HCV infection and coinfection with human immunodeficiency virus (HIV) and HCV; to provide treatment recommendations for specialists and generalists based on published evidence.Evidence Review
A literature search of Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister was conducted from January 1, 2009, to May 30, 2014. Publications describing phase 2, 3, and 4 studies evaluating the treatment of HCV were included. Forty-one studies involving 19 063 adult patients were included. Strength of clinical data and subsequent HCV treatment recommendations were graded according to the Oxford Centre for Evidence-Based Medicine.Findings
Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of SVR (89%-90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%-86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks’ duration: 82%-93%; SVR for genotype 3, 24 weeks’ duration, 80%-95%). Patients with HIV-HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients.Conclusions and Relevance
New, short-duration, simpler therapies result in high SVR rates for HCV-infected patients. In conjunction with increased screening for HCV as suggested by recent Centers for Disease Control and Prevention guidelines, availability of new therapies may lead to the treatment of many more people with chronic HCV infection.
Objectives:
Assessment of treatment response in children with celiac disease (CD) after commencing a strict gluten-free diet (GFD) is generally based on the resolution of clinical features and normalization of serology. Recent adult studies have shown that serologic markers do not correlate with mucosal recovery. We aimed (i) to determine whether anti-tissue transglutaminase immunoglobulin (Ig)A (tTG) and anti-deamidated gliadin peptide IgG (DGP) antibodies are sensitive and specific markers of mucosal recovery in children with CD on a GFD for at least 12 months, and (ii) to determine whether a validated dietary questionnaire of compliance can identify patients with mucosal recovery.
Methods:
A total of 150 children with biopsy-proven CD were prospectively evaluated with duodenal biopsies at ≥12 months on GFD, paired with repeat tTG and DGP serology. The biopsies were reviewed in a blinded manner by two histopathologists and graded by Marsh criteria. A validated questionnaire of dietary compliance was also administered.
Results:
Of 150 children recruited, 27 (18%) had positive serology, 97 (65%) had negative serology, and 26 (17%) had equivocal serology. Of the 97 children with negative serology, none had Marsh type 3 enteropathy. Of the 27 patients with positive serology, only 6 had Marsh type 3 changes. The sensitivity and specificity of serology as a marker of significant mucosal pathology was 75 and 85%, respectively, with a positive predictive value of 22% but a negative predictive value of 98%. Of the 129 (86%) questionnaires completed, 88% reported good or excellent compliance with a GFD (negative predictive value 97%).
Conclusions:
This study suggests that follow-up using two serological tests in children with CD on a GFD may obviate the need for repeat mucosal biopsy in the majority of patients. A standardized dietary questionnaire may be useful in identifying patients who require further evaluation.
Hamartomatous Polyposis Syndromes (HPS) are genetic syndromes, which include Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumour syndrome (Cowden Syndrom, Bannayan-Riley-Ruvalcaba and Proteus Syndrome) as well as hereditary mixed polyposis syndrome. Other syndromes such as Gorlin Syndrome and multiple endocrine neoplasia syndrome 2B are sometimes referred to as HPS. HPS is characterized by the development of hamartomatous polyps in the gastrointestinal tract as well as several extra-intestinal findings such as dermatological and dysmorphic features or extra-intestinal cancer. The syndromes are rare and inherited in an autosomal dominant manner.
The diagnosis of HPS has traditionally been based on clinical criteria, but can sometimes be difficult as the severity of symptoms range considerably from only a few symptoms to very severe cases - even within the same family. De novo cases are also frequent. However, because of the discovery of several associated germline-mutations as well as the rapid development in genetics it is now possible to use genetic testing more often in the diagnostic process. Management of the syndromes is different for each syndrome as extra-intestinal symptoms and types of cancers differs.
Clinical awareness and early diagnosis of HPS is important, as affected patients and at-risk family members should be offered genetic counselling and surveillance. Surveillance in children with HPS might prevent or detect intestinal or extra-intestinal complications, whereas in adulthood surveillance is recommended due to an increased risk of cancer e.g. intestinal cancer or breast cancer.
