Search

Enemas are used in pediatric patients with constipation. Retention of phosphate containing enemas with prolonged resorption or reduced renal elimination of phosphate can result in life-threatening hyperphosphatemia with subsequent lethal hypocalcemia and acidosis.We report the case of a 6-month-old child who received phosphate-containing enema to treat acute aggravation of constipation. The used enema here was not licensed for this age group. Phosphate intoxication resulted (phosphate 19.87 mmol/l) and presented like a sepsis. Hyperphosphatemia was treated by hemodialysis. A non-diagnosed Hirschsprung disease had led to prolonged resorption of phosphate containing enema and to an ileus and toxic megacolon that had to be operated.Insufficient elimination of phosphate containing enema can result in lethal or life threatening hyperphosphatemia, hypocalcemia and metabolic acidosis. These can be treated efficaciously by hemodialysis. Because of the high risk of intoxication in using enemas containing phosphate in infants or in patients with gastrointestinal or renal comorbidities, physicians treating constipation should choose enemas without phosphate but with ingredients with lower risk like glycerol or sorbitol in this age group.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome with the major components medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Due to the clinical course three distinct subtypes are distinguished, MEN 2A, MEN 2B and familial medullary thyroid carcinoma. The disease is caused by germ-line mutations of the RET proto-oncogene and the localization of these mutations correlates with the onset of the development of medullary thyroid carcinoma, which is crucial for the clinical course and outcome of the disease. It therefore has a substantial influence on the clinical management of the affected patients and their relatives. This review summarizes the morphology and clinic of MEN 2-associated tumors and their respective precursor lesions.

The experience gained by the Basel Hirschsprung Competence Center over 20 years is presented.A total of 19,365 rectal mucosal biopsies were investigated in the 20 years between 1987 and 2006. All biopsies of rectal mucosa originated from 6,615 children aged between 1 week and 4 years. Biopsies were collected in teaching hospitals all over Germany and transported on dry ice by Intercity Courier Service. Serial sections of frozen tissue were made using a cryostat. Enzyme histochemical staining was performed.A total of 935 cases of Hirschsprung's disease (14%) were observed (769 cases of classical Hirschsprung's disease, 68 total colon aganglionosis, 98 ultrashort rectum aganglionosis). Total colon aganglionosis was found in 1.0% and the frequency of ultrashort Hirschsprung' disease was 1.4%. The quality of the histological results was confirmed by a second independent investigator. There were neither false positive nor false negative diagnoses. Enzyme histochemical staining results were readable within 2 h. Acetylcholinesterase, which is significantly increased in Hirschsprung's disease, was used for nerve fiber staining. Succinic and lactic dehydrogenases and nitric oxide synthase served as confirmatory proof of aganglionosis (elective nerve cell staining of the submucous plexus).Among 100 children with chronic constipation an average of 12 children were diagnosed with Hirschsprung's disease. Of these 2% showed total colon aganglionosis or ultrashort Hirschsprung's disease. Enzyme histochemical diagnosis of Hirschsprung's disease proved 100% reliable and time saving.

Various outcomes following operative therapy for Hirschsprung's disease and anorectal malformations have been reported. Operative techniques for anorectal reconstruction have been modified several times in the past. Repair of anorectal -malformations have been performed through a posterior sagittal approach since the 1980s. This -allows an anatomically correct reconstruction of the anorectal canal. Abdominoperineal or sacro-abdominoperineal pull-through procedures, as the classical operative techniques, have been abandoned by most surgeons. Rectosigmoid-ectomy with colo-anal anastomosis, as described by Swenson and Bill in 1948, as well as the retro-rectal pull-through (Duhamel) and the endorectal pull-through (Soave) are still frequently used in surgery for Hirschsprung's disease. The development of the transanal endorectal pull-through with (Georgeson) or without (de la Torre) laparoscopic assistance has eliminated the necessity of laparotomy in selected cases. Despite significant progress in the understanding of the pathophysiology of and therapy for Hirschsprung's dis-ease and anorectal malformations, the functional results remain unsatisfactory. Functional problems occur already in early childhood and de-crease the quality of life significantly. Although complications resolve with time and the quality of life normalises in adolescence and adulthood, this might be mainly due to an adaptation strategy by the patients. For the future, a standardised and prospective study design is necessary to compare different procedures and to provide a basis for the further development of therapeutic strategies.

