Novel Classification and Pathogenetic Analysis of Hypoganglionosis and Adult-Onset Hirschsprung��s Disease

Background and Aims

Researchers have not clearly described the clinical and pathogenetic features of hypoganglionosis and adult-onset Hirschsprung??s disease, which cause pseudo-obstruction or intractable constipation. We conducted this study to explore these features of hypoganglionosis and adult-onset Hirschsprung??s disease in Korean patients.

Methods

We enrolled 24 patients pathologically confirmed as having hypoganglionosis and 11 as having adult-onset Hirschsprung??s disease. We recruited 26 subjects who had undergone operation for nonobstructive colon cancer and 45 healthy volunteers as controls. We described their clinical features, investigated ganglion cells and interstitial cells of Cajal (ICC), and analyzed RET, EDNRB, EDN3, and SOX10 genes.

Results

We classified hypoganglionosis patients into two groups: type I (focal type, n = 13), with focally narrowed transition zone (TZ); and type II (diffuse type, n = 11), without transition zone. Hypoganglionosis patients had significantly fewer ganglion cells than the controls, and those cells were scarcer in the transition zone than in the proximal dilated area (P < 0.05). The ICC numbers in both diseases were significantly lower than in controls; however, they were similar between transition zone and the proximal dilated area in hypoganglionosis. In adult-onset Hirschsprung??s disease, two significant intronic RET polymorphic variants, IVS14-24G>A and IVS19+47T>C, were significantly associated with adult-onset Hirschsprung??s disease (P = 0.0122 and 0.0295, respectively), but not with hypoganglionosis.

Conclusions

Hypoganglionosis and adult-onset Hirschsprung??s disease have different pathophysiologic characteristics, although their clinical presentations are similar. We suggest that there are two subgroups of hypoganglionosis: those with or without a focally narrowed transition zone with a profoundly diminished number of ganglion cells.     

Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence

The ability to discriminate between deleterious and neutral amino acid substitutions in the genes of patients remains a significant challenge in human genetics. The increasing availability of genomic sequence data from multiple vertebrate species allows inclusion of sequence conservation and physicochemical properties of residues to be used for functional prediction. In this study, the RET receptor tyrosine kinase serves as a model disease gene in which a broad spectrum (> or = 116) of disease-associated mutations has been identified among patients with Hirschsprung disease and multiple endocrine neoplasia type 2. We report the alignment of the human RET protein sequence with the orthologous sequences of 12 non-human vertebrates (eight mammalian, one avian, and three teleost species), their comparative analysis, the evolutionary topology of the RET protein, and predicted tolerance for all published missense mutations. We show that, although evolutionary conservation alone provides significant information to predict the effect of a RET mutation, a model that combines comparative sequence data with analysis of physiochemical properties in a quantitative framework provides far greater accuracy. Although the ability to discern the impact of a mutation is imperfect, our analyses permit substantial discrimination between predicted functional classes of RET mutations and disease severity even for a multigenic disease such as Hirschsprung disease.     

Increased expression of HOXA9 gene in Hirschsprung disease

OBJECTIVE: Hirschsprung disease is characterized by segmental aganglionosis of the terminal bowel. Neurons of the enteric nervous system arise from neural crest, migrate and colonize intestinal muscle coat where they proliferate and differentiate. The first pathophysiologic hypothesis suggests an absence of neural cell migration. The most recent hypothesis involves disorders of their homing and/or their differentiation due to an altered intestinal microenvironment. PATIENTS AND METHODS: We analyzed the expression of muscle markers and laminin isoforms by immunocytochemistry and of homeotic genes involved in the regionalization of the intestinal mesenchyme during development (HOXA4, HOXA9, HOXD9) by RT-PCR, in colon specimens from two children with Hirschsprung disease (pathological and transition regions) and from healthy adult controls. RESULTS: We showed an increase in HOXA9 gene expression in Hirschsprung disease specimens while HOXA4 and HOXD9 mRNA expressions were unchanged. No significant differences in the muscle markers nor in the laminin isoforms were noted. CONCLUSION: These data suggest that intrinsic dysregulation of the intestinal wall microenvironment could account for the pathophysiology of Hirschsprung disease.     

