Congenital Aganglionic Megacolon Research Articles

Frequency of RET mutations in long- and short-segment Hirschsprung disease.

Hirschsprung disease, or congenital aganglionic megacolon, is a genetic disorder of neural crest development affecting 1:5,000 newborns. Mutations in the RET proto-oncogene, repeatedly identified in the heterozygous state in both long- and short-segment Hirschsprung patients, lead to loss of both transforming and differentiating capacities of the activated RET through a dominant negative effect when expressed in appropriate cellular systems. The approach of single-strand conformational polymorphism analysis established for all the 20 exons of the RET proto-oncogene, and previously used to screen for point mutations in Hirschsprung patients allowed us to identify seven additional mutations among 39 sporadic and familial cases of Hirschsprung disease (detection rate 18%). This relatively low efficiency in detecting mutations of RET in Hirschsprung patients cannot be accounted by the hypothesis of genetic heterogeneity, which is not supported by the results of linkage analysis in the pedigrees analyzed so far. Almost 74% of the point mutations in our series, as well as in other patient series, were identified among long segment patients, who represented only 25% of our patient population. The finding of a C620R substitution in a patient affected with total colonic aganglionosis confirms the involvement of this mutation in the pathogenesis of different phenotypes (i.e., medullary thyroid carcinoma and Hirschsprung). Finally the R313Q mutation identified for the first time in homozygosity in a child born of consanguineous parents is associated with the most severe Hirschsprung phenotype (total colonic aganglionosis with small bowel involvement).

Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient.

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. HSCR may be inherited as a single gene disorder with reduced penetrance or as a multigenic trait. HSCR mutations have been identified in the RET receptor tyrosine kinase, endothelin-B receptor (EDNRB) and its physiological ligand, endothelin 3 (EDN3). Although RET's ligand has remained elusive, it is expected to be an extracellular neurotrophic molecule expressed in the developing gut and kidney mesenchyme, based on the phenotypes of intestinal aganglionosis and renal agenesis observed in homozygous RET knockout (Ret -/-) mice. The glial cell line-derived neurotrophic factor (GDNF) is such a molecule. Recently, mice carrying two null alleles for Gdnf were shown to exhibit phenotypes remarkably similar to Ret-/- animals. We screened 106 unrelated HSCR patients for mutations in GDNF by direct sequencing. We identified one familial mutation in a HSCR patient with a known de novo RET mutation and malrotation of the gut. No haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surrounding GDNF on human chromosome 5p. Our data suggest that GDNF is a minor contributor to human HSCR susceptibility and that loss of its function in enteric neurogenesis may be compensated for by other neurotrophic factors or via other pathways. However, it may be that in rare instances, RET and GDNF mutations act in concert to produce an enteric phenotype.

Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color.

Mutations in the gene encoding the endothelin receptor type B (EDNRB) produce congenital aganglionic megacolon and pigment abnormalities in mice and humans. Here we report a naturally occurring null mutation of the EDNRB gene in spotting lethal (sl) rats, which exhibit aganglionic megacolon associated with white coat color. We found a 301-bp deletion spanning the exon 1-intron 1 junction of the EDNRB gene in sl rats. A restriction fragment length polymorphism caused by this deletion perfectly cosegregates with the sl phenotype. The deletion leads to production of an aberrantly spliced EDNRB mRNA that lacks the coding sequence for the first and second putative transmembrane domains of the G-protein-coupled receptor. Radioligand binding assays revealed undetectable levels of functional EDNRB in tissues from homozygous sl/sl rats. We conclude that EDNRB plays an essential role in the normal development of two neural crest-derived cell lineages, epidermal melanocytes and enteric neurons, in three mammalian species--humans, mice, and rats. The EDNRB-deficient rat may also prove valuable in defining the postnatal physiologic role of this receptor.