Hirschsprung's disease is the most important type of gastrointestinal dysmotility in neonatal pathology. Aberrant craniocaudal migration of neural crest stem cells results in an intestinal aganglionic segment of variable length. In 'classical' Hirschsprung's disease (60-75% of cases), the aganglionic segment spans the rectum and sigma. Ultrashort Hirschsprung's disease (5-10%) is restricted to the most distal 3-4 cm or immediate rectoanal transition only. In the normal enteric nervous system, myenteric ganglia modulate the parasympathetic innervation of the sacral roots S2-S4. The absence of myenteric ganglia in Hirschsprung's disease results in massively increased parasympathetic activity with abundant acetylcholine release and pseudo-obstruction in the aganglionic segment. This can be demonstrated in an enzyme histochemical reaction for acetylcholinesterase on frozen sections, which is sufficient to diagnose the classical disease in rectal mucosal biopsies. In ultrashort Hirschsprung's disease, increased acetylcholinesterase activity is demonstrable only in nerve fibres of the muscularis mucosae and submucosa, but not the lamina propria mucosae. Submucosal and myenteric ganglia are physiologically scarce in the most distal rectum; absence of ganglia in a biopsy of the rectoanal transition must not be (wrongly) interpreted as ultrashort Hirschsprung's disease. Therefore, a diagnosis of ultrashort Hirschsprung's disease can be made exclusively using an enzyme histochemical reaction for acetylcholinesterase.

Hirschsprung's disease constitutes a neural crest stem cell disorder (neurocristopathy) which is caused by absent or malfunctional intestinal intramural ganglion cells. The rostral extension of the aganglionic segment is variable. Hirschsprung's disease can be classified into type 1 (short segment) and type 2 (long segment) forms. It is limited to the gastrointestinal tract, but may occur in the syndromal context of manifold genetic diseases in 12% of patients. The prevalence is 1:5,000 with a distinct male predominance of 4-5:1. Numerous genes and non-coding polymorphous DNA sequence variants are involved in the pathogenesis of Hirschsprung's disease. The most important gene is RET. Susceptibility loci on 3p21, 9q31 and 19q12 interact with this gene. Downstream of RET, two new genes, GALNACT-2 and RASGEF1A, have also been identified. A recently described, frequent, non-coding RET variant, RET+3, is significantly associated with susceptibility to Hirschsprung's disease and carries a 20-fold increased risk of contracting the disease compared to rarer alleles.

The proto-oncogene RET is the major gene responsible for Hirschsprung's disease (HSCR), with RET mutations also implied in different pathologies. A variety of mutations of the RET proto-oncogene have been detected in HSCR patients. Special attention should be paid to rare patients who carry mutations of one of the critical cysteine residues of these exons, known to predispose to MEN2A. In these cases, HSCR can be associated with the development of neuroendocrine tumors such as medullary thyroid carcinoma (MTC) or MEN2A, for which a prophylactic thyroidectomy is advisable in the presence of a tumor causing RET mutation. In combined MEN2A/HSCR families, RET gene testing, tumor screening and prophylactic thyroidectomy are indicated as in MEN2A. The multigenic origin of HSCR and the absence of a "standard" RET mutation associated with HSCR currently make a routine molecular diagnosis impossible.

Stem cells are self-renewing cells with the potential to generate different cell types. The human organism depends on stem cells for organ development during embryogenesis. Upon completion of organogenesis, stem cells are also necessary for organ maintenance ("homeostasis") and for tissue regeneration. In view of the manifold functions of stem cells, it is not surprising that their malfunction results in diseases like Hirschsprung's disease, a disorder of the enteric nervous system of complex etiology. Potential stem cell application for the regeneration of diseased organs, such as the enteric nervous system in Hirschsprung's disease, is currently a focus of intense research.

Hirschsprung's disease (HD, aganglionosis) is the most important form of congenital disturbance of intestinal innervation, requiring surgical intervention. Furthermore, hypoganglionosis of the transitional zone forms the most significant factor in morbidity. Pre-operative definition of the length of neuronally disturbed segment is still a diagnostic challenge for both clinical physician and pathologist. Enzyme histochemical studies form the method of choice, but certain limitations in their use must be observed. Other dysganglionoses, particularly the so-called "Intestinal Neuronal Dysplasia" (IND) cannot-because of an excessive overlapping with age-correlated normal values-unequivocally be defined as an entity on its own. The only exception to this, is the ganglionic neuromatosis, which arises as part of a genetic illness.