Upper gut motility of Hirschsprung's disease and its allied disorders in adults

BACKGROUND/AIMS: To clarify the significance of upper gut motility for Hirschsprung's disease and its allied disorders in adults, we studied the upper esophagogastroduodenal motility of adult patients with Hirschsprung's disease and its allied disorders such as hypoganglionosis and intestinal neuronal dysplasia. METHODOLOGY: Twelve patients (7 men and 5 women, aged between 20 and 55 years with a mean age of 39.6 years) with Hirschsprung's disease (2 cases) or its allied disorders (8 cases of hypoganglionosis and 2 cases of intestinal neuronal dysplasia) were studied. As a control, 15 healthy volunteers (8 men and 7 women aged between 27 and 69 years with a mean age of 49.0 years) were also examined. To obtain the upper gut motility in Hirschsprung's disease, hypoganglionosis, and intestinal neuronal dysplasia, we performed gastrointestinal transit time study, esophageal manometry, and gastroduodenal manometry. RESULTS: On gastrointestinal transit time, barium stagnated in the upper jejunum in 2 cases of hypoganglionosis, in the terminal ileum in one case of hypoganglionosis and intestinal neuronal dysplasia, and in the colon in the remaining patients. In two of the 12 cases of Hirschsprung's disease and its allied disorders such as hypoganglionosis and intestinal neuronal dysplasia, abnormal esophageal motilities, and absence of interdigestive migrating motor complex, phase III from the stomach were observed. These findings suggested that the entire digestive tract might have been affected in these two cases, i.e., these 2 patients had total gut involvement type of hypoganglionosis. CONCLUSIONS: Gastrointestinal transit time and upper esophagogastroduodenal manometry should be performed because of the relatively frequent association of upper gut dysmotilities with these disorders.     

Coincidence or causality: celiac and Crohn diseases in a case of Turner syndrome

We describe a 29-year-old woman presenting with chronic diarrhea, growth retardation, and primary amenorrhea who was diagnosed as having celiac disease coexisting with Crohn disease and Turner syndrome. The association of Turner syndrome, inflammatory bowel disease, and celiac disease is reviewed with insights into the genetics of immunologic disorders and possible chromosomal derangements leading to inflammatory bowel disease. To our knowledge, this is the first case of Crohn disease associated with celiac disease and Turner syndrome.     

Pediatric intestinal motility disorders

Pediatric intestinal motility disorders affect many children and thus not only impose a significant impact on pediatric health care in general but also on the quality of life of the affected patient.Furthermore,some of these conditions might also have implications for adulthood.Pediatric intestinal motility disorders frequently present as chronic constipation in toddler age children.Most of these conditions are functional,meaning that constipation does not have an organic etiology,but in 5% of the cases,an underlying,clearly organic disorder can be identified.Patients with organic causes for intestinal motility disorders usually present in early infancy or even right after birth.The most striking clinical feature of children with severe intestinal motility disorders is the delayed passage of meconium in the newborn period.This sign is highly indicative of the presence of Hirschsprung disease(HD),which is the most frequent congenital disorder of intestinal motility.HD is a rare but important congenital disease and the most significant entity of pediatric intestinal motility disorders.The etiology and pathogenesis of HD have been extensively studied over the last several decades.A defect in neural crest derived cell migration has been proven as an underlying cause of HD,leading to an aganglionic distal end of the gut.Numerous basic science and clinical research related studies have been conducted to better diagnose and treat HD.Resection of the aganglionic bowel remains the gold standard for treatment of HD.Most recent studies show,at least experimentally,the possibility of a stem cell based therapy for HD.This editorial also includes rare causes of pediatric intestinal motility disorders such as hypoganglionosis,dysganglionosis,chronic intestinal pseudo-obstruction and ganglioneuromatosis in multiple endocrine metaplasia.Underlying organic pathologies are rare in pediatric intestinal motility disorders but must be recognized as early as possible.     

