eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Congenital Microvillus Atrophy

Author: Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital
Coauthor(s): Agostino Nocerino, MD, PhD, Chief of Pediatric Oncology, Department of Pediatrics, University of Udine, Italy
Contributor Information and Disclosures

Updated: Nov 17, 2008

Introduction

Background

Microvillus atrophy is the leading cause of secretory diarrhea in the first weeks of life. A group of infants with a familial enteropathy characterized by protracted diarrhea from birth and villus hypoplastic atrophy had been described in 1978 by Davidson et al.¹ The term microvillus atrophy was first used to identify the disease in 1982. The typical clinical presentation is watery profuse secretory diarrhea starting in the first hours of life. The peak age of onset is the neonatal period. Although later-onset cases have been described, cases have never been described beyond the first few months of life.

Three variants of the disease have been identified: congenital microvillus atrophy, late-onset microvillus atrophy, and atypical microvillus atrophy.

In congenital microvillus atrophy, diarrhea starts in the first days of life and is immediately life threatening. Oral alimentation in nutritionally significant amounts is impossible. In late-onset microvillus atrophy, diarrhea starts later in life, usually in the second month. Diarrhea tends to be less severe than in the other form, and some alimentation is possible. A few cases have been termed atypical microvillus atrophy, in which the onset can be congenital or late, but the histologic picture is different.

The hallmark of the disease is the electron microscopic finding of disrupted enterocytic microvilli (ie, digitations of the apical membrane of the intestinal epithelial cell protruding into the lumen) and the appearance of characteristic inclusion vacuoles, the inner surfaces of which are lined by typical microvilli. Both lesions are seen only on electronic microscopy. In a notable percentage of consanguineous families, more than one child is affected; therefore, the disease appears to be transmitted as an autosomal recessive trait.

Pathophysiology

The pathogenesis of the disease remains unknown. Severe perturbation of the microvillar cytoskeleton may disrupt the transport of brush border components that have to be assembled at the apical membrane.

Biopsy samples from the small intestine of 2 infants with congenital microvillus atrophy were examined to analyze the membrane protein of the brush border. The samples demonstrated striking diminutions of the myosin bands. The genetic defect appears likely to cause abnormal binding of the myosin to the actin cable. In one patient with late-onset microvillus atrophy, the molecular defect involved a different protein, supposedly identified as vinculin.

Other studies have suggested an alternative hypothesis, namely that a defect in the autophagocytosis pathway²  or an increase in enterocyte apoptosis and proliferation³  explains the abnormalities observed in congenital microvillous disease.

The postulated abnormality in the cytoskeleton causes a block in exocytosis, mainly of periodic acid-Schiff (PAS)–positive material (eg, polysaccharides, glycoproteins, glycolipids, neutral mucopolysaccharides). As a consequence, small secretory granules that contain a PAS-positive material accumulate in the apical cytoplasm of epithelial cells.

Substantial progress has been made in identifying the molecular nature of the secretory granules. A neutral, blood group antigen–positive glycosubstance that contains acetylated sialic acid accumulates in these granules. Acetylated sialic acid has been identified as a common component of the glycocalyx, suggesting that microvillus atrophy involves a defect in exocytosis of the glycocalyx or some of its components. To support this possibility, immunoreactivity against glycocalyx is found in secretory granules in microvillus atrophy.

The microvilli in the brush border are scanty, disorganized, and short.

Because of these alterations, mature enterocytes inefficiently absorb ions and nutrients, causing a malabsorption syndrome; however, the diarrhea is caused mainly by active secretion of water and electrolytes in the intestinal lumen (secretory diarrhea). The pathogenesis of the secretory diarrhea is unknown; it is assumed to result from an unbalance between decreased absorption and unaltered secretion. Data suggest that the morphologic changes of the disease result in a secondary decrease in the amount of messenger RNA (mRNA) encoding for apical membrane-transport systems.

Frequency

United States

A cluster of cases from the Navajo reservation in northern Arizona suggests an incidence as high as 1 case per 12,000 live births.

International

A survey completed in 1987 among centers known for their involvement in pediatric gastroenterology identified more than 30 cases worldwide. Additional cases were later published. Typical congenital microvillus atrophy accounts for 80% of cases. The remaining 20% are due to mainly late-onset disease.

Mortality/Morbidity

The survival of patients with typical cases depends on total parenteral nutrition (TPN).

• Most infants of early series died when aged 3-9 months. The leading causes of death were dehydration, malnutrition, and sepsis.
• Successful outcomes of small intestinal transplantation have been reported, and evidence suggests that an early transplant might be beneficial.^4,5,6
• However, the prognosis remains poor, with most patients dying by the second decade of life as a result of complications of parenteral alimentation. Even patients who have undergone small-bowel transplantation have a mean 5-year survival rate of about 50%. Patients with late-onset microvillus atrophy appear to have an improved prognosis.

Sex

A female preponderance has been observed among the published cases, with a female-to-male ratio of 2:1.

Age

The classic form of congenital microvillus atrophy appears in the first 72 hours of life (usually on the first day) and is immediately life threatening. Late-onset microvillus atrophy starts after 6-8 weeks in a normal-appearing infant.

Clinical

History

Pregnancy and birth are usually normal in individuals with microvillus atrophy, and polyhydramnios is usually absent, in contrast to the clinical picture of patients with other causes of congenital secretory diarrhea.

• Severe diarrhea typically appears in the first days of life, usually within the first 72 hours, but a late-onset form is also known, with onset at 6-8 weeks of age.
• The stools are watery, and the stool output is 100-500 mL/kg/d when the infant is fed, a volume comparable to or higher than that observed in cholera.
• The diarrhea is of secretory type; therefore, it persists at a stable rate of 50-300 mL/kg/d despite fasting, and the electrolyte content of the stools is increased, without an osmotic gap. However, the mucosal atrophy causes osmotic diarrhea. For this reason, alimentation increases the fecal output.
• The infant rapidly becomes dehydrated unless vigorous intravenous rehydration is started.
• Microvillus atrophy is usually characterized by growth retardation and some developmental delay later in infancy. Associated abnormalities include Meckel diverticula, abdominal adhesions, inguinal hernias, renal dysplasia, an absent corpus callosum, and hydronephrosis.
• Microvillus atrophy has been reported in association with Down syndrome and aganglionic megacolon.

Physical

• The infant appears severely dehydrated.
• Growth retardation and some developmental delay are usually present.
• No other specific findings can be detected. However, the disease is associated with other abnormalities, including Meckel diverticulum, mesenteric duct remnants, craniosynostosis, abnormal vertebrae, an absent corpus callosum, and hydronephrosis.

Causes

• Microvillus atrophy is an autosomal recessive disease, the pathogenesis of which remains unclear.
• In contrast to other congenital secretory diarrheas, polyhydramnios has not been noticed. This suggests that some environmental factor triggers the disease in a newborn who previously apparently healthy.
• At least 5 patients with congenital microvillus atrophy have presented clinical and laboratory findings suggestive of dihydropyrimidinase deficiency. In 2 of these patients, the enzymatic defect was demonstrated. Whether this association can be caused by a contiguous gene syndrome remains speculative.
• The clinical course of isolated dihydropyrimidinase deficiency varies, but most patients present with neurologic signs.

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