Three cases of latex anaphylaxis occurring during surgery are reported. Sudden cardiorespiratory collapse 40 to 90 minutes after induction of anaesthesia was treated with oxygen, crystalloid solution, adrenaline and methylprednisolone. Laboratory findings showed markedly elevated antibodies against latex postoperatively. All three patients had anorectal malformations. As children with malformations have to be operated on in early childhood, they have a high risk of developing antibodies against latex. Primary prophylaxis requires a general avoidance of latex products in children with malformations from the time of birth on.

The gastrointestinal tract contains the largest amount of nerve cells apart from the central nervous system constituting together with glial cells the enteric nervous system (ENS). The morphology of the ENS is characterized by intramurally located ganglionated and non-ganglionated plexus of different structure. The diversity of neurotransmitters synthesized by the different nerve cell types as well as the complex neuronal circuits establish the basis for the mediation of a coordinated intestinal motility. Subsequently abnormalities of the ENS may cause severe constipation. The most acknowledged intestinal innervation disorder represents aganglionosis (Hirschsprung's disease) characterized by the absence of intramural nerve cells and the hypertrophy of nerve fiber bundles within the affected intestinal segment. Non-aganglionic intestinal innervation disorders include intestinal neuronal dysplasia (IND), hypoganglionosis and heterotopic ganglia. The pathogenesis of intestinal neuronal malformations is mainly attributed to development disorders of the ENS, in part caused by genetic defects. Furthermore, the ENS can sustain damage during the postnatal period by ischemic, inflammatory, autoimmunological processes or neurotoxic agents. The histopathological diagnosis of intestinal innervation disorders is achieved by enzyme- and immunohistochemical methods. The examination of the ENS can be carried out on mucosal, deep submucosal or full-thickness biopsies using serial transverse sections as well as on intestinal whole-mount preparations allowing a three-dimensional demonstration and assessment of the intramural plexus. Structural abnormalities of the myenteric and submucosal plexus and an abnormal content of neurotransmitters have been considered to be responsible for primary chronic constipation. However, until now no unified pathophysiological concept has been established due to the partly contradictory findings. Therefore, an important goal in patients with chronic constipation should be a detailed quantitative and qualitative assessment of the underlying neurohistopathology. The correlation of these data with functional parameters of intestinal motility may represent an useful tool for the differential diagnostic and therapeutic considerations.

Three causes of constipation are known: Chagas' disease, congenital megacolon (Hirschsprung's disease) and continent obstipation. Those diseases are rare, they can be treated successfully by drugs, surgery or psychotherapy. More common is the idiopathic chronic constipation, observed manly in females. A frequent cause is the laxative abuse for many years. The possible etiologic factors are discussed. Based on the fact, that constipation never occurs in patients with a colostomy, reasons for the development of chronic idiopathic constipation are presumed in a disturbance in the distal colon and the anorectum. A possible explanation for the malfunction of defecation could be a different calibre between the usually tight pelvic colon and the wide rectum. In contrast to the apolar structure of the large bowel, the rectum shows a polar fibrous configuration. An additional disorder in the feedback mechanism between continence and defecation could impede the bowel passage. Because of these observations and thoughts, we performed a deep resection of the rectum in 18 patients instead of resecting the dilated and elongated colon. All patients operated that way experienced a major improvement of their bowel function. Postoperatively the bowel movements were regular and normal.

Severe constipation in adults with megarectum may be a manifestation of Hirschsprung's disease or idiopathic megarectum. The differential diagnosis is discussed in the light of two case histories. Total abdominal proctectomy with coloanal anastomosis eliminated the aganglionic rectal segment in Hirschsprung's disease and the adynamic distal colorectum of idiopathic megarectum respectively. The surgical and functional results of a hand-sewn transanal end-to-end-anastomosis were excellent in both patients.