Infliximab for the treatment of pediatric ulcerative colitis

Ulcerative colitis is a chronic, idiopathic, inflammatory disease of the colon and rectum that may be associated with growth failure, nutritional derangements and psychosocial ramifications in affected children. Multiple medical options are available to achieve disease remission; however, some of these medications can have unwanted side effects, especially in younger patients. With increased understanding of the etiology of the disease, newer therapeutic alternatives have arisen in the form of biologic therapies, namely monoclonal antibodies targeted to a specific protein or receptor. Specifically, infliximab, an anti-TNF-α agent, has been shown to be safe and effective for the treatment of moderate-to-severe pediatric ulcerative colitis.     

Diabetic heart disease--Part II: The clinical and pathological spectrum

Diabetes mellitus is a significant condition, affecting major segments of all population groups studied. With the introduction of insulin and oral hypoglycemic therapy, together with better understanding of diet and weight control gained over the past half century, the primary causes of diabetic morbidity and mortality have shifted in varying proportions from metabolic derangements, infection, and renal insufficiency to different types of cardiovascular disease. Despite extensive clinical and laboratory research on the etiology, pathogenesis, and even the existence of cardiovascular disease associated with diabetes mellitus, however, considerable debate is still apparent in this field. Our purpose is to present an overview of the subject of diabetic heart disease, with a critical analysis of epidemiologic, clinical, and pathological data. Some of this material will be addressed from the perspective of research in this area over the past decade by one of us (SMF), particularly in experimental hypertensive and diabetic cardiomyopathy. However, overall, an attempt will be made to provide an objective and balanced analysis in order to answer the question: does diabetic heart disease exist?     

Hirschsprung's disease and its allied disorders in adults' histological and clinical studies

BACKGROUND/AIMS: To accurately diagnose for Hirschsprung's disease and its allied disorders in adults, we studied the histology and clinical future of 12 adult patients with prolonged, refractory constipation with abdominal distension and pain. METHODOLOGY: Based on clinical signs and symptoms noted on admission, all of 114 patients (12 males and 104 females, aged 20-74 years with a mean age of 56.6 years) were suspected to have refractory chronic constipation. To obtain an accurate diagnosis, we performed rectal biopsy. Tissue samples were frozen and 12-micron sections were stained with hematoxylin-eosin, with acetylcholinesterase by the method of Karnovsky and Roots, and with NADPH-diaphorase by the modified Scherer-Singler's method. RESULTS: 1) Histological examinations; On the basis of histological studies (rectal biopsies), 8 were diagnosed with hypoganglionosis, 2 with Hirschsprung's disease, and 2 with intestinal neuronal dysplasia. It was possible to diagnose Hirschsprung's disease and intestinal neuronal dysplasia using rectal mucosal biopsies with hematoxylin-eosin and acetylcholinesterase staining. However, accurate diagnosis of hypoganglionosis could be made only through examination of the myenteric plexus by NADPH-diaphorase staining in full-thickness rectal specimens. 2) Clinical symptoms; All patients had refractory chronic constipation with abdominal pain and distension. Two patients with Hirschsprung's disease had constipation neonatally. Of the 8 patients with hypoganglionosis, one had constipation neonatally at sucking age, 2 as infants, 2 at school age, and 2 after operation as adults. Two patients with intestinal neuronal dysplasia had constipation while infants. Onset of signs and symptoms before school age was significantly revealed than that found after operation as adults (P < 0.01). Frequency of bowel movements was 1/7-10 days for Hirschsprung's disease, 1/7-14 days for hypoganglionosis, and 1/7-30 days for intestinal neuronal dysplasia. CONCLUSIONS: We were able obtain accurate histological diagnosis of patients with Hirschsprung's disease and intestinal neuronal dysplasia by rectal mucosal biopsy with hematoxylin-eosin and acetylcholinesterase staining. Patients with hypoganglionosis obtained accurate histological diagnosis by full-thickness rectal biopsy with NADPH-diaphorase staining. Onset of symptoms of disease occurred predominantly before school age. In all of the patients, bowel movements occurred less than once per week.     