Inflammatory bowel disease (IBD) is a chronic disease mostly involved with intestine with unknown etiology. Diagnosis, evaluation of severity, and prognosis are still present as challenges for physicians. An ideal biomarker with the characters such as simple, easy to perform, noninvasive or microinvasive, cheap, rapid, and reproducible is helpful for patients and clinicians. Currently biomarkers applied in clinic include CRP, ESR, pANCA, ASCA, and fecal calprotectin. However, they are far from ideal. Lots of studies are focused on seeking for ideal biomarker for IBD. Herein, the paper reviewed recent researches on biomarkers of IBD to get advances of biomarkers in inflammatory bowel disease.
Autoimmune diseases due to probable common pathogenesis tend to coexist in some patients. Complex clinical presentation with diverse timing of particular symptoms and sophisticated treatment with numerous side effects, may cause diagnostic difficulties, especially in children. The paper presents diagnostic difficulties and pitfalls in a child with Graves' disease, celiac disease and liver function abnormalities.
The purpose of this study was to assess GH sensitivity in children with Alagille syndrome (syndromic intrahepatic bile duct paucity) by examining their response to short term administration of recombinant human GH (rhGH). Serum levels of insulin-like growth factor-I (IGF-I) were low despite elevated overnight integrated serum GH concentrations. Administration of rhGH (0.05 mg/kg.day for 3 days) to four growth-retarded children with Alagille syndrome did not significantly alter the serum concentrations of IGF-I and insulin, blood urea nitrogen, or urinary calcium excretion. In contrast, circulating IGF-I increased 2-fold in two children with Alagille syndrome and normal stature. In the control group, consisting of seven prepubertal children with GH deficiency, the predicted changes in response to rhGH in serum concentrations of IGF-I and insulin, urea nitrogen, and urinary calcium excretion were observed. Serum GH-binding protein levels, measured by a ligand-mediated immunofunctional assay, were significan...
Background
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is widely recognized to be a flat, stationary condition. Although it can show minimal increase in diameter, it has not been known to spawn nodular tumor that is evident ophthalmoscopically.
Objectives
To report 5 cases of CHRPE that gave rise to an elevated lesion and to describe the clinical features of these unusual nodules.
Methods
Retrospective medical record review.
Results
Of 5 patients with a nodular lesion arising from CHRPE, there were 4 women and 1 man, 4 whites and 1 black. Three patients were followed up for typical CHRPE for longer than 10 years before the tumor developed; 2 patients were recognized to have CHRPE and the elevated tumor concurrently. Visual acuity was decreased in 3 patients, mainly due to cystoid macular edema. The tumor was located between the equator and ora serrata in all 5 patients. There was no predilection for quadrant of the fundus. The flat part of the lesion was black and had visible lacunae in all 5 patients. The CHRPE ranged in basal diameter from 3 × 3 mm to 13 × 11 mm. The size of the elevated lesion ranged from 2 × 2 × 2 mm to 8 × 8 × 4 mm. The nodular component in all cases was supplied and drained by slightly prominent, nontortuous retinal blood vessels. Yellow retinal exudation occurred adjacent to the nodule in all 5 patients and 1 patient developed a secondary retinal detachment. Two tumors that showed progressive enlargement, increasing exudation, and progressive visual loss were treated with iodine 125–labeled plaque brachytherapy, resulting in deceased tumor size but no improvement in the visual acuity.
Conclusions
Congenital hypertrophy of the retinal pigment epithelium can spawn a nodular growth that slowly enlarges, attains a retinal blood supply, and causes exudative retinopathy and chronic cystoid macular edema. Although no histopathologic evidence is yet available, we believe that the tumor probably represents either an acquired adenoma or a reactive proliferation of the retinal pigment epithelium. The best treatment of these lesions is not yet established.
• Although acute anterior uveitis has been noted in children with inflammatory bowel disease, it has not been appreciated in the absence of ocular symptoms. To determine the presence of asymptomatic uveitis, slit-lamp examinations were performed in 19 children with granulomatous bowel disease and seven with ulcerative colitis. In the former group, six had uveitis, while no abnormalities were noted in those with ulcerative colitis. Abnormalities consisted of cells and flare in the anterior chamber. In the group with asymptomatic uveitis, all were male, three were black, and all had colonic involvement. No positive correlations were noted between the presence of uveitis and bowel symptoms, duration of illness, extraintestinal manifestations, or specific treatment regimens. None of the six children with uveitis had evidence of spondylitis, and five were HLA-B27-negative. Repeated eye examinations six to 12 months later disclosed no evidence of uveitis in four of five children and improvement in the remaining child. These data suggest that asymptomatic transient uveitis is common in children with granulomatous bowel disease, but progression to severe adult uveal disease remains unclear.