We studied retrospectively 210 anorectal manometries of constipated children. Of the 87 patients with an anal fissure or a functional constipation, 83 had normal sphincter relaxation. All of the 23 patients with Hirschsprung's disease lacked the sphincter relaxation, as well as 22 of the patients with a dysganglionosis. Eleven patients with innervation defects showed pathologic sphincter contractions. Anorectal manometry is a valuable tool to differentiate between innervation defects and constipation of other etiologies.

In a prospective study 106 children with intestinal neuronal malformations underwent intestinal transit-time studies. In only 50% of the children with intestinal neuronal dysplasia type B or immature ganglia was the transit time prolonged. On the contrary, hypoganglionosis and heterotopia of the submucous plexus led to severe transport disorders with subsequent bowel resection.

Anal sphinctermyectomy according to Lynn is an established therapy for chronic constipation in children. However, no consensus on indications exists and, according to the literature, results are contradictory. In order to clarify this problem, 33 children were examined and divided into two groups: I (n = 12) chronic constipation, and II (n = 21) dysganglionosis. All children were treated conservatively for at least a 6-month period and showed elevated anal resting tone in manometry. The operative results were assessed by anorectal manometry and a physical examination; subjective opinion was evaluated using a questionnaire. Anorectal manometry showed a marked decrease of anal resting tone of 30%, correlating to subjective relief of the symptoms.

Morpho- und histometric investigations of brains, pituitary and thyroid glands as well as thyroid-related functional parameters in the blood of purebred and hybrid rabbits revealed a predisposition to hypothyreotic conditions in homozygous, megacolon-prone genotypes. In addition to this also a hypoganglionotic state in different gut wall localizations was confirmed; pituitary traits however did not indicate a primary contribution of this gland to the syndrome, though some alterations were found, which are interpreted as secondary sv. symptomatic. Gender influences varied hormonal characteristics and disease manifestations too: A dramatic fall in severely diseased does with respect to T3-concentration as well as a seemingly more inactive thyroid gland compared to bucks underline hormonal influences. As a consequence of these results it is concluded, that hybridisation within spotted rabbits does not amend the inclination to megacolon in animals homozygous for the K (En) gene, though it may influence its manifestation.

The lethal white foal syndrome (congenital intestinal aganglionosis) was diagnosed by history, clinical signs and pathological findings in a female foal, born in March 1992, that was an offspring of two overo-spotted paint horses. The syndrome is a congenital innervation defect of the gastrointestinal tract. A literature review of this condition, relatively unknown in Germany, is given.

Paediatric surgeons are engaged in different causes of chronic constipation. Aganglionosis usually needs surgical therapy, but in dysganglionosis a distinct differentiation is necessary between patients sufficiently treated by conservative methods and others requiring surgery. Sometimes the operation seems to be an "ultima ratio" in these patients. Otherwise surgery can be necessary early in enterocolitis, ileus or toxic megacolon. In the spectrum of anal malformations constipation may be a primary symptom (anal ectopia, anal stenosis, low anal atresia with anocutaneous fistula) or appears as a post-operative complication (intermediate or high anal atresia). In secondary megacolon, surgery is performed to remove the result of therapeutic negation over many years. The operation may be the supposition to follow up with conservative treatment. In the management of constipated patients an exact diagnostic clarification has a central position. This especially includes anorectal manometry, x-ray examination with contrast medium application and defaecography and as last rectal biopsy.

The clinical disease pattern of an "acute abdomen" is by no means rare in newborn and very young infants and always signals an emergency situation. Besides inflammatory causes, congenital anomalies are among the most prominent reasons responsible for this condition. The example of 3 own patients serves to illustrate the disease pattern of Hirschsprung's disease, which is discussed with special reference to neonatology.

A case of Ehlers-Danlos syndrome is reported, which was associated with mental retardation and early infantile autism. The patient died at the age of 19 by ectasy of the stomach as the result of extreme aerophagy causing a megacolon and by compression so finally resulting in a mechanical ileus. Investigation of the cerebellum revealed a significant rarefication and diminuation of the Purkinjè cells as well as the cells of the stratum granulare in the lobuli VI and VII, obviously due to a genetically determined malformation.

