Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare, congenital, and generally fatal cause of intestinal obstruction in the newborn. The syndrome was first described in 1976 by Berdon et al. (1) and is characterized by abdominal distention, caused by a distended, nonobstructed urinary bladder, a microcolon, and decreased or absent intestinal peristalsis. Usually incomplete intestinal rotation and shortened small bowel are associated. The etiology of this syndrome is not fully understood. Puri et al. (2) in 1983 demonstrated vacuolar degenerative changes in the smooth muscle cells in the bowel and bladder of patients with MMIHS and suggested that a degenerative disease of smooth muscle cells may be the cause. Often ganglion cells and nerve fibers in the myenteric and submucous plexuses were normal in number and appearance, but abnormalities in the distribution of nerve fibers and ganglion cells were also observed in some patients. This report reviews the clinical, radiological, surgical and pathologic findings in all reported cases of this syndrome. CLINICAL MATERIAL A review of the literature showed that 75 cases of MMIHS have been reported to date. (1-27,28-54) These cases were seen in 61 female and 14 male infants (ratio 4:1). In 2 cases pregnancy was terminated after ultrasonography detected the syndrome, which was confirmed at autopsy in both cases (34,36). In 1 case pregnancy ended in miscarriage (33). Ten patients were alive, the oldest being 7 years old (38). Nine were being maintained by total parenteral nutrition. PRENATAL DIAGNOSIS Thirty-two previous reports have described fetal ultrasound findings associated with MMIHS. The most frequent finding was enlarged bladder (88%), with hydronephrosis seen in 17 patients (53%). Normal amniotic fluid volume was revealed in 18 cases (56%), increased volume in 11 (34%), and decreased volume in 3 (10%). In 3 cases (10%) (19,36,52) abdominal distention caused by dilated stomach was detected. Three cases of oligohydramnios during the second and early third trimesters were reported (13,23,46), probably related to the functional bladder obstruction. In 1 case (46), oligohydramnios changed in polyhydramnios at the end of the third trimester. Serial obstetrical ultrasonography showed that the earliest finding in MMIHS is enlarged bladder, detectable from 16 weeks of gestational age (46,47,52). A later finding is hydronephrosis, caused by the functional obstruction of the bladder. Usually polyhydramnios develops late, appearing during the third trimester. GESTATION AND DELIVERY Although age was mentioned in only 24 out of 75 reports, advanced maternal age did not appear to be involved in MMIHS. The maternal age ranged from 18 to 36 years (mean 27 years). In 2 patients, exposure to drugs (clomiphene [31], scopolamine, trimethoprim-sulfadiazine, and dypirone [41]) during the first weeks of gestation was reported. The duration of pregnancy was reported in 49 cases. Twenty-six patients (54%) were born at term, 11 (22%) at 36 to 39 weeks of gestation, 11 (22%) at 32 to 35 weeks, and 1 (2%) at 31 weeks. Dystocis delivery caused by abdominal distention was reported in seven cases. In four cases cesarean section was required (14,33,36,45), and in three cases the bladder was so distended that the baby could only be delivered vaginally after removal of 250, 500, and 650 ml of urine, respectively, from fetal bladder by paracentesis (2,39,43). The mean birth weight was normal (3 kg) for gestational age. HEREDITY Ten sets of siblings affected with MMIHS were reported. Nine families had two affected siblings and one had three. Four sets of affected siblings occurred to consanguineous parents (20,29,36,37). In another case (52) an affected child was born to a member of the family reported by Penman, and consanguinity was also present in these parents. In three further cases an elder sibling of the affected child died just after birth because of intestinal obstruction (5) or multiple abnormalities (34,54); in another case a sibling of the patient was affected by prune-belly syndrome (16). The occurrence of MMIHS in ten sets of affected siblings together with consanguinity in four sets of parents suggest an autosomal recessive pattern of inheritance (29,36,52). CLINICAL SYMPTOMS The clinical symptoms of MMIHS are similar to other neonatal intestinal obstructions. Characterized by abdominal distention, bile-stained vomiting, and absent or decreased bowel sounds, abdominal distention was a constant and early finding. A consequence of the distended, nonobstructed urinary bladder, it was relieved by catheterization. Of 75 cases, 34 had bilious vomiting, and failure to pass meconium was clearly reported in only 11 cases. In 12 cases a lax abdominal wall was noted (1,4,5,16,18,19,29,36,44,46). Most patients were not able to void the bladder spontaneously. Vesical globe and