(Am J Dis Child 133:170-171, 1979)
The quantification of the burden of disease attributable to hepatitis B virus (HBV) infection and the adaptation of prevention and control measures requires knowledge on its prevalence in the general population. For most countries such data are not routinely available. We estimated the national, regional, and global prevalence of chronic HBV infection.
For this systematic review and pooled analysis, we searched for data on prevalence of chronic HBV infection published between Jan 1, 1965, and Oct 23, 2013, in the databases Medline, Embase, CAB Abstracts (Global health), Popline, and Web of Science. We included studies reporting the hepatitis B surface antigen (HBsAg) serological marker of chronic HBV infection in non-high-risk groups and extracted data into a customised database. For each country, we calculated HBsAg prevalence estimates and 95% CIs weighted by study size. We extrapolated prevalence estimates to population sizes in 2010 to obtain the number of individuals with chronic HBV infection.
Of the 17 029 records screened, 1800 report on the prevalence of HBsAg covering 161 countries were included. HBsAg seroprevalence was 3·61% (95% CI 3·61-3·61) worldwide with highest endemicity in countries of the African region (total 8·83%, 8·82-8·83) and Western Pacific region (total 5·26%, 5·26-5·26). Within WHO regions, prevalence ranged from 0·20% (0·19-0·21; Mexico) to 13·55% (9·00-19·89; Haiti) in the Americas, to 0·48% (0·12-1·90; the Seychelles) to 22·38% (20·10-24·83; South Sudan) in the African region. We estimated that in 2010, globally, about 248 million individuals were HBsAg positive.
This first global assessment of country-level population prevalence of chronic HBV infection found a wide variation between countries and highlights the need for continued prevention and control strategies and the collection of reliable epidemiologic data using standardised methodology.
World Health Organization.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Background
Alagille syndrome (AGS) is a multi-system, autosomal dominant disorder with highly variable expressivity, caused by mutations within the Jagged1 (JAG1) gene.
Methods
We studied 53 mutation positive relatives of 34 AGS probands to ascertain the frequency of clinical findings in JAG1 mutation carriers.
Results
Eleven of 53 (21%) mutation positive relatives had clinical features that would have led to a diagnosis of AGS. Seventeen of the 53 (32%) relatives had mild features of AGS, revealed only after targeted evaluation following the diagnosis of a proband in their family. Twenty five of the 53 (47%) mutation positive relatives did not meet clinical criteria, and two of these individuals had no features consistent with AGS at all. The frequency of cardiac and liver disease was notably lower in the relatives than in the probands, characterising the milder end of the phenotypic spectrum. The characteristic facies of AGS was the feature with the highest penetrance, occuring almost universally in mutation positive probands and relatives.
Conclusions
This study has implications for genetic counselling of families with AGS and JAG1 mutations.
Autoimmune hepatitis (AIH) is a severe hepatopathy characterised by female preponderance, hy-pertransaminasaemia, elevated levels of immunoglobulin (IgG), presence of serum autoantibodies and, his-tologically, by interface hepatitis. AIH occurs both in adults and children, being particularly aggressive in the latter. According to the type of serum autoantibodies, AIH can be differentiated in two forms: one positive for smooth muscle antibody (SMA) and/or antinuclear antibody (ANA) (type 1 AIH, AIH-1) and another positive for liver kidney microsomal antibody type 1 (LKM-1) (type 2 AIH, AIH-2). These two forms differ with regard to age at onset (earlier in the case of AIH-2), mode of presentation (fulminant hepatic failure more frequently observed in AIH-2) and association with IgA deficiency (more frequent in AIH-2). AIH responds satisfactorily to immuno-suppressive treatment (corticosteroids with or without azathioprine) that should be started as soon as the diagnosis is made. Despite immune suppression, some 40% of patients experience relapse and 9% undergo liver transplantation. Though the exact mechanism leading to loss of immune-tolerance in AIH is still unclear, recent evidence has pointed to a numerical and functional defect of CD4 pos CD25 pos regulatory T-cells as a factor permitting autoaggressive CD4 and CD8 T-cells to react against liver autoantigens. The generation and expansion of regulatory T-cells with liver autoantigen specificity in vitro represents a potential immunotherapeutic tool for the reconstitution of immune-tolerance in AIH without the drawback of pan-immunosuppression.