Child with manifestations of dermotrichic syndrome and ichthyosis follicularis‐alopecia‐photophobia (IFAP) syndrome

We report on a boy with short stature, mental retardation, seizures, follicular ichthyosis, generalized alopecia, hypohydrosis, enamel dysplasia, photophobia, congenital aganglionic megacolon, inguinal hernia, vertebral, renal and other anomalies, and a normal chromosome constitution. The clinical findings include all the features that dermotrichic and ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome have in common and in addition those that characterize IFAP syndrome (photophobia, recurrent respiratory infections, etc.), those that are present only in dermotrichic syndrome (nail anomalies, hypohydrosis, megacolon, vertebral defects, etc.) and additional ones (enamel dysplasia, renal anomalies, inguinal hernia, etc.). Two maternal uncles were referred as being affected by alopecia and ichthyosis suggesting X-linked recessive transmission. Various hypotheses concerning the relationship between the 2 syndromes and the present case are discussed.

ASSOCIATION BETWEEN CLOSTRIDIUM DIFFICILE AND ENTEROCOLITIS IN HIRSCHSPRUNG'S DISEASE

High titres of a cytopathic toxin were found in the faeces of four of six children with Hirschsprung's disease (congenital aganglionic megacolon). The toxin was fully neutralised by Clostridium sordellii antiserum. C. difficile was isolated from the faeces of five patients. In two of the four children from whom tissue specimens were obtained there were histological features of pseudomembranous colitis. C. difficile may be implicated in the pathogenesis of some cases of Hirschsprung's enterocolitis.

Embryogenesis of the enteric ganglia in normal mice and in mice that develop congenital aganglionic megacolon

ABSTRACT Embryological studies on the mouse indicate that, contrary to the classical concept, all the enteric ganglia are from a single, vagal, neural crest source. The immature ganglion cells first enter the gut by way of the newly formed vagal outgrowth at 10 days gestation. The neuroblasts then migrate down the gut in a cranio-caudal direction, being replaced by more neuroblasts from the vagus. By 15 days 12 h the process is complete and ganglion cells are present throughout the gut. The process is continuous and there is no evidence of a lumbosacral origin for any of the intramural ganglia. In mice which develop aganglionic megacolon the process is basically the same except that the neuroblasts appear to migrate at a slower rate than normal. The result is that the migration of the neuroblasts and the elongation of the gut are out of phase so the migrating neuroblasts cannot reach the end of the gut, despite the fact they migrate 6 – 7 days longer than normal.

Congenital aganglionic megacolon (Hirschsprung's disease) : R. T. Soper and F. E. Miller. Arch. Surg. 96:554 (April) 1968

Congenital aganglionic megacolon (Hirschsprung's disease) : R. T. Soper and F. E. Miller. Arch. Surg. 96:554 (April) 1968

Pseudomembranous enterocolitis—A fatal complication of congenital aganglionic megacolon : Capt. Frederick P. Hobin. MC. Amer. J. Dis. Child. 111:661–663, June 1966

Pseudomembranous enterocolitis—A fatal complication of congenital aganglionic megacolon : Capt. Frederick P. Hobin. MC. Amer. J. Dis. Child. 111:661–663, June 1966

Pseudomembranous Enterocolitis

THIS REPORT is to record the occurrence of the death of an infant with congenital aganglionic megacolon which is attributed to the development of pseudomembranous enterocolitis. It is believed that this combination of events has not been previously reported. The features of the case reported herein reflect the diagnostic difficulties of congenital megacolon in infancy and the alarming rapidity with which an apparently minimally ill infant can progress into the moribund state. Prior case studies, 1,2 have documented that signs and symptoms of intestinal obstruction develop in congenital megacolon. In large measure, the threat to these infants' lives is due to the development of a nonspecific enterocolitis. 3 The latter observation, as well as an increased incidence of pseudomembranous enterocolitis in postoperative adult patients with clinical evidence of intestinal obstruction, 4 suggest that pseudomembranous enterocolitis might be a reasonably expected development in certain infants with congenital megacolon. Report of a