dribbling incontinence were common findings. RADIOLOGIC FINDINGS Radiologic evaluation usually suggested the diagnosis of MMIHS. Plain abdominal films showed either dilated small bowel loops or a gasless abdomen with evident gastric bubble. An enlarged urinary bladder was present in all patients who had cystography (Fig. 1) or ultrasonography. Cystography showed vesicoureteral reflux in 3 patients (6,10,19) and an urachal remnant in 1 case (16). Intravenous urography and ultrasonography detected unilateral or bilateral hydronephrosis in 53 (Fig. 2) patients. In 1 case ultrasonography detected a dysplastic right kidney (44). Twenty-three patients had an upper gastrointestinal series both before and after laparotomy: hypo- or aperistalsis in stomach, duodenum, and small bowel was a constantly detected symptom. In 3 cases reverse peristalsis from small bowel into the stomach was also observed (1,11). In 2 cases hypoperistalsis was associated with gastroesophageal reflux (7,28), and in 1 case the esophagus was aperistaltic (46). Barium enema showed microcolon (Fig. 3) in all 39 patients in whom this study was performed; in 26 cases malrotation was associated. ASSOCIATED ABNORMALITIES Associated abnormalities were reported in 10 patients. In 1, patient the abnormalities were cleft palate, syndromic facies, and malformations of limbs were associated (29); in another, cleft palate and cryptorchidism (26); in another cardiopathy and cryptorchidism (6). Cases of omphalocele (9,13), cardiopathy (45), blindness and partial deafness (48), unilateral dysplastic kidney (44), urachal remnant (16), and syndromic facies (29) were also described. STUDIES ON GASTROINTESTINAL MOTILITY Some authors (2,18,25,40,49) have reported manometric and electrophysiologic studies on gastrointestinal motility in patients with MMIHS. In all cases the occurrence of interdigestive migrating contractions was much less frequent or was absent, and the amplitude was significantly decreased. In one case esophageal motility was perturbed (43). Kubota (40) studied in vitro the pattern of spontaneous activity and innervation in some specimens of muscle from a case of MMIHS: autonomic inhibitory input to the smooth muscle of the small bowel was decreased. Anorectal manometry was performed in three cases: in two cases findings were normal; (18,25) in one case rectosphincteric reflex was present, but atypical (39). Several authors (1,2,7,10-12,21,28,39,44,45,54) used prokinetics drugs and gastrointestinal hormones without success. SURGICAL OR AUTOPSY FINDINGS Megacystis and microcolon were the two most frequent findings at surgery or autopsy and were present in all patients. Short-bowel syndrome was found in 22 cases, dilated proximal small bowel in 9, segmental stenosis of the small bowel in 3, duodenal web in 1, Meckel's diverticulum in 1. Malrotation was found in a total of 50 cases. Although surgical management was not mentioned in several reports, 51 patients (70%) underwent one or more surgical procedures. Different kinds of interventions were performed: gastrostomy, jejunostomy, ileostomy, cecostomy, segmental resection of jejunum and ileum, lysis of adhesions, and internal sphincter myectomy. Surgical manipulation of the gastrointestinal tract generally has been unsuccessful, and in most patients total parenteral nutrition was required. In 21 patients vesicostomy was performed to decompress the urinary tract and to preserve renal function. HISTOLOGIC FINDINGS Histologic studies of the myenteric and submucous plexuses were reported in 53 out of 75 cases (Table 1). In 42 the ganglion cells were normal in appearance and number. Young (12) found 1 case of diffuse hypoganglionosis and Vezina (5) found aganglionic zones together with hyperganglionic zones in another case. Immature ganglion cells were found by Manco (21) in 1 case. Kirtane (20) found 2 cases with immature ganglion cells and hypoganglionosis. Krook (7) found both aganglionic zones and immature zones throughout the bowel. In 4 cases hyperganglionosis (11,15,53) was evident. Bindl (35) reported neuronal intestinal dysplasia type B in 1 case. In 16 cases observations on the nerve fibers in the intestinal plexuses were reported: In 9 cases the appearance was normal, in 6 the nerve fibers were observed to be increased, and in 1 they were decreased. Taguchi (39) noted an abnormal peptidergic innervation caused by a decrease in vasoactive intestinal polypeptide and peptide histidine methionine fibers and an increase in substance P and leucine-enkephalin fibers. At autopsy, neonatal axonal dystrophy was found in a patient with previous findings of hypertrophic nerve bundles and dystrophic neurites in the rectal biopsy (48). Recently we observed hyperganglionosis of the submucous and myenteric plexuses, giant ganglia, and ectopic ganglia throughout the entire gastrointestinal tract in 2 patients (53). Acetylcholinesterase staining and neural cell adhesion molecule (NCAM) staining of the uterus in 1 patient demonstrated a large number of ganglioneuromas (Fig. 4). The majority of reports do not mention the histologic findings in the muscle layers of bowel and bladder wall. Nevertheless some authors found significant abnormalities (Table 2). In 9 cases (2,19,33,34,42,53) thinning of the longitudinal muscle was found on light microscopy. Electron microscopy showed vacuolar degeneration in the center of the smooth muscle of the bowel in 5 cases (2,33,34,44) and of the bladder in 5 cases (Fig. 5)(2,33,34,53). Connective tissue proliferation was found in the bowel in 4 cases (15,53) and in the bladder in 4 cases (34,42,50). In 3 more cases the bladder showed elastosis (12,19). In 2 of our recent patients electron microscopy revealed vacuolar degeneration of smooth cells in the muscle layers of the bowel and the bladder in addition to neuronal abnormalities (53). OUTCOME The outcome is reported in 72 cases out of 75. Generally fatal, MMIHS caused the deaths of 59 out of 69 live newborn (86%). Twenty-two deaths (32%) were recorded before the end of the first month of age, 22 (32%) during the period after the first month and before the end of the sixth month, and 50 (72%) within 1 year of age. Death was mostly caused by postoperative complications, sepsis, and liver failure. A patient suddenly died at 40 months of age because of heart block caused by a cardiac rhabdomyoma (45). Ten children were alive: of those, eight were older than 1 year. Only one patient, a 4-year-old boy, was able to assume full oral feeding after a 7-month treatment involving total parenteral nutrition (26). Nine patients were still dependent on total parenteral nutrition: The oldest one was 7 years old (38), and during her life 25 central venous catheters had been inserted. DISCUSSION The etiology of MMIHS is unknown. The occurrence of this condition in siblings, together with a history of consanguinity in parents, suggests an autosomal recessive pattern of inheritance for this syndrome. Penman and Lilford have proposed that MMIHS is the result of an autosomal, recessive end-organ receptor defect confined to the smooth muscle of the urinary and gastrointestinal tracts. It is therefore recommended that a prenatal ultrasound examination be performed in subsequent pregnancies. The ultrasonographic findings associated with MMIHS include fetal megacystis, hydronephrosis, hydroureter, normal or decreased amniotic fluid in the second trimester, and polyhydramnios in late gestation. Recognition of these ultrasonographic findings, particularly in the female fetus should permit the prenatal identification of MMIHS (46). However, accurate ultrasonographic diagnosis of MMIHS may only be possible late in pregnancy when megacystis has developed. Hypoperistalsis in MMIHS is variously attributed to visceral myopathy; (2) imbalance in gut peptides; (39) defective autonomic inhibitory neuroeffector activity; (40) and, more recently, neuroaxonal dystrophy (48). Srikanth et al. have recently speculated that the initial event in the pathogenesis of MMIHS is an intramural inflammatory process that affects the gastrointestinal and urinary tracts, leading to extensive fibrosis that destroys the intestinal neural network, producing hypoperistalsis. In the vast majority of reported cases of MMIHS, little attention was given to a detailed histopathologic examination of the bowel and urinary bladder. Future studies using immunohistochemical and electromicroscopic techniques should give further insights into the pathogenesis of this condition. The management of patients with MMIHS is frustrating. A number of prokinetic drugs and gastrointestinal hormones have been tried without success. Surgical manipulation of the gastrointestinal tract has generally been unsuccessful. The outcome of this condition is generally fatal; only 10 of the 75 reported patients are alive and 9 of those are dependent on total parenteral nutrition. The need for surgical intervention should be made carefully and individualized, in that most explorations have not been helpful and probably are not necessary.FIG. 1: . Micturating cystogram showing massively enlarged urinary bladder in a 1-day-old female infant.FIG. 2: . Urogram showing bilateral hydronephrosis in a newborn with megacystis-microcolon-intestinal hypoperistalsis syndrome.FIG. 3: . Radiograph with barium enema showing microcolon. Note contrast in the enlarged urinary bladder from cystography performed 8 hours previously.FIG. 4: . A uterus with acetylcholinestrase staining showing ganglioneuromas (original magnification ×200)FIG. 5: . An ileum in an electron photomicrograph showing vacuolar changes in the center of smooth muscle cells. Note excessive amount of collagen between muscle cells (original magnification ×6,800)