Rectal biopsies of 5 children with Hirschsprung's disease and biopsies of 41 patients with chronic constipation of other causes, such as neuronal intestinal dysplasia, hypoganglionosis and chronic intestinal pseudo-obstruction (CIPSO), were investigated, using a monoclonal antibody against synaptophysin. Electron microscopy was performed in some cases. Synaptophysin, which stained adrenergic, cholinergic and neuroendocrine structures, as well, consequently, was not a suitable marker for one particular transmitter system. Normo-, hypo- and hyperganglionotic submucous plexuses were reliably stained. Hypertrophic submucosal nerve fibers, characteristic of Hirschsprung's disease, were of poor synaptophysin positivity, whereas acetylcholinesterase-positive mucosal nerve fibers exhibited stronger immunoreactivity. A comparable but regionally varying staining reaction in mucosal nerve fibers was found in CIPSO cases. Mucosal portions of histologically normal biopsies were synaptophysin-negative. Synaptophysin antibodies may support acetylcholinesterase investigation and thus are useful under diagnostic aspects. However, they are practicable neither for better distinction in differential diagnosis of Hirschsprung's disease nor for pathogenetic research.

This case report concerns a 53-year old woman suffering from recurrent spastic pain and a painful "resistance" in the left lower bowel for the last 30 years. Earlier clinical investigations including endoscopy and laparoscopy did not yield any results. In a recent investigation, only sonography showed wall thickening and an echo-poor wall pattern of the sigmoid colon indicating this to be the site of painful resistance. Resection of the sigmoid colon was performed. Histologically a slight hypogangliosis of the colon and muscular hypertrophy were detected (as the only pathological signs). The patient was free from symptoms since operation. This case report proves that ultrasound may yield pointers (or confirm the diagnosis) in unclear abdominal diseases.

In patients with primary chronic constipation (n = 18) and diverticulosis of the sigmoid (n = 17) biopsies were examined enzyme-histochemically and the diagnosis of neuronal colonic dysplasia of the rectosigmoid was established. In eleven controls however a normal innervation was observed (p less than 0.001). Patients with neuronal colonic dysplasia usually failed to respond to conservative methods of treatment. Indication for surgery depended upon the duration and severity of the symptoms. The actual treatment--partial lateral submucous sphincterotomy, resection of the sigmoid colon or subtotal colectomy--was determined by the extent of the morphologically and functionally altered intestinal segment.

Report about a 17 1/2 year-old girl with severe mental retardation, dwarfism, hypogenitalism and short segment type of HIRSCHSPRUNG's disease, abortive SMITH-LEMLI-OPITZ syndrome is supposed. Literature about etiology and genetics of HIRSCHSPRUNG's disease is reviewed.

Since 1987 we perform a new technique of colorectal anastomosis in 6 babies resected because of severe Hirschsprung's disease. The operation was done electively in the seventh to eight month of age. In the method of the so-called compression anastomosis the instrument is inserted through the anorectal canal at the head fitted with two plastic rings (see illustrations). In the rectal stump the instrument is opened up, the rectal bowel edge is slipped over the distal ring. The prepared proximal bowel edge is slipped over the second white coloured ring. The rings are approached to one another and the instrument is released. The knife on the inside cuts the bowel. The two rings are then joined by means of springs. The compression anastomosis is completed. The two bowel edges are joined by compression via the two intraluminal plastic rings. These rings will pass spontaneously with the faeces days after operation. The diameter of the rings is 18 mm. Different diameters are available. Our good experiences in more than 160 compression anastomoses in colorectal surgery of adults encouraged us to use the method also in children. We saw one complication of a rectovaginal fistula 4 weeks after the operation followed by a severe stenosis of the anastomosis. The passing of the plastic rings was without any problem in all the cases. In the follow-up a bouginage was required only in the case mentioned above.

Neuronal intestinal dysplasia is defined as a structural disorder of the innervation of the gut which clinically resembles Hirschsprung's disease. Between 1977 and 1988 12 patients were diagnosed by enzyme histochemistry. In 3 of these patients Hirschsprung's disease was associated. Constipation was the main symptom in 6 patients with neuronal intestinal disease and in all three patients with associated Hirschsprung's disease. The other patients firstly presented with an enterocolitis, a congenital atresia of the jejunum and a chronic enteritis with malabsorption. The wide clinical variability and the lack of a clear therapeutic management valid for all patients is conspicuous.