The meconium plug syndrome revisited

The intelligent management of newborn infants who have symptoms or signs of intestinal obstruction requires a familiarity with the meconium plug syndrome. Although recognized and described a decade ago, 1 this syndrome has not yet been widely discussed in the surgical and pediatric literature. Some questions arose at the time of the original report, particularly related to the etiology and the relationship of this type of obturant obstruction to meconium ileus associated with fibrocystic disease and to dyskinetic colonic function associated with congenital aganglionic megacolon. Although we have acquired little additional information regarding the etiology of the meconium plug syndrome, sufficient time has now elapsed to provide a greater body of experience for analysis and to bring to the reader's attention some of the problems that we have encountered in the management of this entity. For these reasons we propose to reconsider the meconium plug syndrome and to recount our experience with the nine originally reported infants and 21 additional patients treated at the Columbus Children's Hospital.

AGANGLIONIC AND FUNCTIONAL MEGACOLON IN CHILDREN—A DIAGNOSTIC DILEMMA

Megacolon in early infancy and childhood may be due to a number of causes. The proper treatment must necessarily depend upon the accuracy of the diagnosis as to etiology in each patient. We have reviewed our cases of functional megacolon, i.e., "meconium plug syndrome," "acquired constipation," or "colonic inertia" and have encountered examples of unnecessary enterostomy, colostomy and/or pull-through procedures which were performed for what appeared to be congenital aganglionic megacolon. We have also observed numerous examples of prolonged unproductive conservative treatment in patients who were subsequently proven to have aganglionic megacolon. A review of the conventional signs and symptoms and radiographic studies which were carried out on these patients suggests that these observations alone are insufficient to establish a diagnosis and allow for definitive therapy. The full thickness rectal wall biopsy has, by contrast, been an extremely valuable diagnostic aid. At the present time, we do not feel that a definite diagnosis can be established without rectal biopsy which, when properly performed and studied by an experienced pathologist, will differentiate between patients who require major surgery and those who may be expected to respond to conservative medical management.

STUDIES OF DISTAL COLONIC MOTILITY IN CHILDREN

Three patients with fecal impaction and soiling are described. In each a short area of achalasia proximal to the anus was demonstrable by motility studies. Surgical resection of the achalasic segment resulted in improvement in all, although ganglia could be demonstrated in this segment in each child. The relationship of this syndrome to congenital aganglionic megacolon and to psychogenic obstipation is discussed.

Editorial

During the past few months there have appeared some changes in this journal suggested by the readers to increase its usefulness. In this issue there is introduced a major change in the abstract section, more fully described at the beginning of that section. It is the opinion of the Editorial Board that more complete abstract services are now available, but that our readers will appreciate an opportunity to scan the titles of articles of pediatric interest in the leading journals and to have more complete abstracts of a few selected articles. The Section "Correspondence" is being continued, in which columns we will be glad to publish letters relating to any point of pediatric interest. Another departure is the reproduction of the Scientific Exhibit "Congenital Aganglionic Megacolon" by John F. Mokrohisky, M. D., and George P. Keefer, M. D., in the December, 1955, issue. It is our opinion that valuable exhibits

Hirschsprung's disease (congenital aganglionic megacolon); report of 3 cases in infancy associated with acute colitis.

SummaryThree cases of proven Hirschsprung's disease in infancy have been reported in which there was an associated acute ulcerative colitis of varying degree and in two of which death occurred due to peritonitis secondary to perforation of an ulcer. The third baby died in the early stages of an acute colitis but death was directly caused by massive hemorrhage from an acute duodenal ulcer. No adequate explanation for the development of the ulcerative colitis was forthcoming.Clinically the history and physical examination was atypical and misleading while the roentgen findings were complex or negative. It is, therefore, important to realize that the classical picture of Hirschsprung's disease, though based on a congenital lesion, is a product of time and that in this interval the diagnosis may be difficult.Lastly, attention is drawn to the possible lethal complications of Hirschsprung's disease and cognizance should be taken of this fact, particularly in the management of the disease in infancy. From the viewpoint of the pathologist, the postmortem finding of acute ulcerative colitis in an infant must suggest the possibility of aganglionic megacolon.