Concurrent orbital pseudotumor and Crohn's disease, although rare, have been described. To the best of our knowledge, pseudotumor isolated to the lacrimal gland (dacryoadenitis) with concurrent Crohn's disease has never been reported. We present the clinical course and ultrasonographic and radiologie findings of an acute case of isolated bilateral lacrimal gland pseudotumor in a patient with Crohn's disease. The treatment and review of the literature are discussed. (C)1992The American Society of Opthalmic Plastic and Reconstructive Surgery, Inc.
Incidence of inflammatory bowel disease (IBD) is increasing progressively. Few recent epidemiological prospective studies are available in Spain. The Epicom study, a population-based inception cohort of unselected IBD patients developed within the European Crohn's and Colitis Organization, was started in 2010. Vigo is the only Spanish area participating.
To describe the incidence of IBD in the Vigo area and the phenotypical characteristics at diagnosis and to compare them with previous data available in Spain.
Epidemiological, descriptive, prospective, and population-based study. All incident cases of IBD during 2010 and living in the Vigo area at diagnosis were included. The Copenhagen Diagnostic criteria were used to define cases. Background population at the start of the study was 579,632 inhabitants. Data were prospectively entered in the EpiCom database.
A total of 106 patients were included (57.5% men, median age 39.5 years). Of them 53 were diagnosed of as Crohn's disease (CD), 47 ulcerative colitis (UC) and six IBD unclassified (IBDU). The incidence rate per 100,000 per year for patients aged 15 years or older was 21.4 (10.8 for CD, 9.4 for UC, 1.2 IBDU). Including pediatric population incidence rates were 18.3 (10.3 CD, 8.7 UC, 1.2 IBDU). Median time since onset of symptoms until diagnosis was 2 months.
The incidence rate of IBD in Vigo is the highest compared to former Spanish cohorts, especially in CD patients. Median time since onset of symptoms until diagnosis is relatively short.
Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.
Introduction Inflammatory bowel disease (IBD) is known to be rare in the Asia Pacific region but epidemiological studies are scarce. Methodology Kinta Valley (Ipoh) was chosen as the sample population. Malaysia is a multiethnic population consisting of Malays, Chinese and Indians. New cases over of two years were prospectively captured as well as all known existing cases. Population as a whole and for each ethnic group was obtained. Incidence, prevalence and mean incidence over two decades were then calculated. Results There were ten new cases of IBD diagnosed from April 2011 to April 2013. The crude incidence rates of IBD, ulcerative colitis(UC) and Crohn's disease(CD) respectively were 0.68, 0.46 and 0.20 per 100,000 persons. The highest incidence was among the Indians, 1.91 compared to 0.35 and 0.63 per 100,000 persons among the Malays and the Chinese respectively. The mean incidence of IBD has increased steadily from 0.07 to 0.69 per 100,000 person-year over the last two decades. The UC:CD ratio was 8:1 from 1990-2000 and 3.6:1 from 2000-2010. The prevalence rates of IBD, UC and CD respectively were 9.24, 6.67 and 2.17 per 100,000 persons. The highest prevalence was also among the Indians; 24.91 compared to 7.00 and 6.90 per 100,000 persons among the Malay and Chinese races. Conclusions The incidence and prevalence rates of IBD are low in Malaysia but the incidence appears to be increasing and marked racial differences exist. As in other Asian countries, the incidence of CD is increasing at a more rapid rate relative to UC.
Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Joubert (JBTS) and Meckel-Gruber (MKS) syndromes are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone (TZ), and act as structural components of the so-called "ciliary gate" to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of TZ function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cAMP. However, challenges remain in the interpretation of the pathogenic potential of genetic variants of unknown significance, and in the elucidation of the molecular mechanisms of phenotypic variability in JBTS and MKS. The further genetic and functional characterization of these conditions is essential to prioritize patients for new targeted therapies.
This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.
The objective of this study was to describe the epidemiology and trends in pediatric acute pancreatitis (AP)-associated emergency department (ED) visits in the United States.
Estimates of AP-associated ED visits were calculated in children from birth to 19 years of age using the Nationwide Emergency Department Sample.