Diabetic heart disease: the clinical and pathological spectrum--Part I

Diabetes mellitus is a significant condition affecting major segments of all population groups studied. With the introduction of insulin and oral hypoglycemic therapy, and with better understanding of diet and weight control over the past half century, the primary causes of diabetic morbidity and mortality have shifted in varying proportions from metabolic derangements, infection, and renal insufficiency to different types of cardiovascular disease. Despite extensive clinical and laboratory research on the etiology, pathogenesis, and even the existence of cardiovascular disease associated with diabetes mellitus, however, considerable debate is still apparent in this field. Our purpose is to present an overview of the subject of diabetic heart disease, with a critical analysis of epidemiologic, clinical, and pathological data. Some of this material will be addressed from the perspective of research in this area over the past decade by one of us (SMF), particularly in experimental hypertensive and diabetic cardiomyopathy. However, overall, an attempt will be made to provide an objective and balanced analysis, in order to answer the question: does diabetic heart disease exist?     

Atherosclerosis

It is generally considered that the genetics of atherosclerosis and its complications involves a large number of genes with common alleles having weak effects on disease risk but possibly interacting with each other and with nongenetic factors. In such a complex system, absence of marginal effects (effects of polymorphisms considered one at a time) is insufficient to exclude the implication of a polymorphism on disease risk. Investigating polymorphisms and even genes one by one is no longer appropriate. It is necessary to focus on biological systems and integrate the contribution of genetic as well as non-genetic factors and their interactions. Hopefully, system genetics will ultimately improve our understanding of the genetic architecture of complex traits. “Irecognized that an organism must never be looked upon as a mere mosaic of ‘unit characters’, each determined by a single gene, but rather as a network of interaction systems.”—Sewall Wright     

Hypersplenism

Cytopenias in liver disease are a common finding. In the past they have mostly been attributed to pooling and/or destruction of blood cells in the enlarged spleen, leading to the term 'hypersplenism'. With recent advances in the understanding of the physiology of blood formation, in particular with the discovery of several haematopoietic growth factors, new insight into the pathophysiology of blood cell derangements in liver disease has been obtained. Recombinant haematopoietic growth factors present new opportunities for support of the haematopoietic system, which is required because of toxic antiviral therapies or surgical interventions in these patients.     

Symptomatology,pathophysiology, diagnostic work-up,and treatment of Hirschsprung disease in infancy and childhood

In the majority of infants and children with constipation, no obvious cause can be identified. A rare cause of constipation is Hirschsprung disease (HD). HD is characterized by the absence of ganglion cells from the anorectum for a variable length up to the duodenum. The extent of the aganglionic segment varies, but in most patients the lesion does not extend beyond the rectum and sigmoid colon. This review focuses on the passage of meconium, the recognition of HD, and new insights in its pathophysiology and genetics. The authors also provide a summary of the diagnostic evaluation and treatment of HD in infancy and childhood.     

Genetics in scleroderma

Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA-DRB1?11/?06/?16 allelles. However, through association studies, different candidate genes that belong to the triad of autoimmunity, endothelial disfunction and fibrosis have been proposed as genes implicated in the predisposition to disease. In spite of these initial advances, up until recently most studies have had little statistical power, due to the small number of patients included and the lack of reproduction in independent populations. Recently, the development of genotyping platforms and data analysis has allowed for the application of a new type of strategy known as ?genome wide association studies? the analysis of the genetics to complex diseases, which are potent tools in the study of these multifactorial diseases. This paper pretends to perform a review of the recent advances in the study of the genetics of scleroderma, presenting results obtained in the analysis of the main candidate genes outside the HLA regions and the contribution of GWAS to the understanding of the molecular mechanisms of this disease.     