A premature infant with terminal ileal atresia and iatrogenic bowel perforation with peritonitis developed secondary hypoganglionosis and aganglionosis of the small bowel and colon leading to loss of bowel function with fatal outcome.

Constipation of all degrees is a frequent complaint in childhood. Differentiation between constipation with or without normal ganglia necessitates the following investigations: clinical examination, manometry, rectoscopy, rectal mucosal biopsy, rectal full thickness biopsy. The technique of these investigations as well as their risks are discussed.

It is demonstrated by 3 examples--the relaxation reflex of the internal sphincter, the aganglionic segment in Hirschsprung's disease and intestinal neuronal dysplasia--that a clinical, manometric or roentgenological condition of the intestine can often only be explained in correlation with histochemical or pharmacodynamic results. Some other manometrically detectable parameters such as propulsion or the adaption reaction should be studied in the future.

Pseudomembranous colitis (PMC) is a potentially fatal complication in Hirschsprung's disease. The pathogenesis of PMC which usually takes a fulminant course, is obscure. The disease generally is associated with antibiotic therapy. We describe the clinical course and the pathological findings in a 7 1/2 months old infant with Hirschsprung's disease after surgical treatment. The pseudomembranous colitis of the patient with letal consequence is considered to be connected with antibiotic therapy.

Reports on zonal aganglionosis of the bowel are very rare and the few cases reported concern colon and rectum. We present a case of segmental aganglionosis of the jejunum in a 2-months-old boy. He had to be operated upon twice because of an ileus of the short bowel. At the second operation, a 10 cm long narrow segment of the jejunum was resected. The histological examination revealed a segmental aganglionosis of the plexus myentericus. Possible causes of this rare zonal aganglionosis could be: 1. Local damage of the plexus myentericus through anoxia. 2. Primary abnormity in the gastrointestinal anlage. 3. An intrauterine inflammation. 4. A double migration and development gradient of the precursors of the neuroblasts, from each end to the middle of the gut. A defect in the microenvironment of the enteric neurons would result in their failure in differentiation. This possible explanation would challenge the accepted theory of pathogenesis of colonic aganglionosis.

Regarding the great number and the possible consequences for the patient it's surprising that there is almost no discussion concerning wrong diagnoses in medicine. Based on the experience of a working team at a center for general pediatric surgery we tried to recognize the most common mechanisms leading to wrong or insufficient diagnoses. For better illustration we describe the histories of six patients; in their cases the diagnostic errors could probably have been avoided by an exact examination procedure. One way to decrease pitfalls in daily medicin life seems to be the reflexion upon the errors and try to minimize them and their sources.

Re-assessment was made of 21 children roughly 14 years after operations for Hirschsprung's disease, using Rehbein's technique. Mortality accounted for ten per cent. Relaparotomy was necessary in 20 per cent of the cases. Anastomotic leakage was recorded from 8 per cent and small bowel obstruction due to adhesions from 7 per cent. Obstipation, diarrhoea, and fecal soiling were recorded from 5 per cent each. None of the children exhibited fecal or urinary incontinence. These results are compared with a statistical record on follow-up checks made between 8 and 27 years after surgery.

Vasoactive intestinal peptide (VIP), first isolated from the gut, was originally considered a candidate gastrointestinal hormone. Since about 1975, however, it has become increasingly clear that it is primarily a neurotransmitter or neuromodulator and that it exerts its functions mainly by local release from nerve endings. VIP plays a hormonal role only when it is released in large amounts from a tumor, with a consequent overflow into the circulation and grossly elevated plasma concentrations of the peptide. Moderately increased VIP plasma and tissue concentrations that cause mainly local effects are found in intestinal ischemia. Crohn's disease and some other chronic inflammatory diseases of the bowel. VIP is also measured in increased amounts in the normal fetus and neonate, where it may play an important physiological role. Such an increase of VIP levels in the circulation could enhance perfusion and metabolic activity of tissues during their rapid-growth period. On the other hand, disorders with a disturbed VIP function such as achalasia and Hirschsprung's disease and possibly also asthma and cystic fibrosis seem to be characterized mainly by a derangement of smooth muscle activity and/or exocrine secretion. Considering this list of disorders where VIP has either a proven or suspected role, it is easy to imagine the significance of this peptide in pediatric pathophysiology.