From 2006 to 2011, there were an estimated total of 78,787 ED visits associated with the diagnosis of AP. The greatest number of ED visits occurred in children 15 to 19 years of age (67.0%). A majority of patients were subsequently admitted to the hospital for further care (74.1%). Risk factors independently associated with an increased rate of hospital admission included 3 or more comorbid conditions (adjusted odds ratio [aOR] 12.81; 95% confidence interval [CI], 11.29-14.56), children younger than 5 years (aOR, 1.73; 95% CI, 1.58-1.89), presentation to a teaching hospital (aOR, 1.68; 95% CI, 1.62-1.74) or a hospital in the Western region of the United States (aOR, 1.48; 95% 1.42-1.54), and health coverage with Medicaid (aOR, 1.23; 95% CI, 1.17-1.29). Acute pancreatitis-associated ED visits increased from 14.5 per 100,000 children in 2006 to 16.1 per 100,000 children in 2011 (11.42% increase; P < 0.01).
There has been an increasing incidence of AP-associated ED visits in children from 2006 to 2011.
• We studied prospectively the utility of congenital hypertrophy of the retinal pigment epithelium as a predictor of colonic polyposis in offspring of patients with familial adenomatous polyposis with extracolonic manifestations (Gardner's syndrome). After they underwent initial indirect ophthalmoscopy, we followed up 34 individuals at 50% genetic risk for familial adenomatous polyposis with extracolonic manifestations due to an affected parent. All 34 obtained their first colorectal endoscopic examination during a follow-up period of up to 4 years. The 16 individuals who did not have congenital hypertrophy of the retinal pigment epithelium (aged 13 to 40 years; mean, 25 years) remained polyp free, while 14 of 18 individuals with congenital hypertrophy of the retinal pigment epithelium (aged 9 to 30 years; mean, 18 years) were found to have colorectal adenomatous polyposis. Our findings indicate that the presence of multiple patches of congenital hypertrophy of the retinal pigment epithelium in children and young adults at risk for familial adenomatous polyposis with extracolonic manifestations is a clinically useful predictor of colorectal polyposis.
Vasculopathy is well-described in Alagille syndrome (ALGS); however, few data exist regarding neurosurgical interventions. We report 5 children with ALGS with moyamoya who underwent revascularization surgery. Postsurgical complications included 1 stroke and 1 death from thalamic hemorrhage. Global function improved in survivors. Revascularization is reasonably safe in patients with ALGS and may improve neurologic outcomes.
Copyright © 2014 Elsevier Inc. All rights reserved.
To define an algorithm to improve diagnosis of neonatal hemochromatosis (NH) related to gestational alloimmune liver disease (GALD), which is diagnosed by immunohistochemistry demonstrating activated complement at hepatocytes (IDACH).
We assessed 56 instances of fetal death or neonatal liver failure (NLF; 2006-2009), 29 (7 stillborns, 22 NLF) with NH, and 27 (5 stillborns, 22 NLF) without NH (non-NH). Immunohistochemistry was retrospectively performed in 21 cases. Cases were grouped as follows: (1) GALD as demonstrated by IDACH (n = 17); (2) indeterminate for GALD (n = 28); or (3) alternate diagnosis found (n = 11). We compared cases of immunohistochemically proven GALD with those with an alternate diagnosis.
Of the 12 stillborns, 7 had NH because of GALD (NH-GALD), one was undeterminate, and 4 had alternate diagnoses (GALD excluded). Of the 22 newborns with NH, 6 had NH-GALD, one had mitochondrial respiratory chain disorder (MRCD), and 15 were indeterminate for GALD. Of 22 non-NH newborns, extrahepatic siderosis (EHS) was not assessed in 13 (3 GALD, 1 alternate diagnosis [MRCD] and 9 indeterminate GALD) and excluded in 9 (5 alternate diagnoses and 4 indeterminate GALD). The only clinical features found to be associated with GALD were intrafamilial recurrence, prematurity, and EHS.
In unexplained fetal death or NLF, the diagnosis of subsets of NH requires tissue analysis (autopsy) to assess EHS. In patients with NH, if MRCD is ruled out, NH-GALD is likely. The rate of IDACH in the diagnosis of GALD in cases without NH requires further study.
Copyright © 2014 Elsevier Inc. All rights reserved.
Objectives:
The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data.
Methods:
MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator.
Results:
According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92-0.99) and a specificity of 0.70 (0.59-0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 μg/g there would be 17% (95% CI 15-20) false-positive and 2% (1-3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89-0.94).