Genetics in rheumatoid arthritis

This chapter reviews the latest original research on the genetics of rheumatoid arthritis (RA), with a focus on its relevance for the clinical rheumatologist. The following questions will be dealt with in order to appreciate the recent progress in this field. * Why is a knowledge of genetics useful for an understanding of the pathogenesis of RA? * Is a knowledge of genetic risk factors relevant for day-to-day clinical practice? * What methods are used for identifying genetic risk factors? * Which genetic regions have been identified in susceptibility to RA? * What risk factors have been identified? * What are the future prospects and research agenda?     

Mitochondrial Cardiomyopathy: Pathophysiology,Diagnosis, and Management

Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of inherited mitochondrial disease has been estimated to be greater than 1 in 5,000 births; however, the diagnosis and treatment of this disease are not taught in most adult-cardiology curricula. Because mitochondrial diseases often occur as a syndrome with resultant multiorgan dysfunction, they might not immediately appear to be specific to the cardiovascular system. Mitochondrial cardiomyopathy can be described as a myocardial condition characterized by abnormal heart-muscle structure, function, or both, secondary to genetic defects involving the mitochondrial respiratory chain, in the absence of concomitant coronary artery disease, hypertension, valvular disease, or congenital heart disease. The typical cardiac manifestations of mitochondrial disease—hypertrophic and dilated cardiomyopathy, arrhythmias, left ventricular myocardial noncompaction, and heart failure—can worsen acutely during a metabolic crisis. The optimal management of mitochondrial disease necessitates the involvement of a multidisciplinary team, careful evaluations of patients, and the anticipation of iatrogenic and noniatrogenic complications.In this review, we describe the complex pathophysiology of mitochondrial disease and its clinical features. We focus on current practice in the diagnosis and treatment of patients with mitochondrial cardiomyopathy, including optimal therapeutic management and long-term monitoring. We hope that this information will serve as a guide for practicing cardiologists who treat patients thus affected.Key words: Cardiomyopathies/genetics/pathology/therapy, DNA, mitochondrial/analysis/genetics, energy metabolism/physiology, electron transport/physiology, genetic predisposition to disease, heart diseases/genetics, mitochondria/physiology, mitochondrial diseases/complications/diagnosis/genetics/physiopathology/drug therapy, risk factors, ventricular dysfunction, left/geneticsThe myocardium depends on a high level of aerobic metabolism to supply blood and energy substrate to all organs of the body. The mitochondria have a key role in energy production and in the growth and regulation of cardiac bioenergetic arrangements. Specific mitochondrial diseases have been attributed to mitochondrial mutations, and cardiac involvement is frequent. However, these syndromes are generally not covered comprehensively in cardiology curricula and might not be widely recognized by practicing cardiologists who treat adults. Recent research has shown that derangements of energy metabolism are ultimately implicated in most forms of heart failure. In this review, we describe the biologic characteristics of the mitochondria and their role in cardiac bioenergetic arrangements, discuss the spectrum of mitochondrial disease, and provide a guide for practicing cardiologists to use when treating patients affected by mitochondrial crisis.     

Clinical relevance of advances in genetics and pharmacogenetics of IBD

Crohn's disease and ulcerative colitis result from an inappropriate response of the mucosal immune system to the normal enteric flora in a genetically susceptible individual. During the past decade, exciting progress has been made in our understanding of the contribution of genetics to inflammatory bowel disease susceptibility and phenotype. This article reviews recent advances in the genetics of inflammatory bowel disease and explores how they might impact on clinical practice. Current knowledge of the genetic basis for disease susceptibility, phenotype, and response to therapy is explored and the factors currently limiting the translation of this knowledge to clinical practice is discussed.     

