Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

Introduction

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare and severe condition that is characterized by functional intestinal obstruction with dilated small intestine, microcolon, malrotation, decreased or absent bowel movement, and, prenatally, a massively enlarged nonobstructive urinary bladder often associated with hydroureteronephrosis. The anomaly was first described by Berdon et al. in 1976 and is also termed neonatal hollow visceral myopathy . Female fetuses are affected four to five times more often than male fetuses. In the neonate, the predominant problem is the reduced or absent bowel function and the impossibility of enteral nutrition. Kidneys and the lower urinary tract are not dysfunctional in most cases; however, secondary impairment of the urinary system owing to urethral reflux is frequent.

The usual postnatal therapeutic approaches are total parenteral nutrition combined with a trial of various prokinetic agents (which remain ineffective in most cases). Transabdominal drainage of the urinary bladder is frequently applied to preserve kidney function. Further steps are laparotomy, attempts to milk out or resect dysfunctional parts of the intestine, or drain them via ileostomy. Multiorgan transplantation is a desperate therapeutic effort to provide a viable intestine in these children. Although most authors describe MMIHS as a fatal condition with newborns surviving for only a few months with all therapeutic efforts being made, there are reports of prolonged survival up to the age of 18 years.

Disease

Definition

MMIHS is defined by the presence of a massively distended urinary bladder without lower urinary tract obstruction, a dilated small bowel, and microcolon with decreased or absent peristalsis.

Prevalence and Epidemiology

From the first description in 1976 until 2011, more than 227 cases were reported. Females are affected more often than males. Although a possible autosomal recessive inheritance pattern has been suggested based on cases with a family history or consanguinity, most cases seem to be sporadic. Whole-exome sequencing recently showed that a relevant proportion of MMIHS is caused by de novo heterozygous mutations of the gene encoding the smooth muscle gamma-2 actin, ACTG2. In this case, a recurrence risk would be approximately 1%, while in the majority of familial disease an autosomal dominant inheritance pattern has been postulated.

Moreover, these studies show that the different clinical manifestations depend on the degree of protein malfunction and differential expression of smooth muscle actins.

Etiology and Pathophysiology

Recent findings suggest that the loss of intestinal function is related to intestinal smooth muscle myopathy. Reduction or absence of actin in the circular layer of the small intestine, and vacuolic degeneration of smooth muscle cells with reduction of contractile and cytoskeleton proteins, have also been described. A dysfunctional neuronal nicotinic acetylcholine receptor and an association with chromosome 15q11 deletion are being discussed. Earlier reports suggested various changes in ganglion cells and axons of the myenteric plexus as a reason for intestinal malfunction. An inflammatory process of the intestine and urinary tract, and defects in the synthesis of collagen fibers, are other hypotheses. Similar findings have been described in megacystis, megaureter, and fetal hydronephrosis.

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