Conclusions:
In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients' risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation.
Cowden syndrome (CS) is an autosomal dominant hereditary cancer syndrome causing increased risk for breast, thyroid, renal, uterine, and other cancers as well as benign neoplasias and neurodevelopmental concerns. Timely diagnosis of affected patients is key, as early recognition allows for high-risk screening and other preventative measures prior to a patient enduring multiple cancer diagnoses. This review will highlight the cardinal features of CS and management recommendations for affected patients. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs. © 2008 Wiley-Liss, Inc.
Although the incidence of acute pancreatitis among children is less than that in adults, the physical and psychosocial impact on children and their families can be overwhelming. Pancreatitis is manifested as pain accompanied by a host of other complex issues. These issues are manifested more markedly when the patient has additional concomitant diagnoses. Pain management, liver function tests, amylase and lipase levels, endocrine and exocrine functionality, and recognition of systemic inflammation are especially important. Management after discharge from the hospital is often an ongoing stress for these patients and families, and multiple admissions to the intensive care unit may be necessary for feeding and pain complications. Presented in the context of an actual clinical case at a 500-bed tertiary care pediatric hospital, this patient's scenario illustrates the importance of ensuring adequate nutrition, maintaining hydration, providing appropriate pain management, and preventing infection and thromboembolic events.
Purpose of review:
To summarize the recent advances in celiac disease in children.
Recent findings:
New clues to the pathogenesis of celiac disease continue to emerge that may implicate the role of microbiome changes, antirotavirus VP7 antibodies, and the Parkinson's disease seven gene in celiac disease. Updated guidelines in pediatrics no longer support biopsies in all patients with celiac disease who have been identified by serology, clinical signs, and genetics. Serology screening of total immunoglobulin A in all patients may not be necessary in select patients. Prevalence and additional diseases associated with celiac disease continue to be elucidated.
Summary:
Our knowledge of celiac disease continues to grow with increasing evidence of the pathogenesis, genetics, diagnosis, and risk factors of the disease. Major changes have been made with respect to the guidelines for pediatric celiac disease, and potential improvements to simplify the algorithms for diagnosis and elimination of unessential testing have been proposed by new studies.
Background:
Polyposis syndromes in children are distinct entities clinically and pathologically. These syndromes have multiple genetic characteristics, with development of polyps at various sites of the gastrointestinal (GI) tract, and are associated with an increased risk of colon cancer. They are relatively rare, and have mostly been characterized in the adult population, whereas little epidemiologic data have been reported in children.
Aims:
The aim of this study was to summarize the pediatric experience collected over a period of 11 years on polyposis syndromes in three major Israeli tertiary centers.
Patients and methods:
Medical records of children below 18 years old and their families, diagnosed with polyposis syndromes between 1999 and 2010, were reviewed. The data included disease presentation, genetic profile, surveillance, and treatment.
Results:
Fifty patients with polyposis syndromes were identified. The most frequent syndrome was familial adenomatous polyposis (FAP) in 33 children (66%), of whom 25 children (75.7%) had a known mutation. The mean age at presentation was 10.6±3.9 years (range 4-17 years). Most children were examined because of a family history of a polyposis syndrome (42 children, 84%). Among symptomatic children (32 children), the most frequent complaint was rectal bleeding (42%), followed by abdominal pain (22%), intussusception (10%), and diarrhea (4%). The youngest symptomatic patient was 4 years old at presentation, with rectal bleeding.All patients underwent multiple colonoscopies and upper GI endoscopies according to specific guidelines. Thirteen children underwent colonic surgery (39%); nine children had FAP. Adenocarcinoma of the colon was diagnosed in a 12.5-year-old child.
Conclusion:
In this cohort study, FAP was the most common type of polyposis syndrome diagnosed in this pediatric population. Colon cancer was present at the onset of symptoms in a 12.5-year-old patient with FAP. We therefore recommend strict adherence to the hereditary GI cancer guidelines to prevent morbidity and mortality in FAP and other inherited polyposis syndromes.