Behçet's disease

PURPOSE OF REVIEW: To summarize recent scientific developments in the epidemiology, genetics, pathogenesis and treatment of Beh?et's disease. RECENT FINDINGS: Important genetic and immunologic studies were performed. Tumor necrosis factor-alpha-1031C allele was associated with disease susceptibility. Polymorphisms in interleukin-10, IL-8 and CD28 genes were also associated with Beh?et's disease. Association with endothelial nitric oxide synthase gene polymorphism was confirmed but was ethnic related. Significant T helper type 1 immune reaction was reconfirmed in recent studies, especially during active phases, but T helper type 2 reaction may also play a role. Interleukin-12B heterozygosity is associated with Beh?et's disease susceptibility and plays an important role in mediating T helper type 1 antistreptococcal immune response. Selenium binding protein may be a target antigen in Beh?et's uveitis. Pathergy reaction is most frequently positive in the forearm; multiple needle pricks increase positive rate. Experience with anti-tumour necrosis factor therapy for various manifestations is increasing. Cyclosporin A treatment may be associated with new onset of neuro-Beh?et. There is a high prevalence of headaches with moderate or severe disability. Cardiac manifestations include left ventricular dysfunction and coronary flow abnormalities. Anti-Saccharomyces cerevisiae antibodies may be especially common in intestinal Beh?et's disease and are also increased in healthy relatives of patients. SUMMARY: Considerable progress has been made, particularly in understanding the immunologic and genetic basis of the disease. The importance of novel serological markers and autoantigens merits further investigations.     

Update on juvenile dermatomyositis: new advances in understanding its etiopathogenesis

PURPOSE OF REVIEW: Juvenile dermatomyositis is the most common of the idiopathic inflammatory myopathies in children. It is considered an autoimmune disease of relatively unknown etiology, although environmental exposures and infectious agents are thought to play a role in disease pathogenesis. More recently, data has become available regarding the molecular genetics of children affected with juvenile dermatomyositis and the impact these genes have on disease expression and clinical course. Additionally, features of the immune response, including specific pathways of the humoral and cellular immune systems, have been further described. This article summarizes the most recent advances in understanding the etiopathogenesis of juvenile dermatomyositis. RECENT FINDINGS: This article focuses on advances made in understanding the role that complement, soluble adhesion molecules, thrombospondin-1 levels, and genetics play in the evolution of juvenile dermatomyositis. It also describes microarray technology and gene expression profiling as means of identifying those genes overexpressed in affected children and thus likely involved in disease pathogenesis; microarray technology may also be used to distinguish dermatomyositis from the other inflammatory myopathies, as well as from other myopathies. SUMMARY: In better understanding the pathogenetic mechanisms whereby disease evolves and the means by which genetic profiles influence susceptibility to and expression of disease, immunotherapies to better treat juvenile dermatomyositis may become available in the future.     

Diabetes and the risk of stroke

Diabetes is an important risk factor for the development of ischemic cerebrovascular disease or stroke. Diabetic patients are more susceptible to atherothromboembolic brain infarction and its consequent mortality than nondiabetic patients. Cerebrovascular disease in the diabetic population somewhat follows the same pattern as in the nondiabetic population, however, with greater severity in outcome for the former. The etiopathogenetic mechanisms of strokes and transient ischemic attacks in diabetic patients are apparently due to cerebral hemodynamic and vascular derangements, hyperglycemia, and other related risk factors. There is a great disparity in the wider information on coronary heart disease and stroke than on diabetes and stroke. A better understanding is required for the determinants of stroke and diabetes, and the epidemiology and pathophysiology of specific risk factors in different racial groups. There is a similarity in the evaluation, assessment, and management of diabetic and nondiabetic patients.