We sought to determine if very-early onset childhood IBD (age < 6yr; 20 ulcerative colitis, 8 Crohn's, 2 indeterminate, sequentially diagnosed) was clinically more severe than in older children (6-17yr; 19 ulcerative colitis, 39 Crohn's, 2 indeterminate). Early onset ulcerative colitis was marked by less abdominal pain at presentation, but an aggressive course with a significant reduction in weight-for-age, increased use of immunosuppressants and more surgery. Children with early-onset Crohn's were more likely to have bloody stools at presentation and an isolated colitis. This study supports the suggestion that IBD phenotype differs in early onset disease.
Abnormalities in primary cilia lead to diseases called ciliopathies. Multiple organ involvement is the norm since primary cilia are present in most cells. When cholangiocyte cilia are abnormal, ductal plate malformation ensues leading to such conditions as congenital hepatic fibrosis, Caroli disease or syndrome, or other fibrocystic disease.
Coach Syndrome is a rare cause of Congenital Hepatic Fibrosis associated with neurological features. COACH is a mnemonic comprising of Cerebellar vermis hypo/aplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma and Hepatic fibrosis. Here we describe a 12 years boy who presented with hepatic encephalopathy. He was subsequently found to have marked developmental delay, bilateral ptosis and ataxia. CT scan revealed brain stem molar tooth sign, ophthalmoscopy showed optic disc coloboma and elastography showed hepatic fibrosis to confirm him as a case of COACH Syndrome.
Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid-eye out-patient clinic, 176 (13.4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9.8%) type 1 diabetes, 111 (8.5%) coeliac disease, 60 (4.6%) type A autoimmune gastritis, 57 (4.4%) vitiligo and 25 (1.9%) Addison's disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2.18; P = 0.002 and OR = 6.52; P < 0.001], whereas type 1 diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjogren's syndrome were 'protective' for GD and thus linked to HT, OR = 0.49 (P < 0.001), 0.06 (P < 0.001), 0.25 (P < 0.001), 0.50 (P = 0.090) and 0.32 (P = 0.003), respectively. Of 610 (46.6%) AITD patients with TAO, 584 (95.7%) and 26 (4.3%) had GD and HT, respectively (P < 0.001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1.87, P < 0.001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3.4 and 4.03, both P < 0.001) pertaining to the association with TAO while type 1 diabetes, Addison's disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO.
Two hundred and fourteen patients with Crohn's disease (CD) consecutively admitted during a 5-year period were observed for a mean of 9 years (range, 0-35 years). Sixty-five per cent had their initial symptoms between 10 and 30 years of age and 9.2% after the age of 50 years. The CD diagnosis was delayed for more than 10 years in 8% (mean, 4.5; range, 0-31 years). Large-bowel involvement was seen in 82.5% and was the only localization of the disease in a fourth of the patients. Recurrent abdominal pain occurred in two-thirds of patients with ileal or ileocolic disease. Acute abdominal pain was the cause of laparotomy in 14% of the patients with ileocolic CD. Diarrhea and rectal bleeding occurred significantly more often in colonic CD, whereas fistula complicated ileocolic disease more often than isolated involvement of small or large bowel. Associated extraintestinal diseases were seen in 117 patients (55%), most frequently related to colonic involvement (joint disease, 21%; eye, 12%; skin, 8%). Of 26 patients (12%) with liver pathology, 10 patients had amyloid deposits. Amyloidosis was diagnosed in altogether 12 patients (6%).
Acute pancreatitis is an emerging problem in pediatrics, with an incidence that is rising in the last two decades. Data regarding the optimal management and physician practice patterns are lacking. We present a literature review and updates on the management of pediatric pancreatitis. Prospective multi-center studies defining optimal management of pediatric pancreatitis are needed to guide care and improve outcomes for this patient population.
Previous studies suggested that one or more genes on chromosome 5q21 are responsible for the inheritance of familial adenomatous
polyposis (FAP) and Gardner's syndrome (GS), and contribute to tumor development in patients with noninherited forms of colorectal
cancer. Two genes on 5q21 that are tightly linked to FAP (MCC and APC) were found to be somatically altered in tumors from
sporadic colorectal cancer patients. One of the genes (APC) was also found to be altered by point mutation in the germ line
of FAP and GS patients. These data suggest that more than one gene on chromosome 5q21 may contribute to colorectal neoplasia,
and that mutations of the APC gene can cause both FAP and GS. The identification of these genes should aid in understanding
the pathogenesis of colorectal neoplasia and in the diagnosis and counseling of patients with inherited predispositions to
colorectal cancer.