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Original Articles: Gastroenterology

Microvillous Atrophy

Atypical Presentations

Perry, Ariane*,†,‡; Bensallah, Hayet*,†,‡; Martinez-Vinson, Christine; Berrebi, Dominique*,†,‡; Arbeille, Brigitte§; Salomon, Julie||,¶; Goulet, Olivier||,¶; Marinier, Evelyne; Drunat, Séverine; Samson-Bouma, Marie-Elisabeth¶,#; Gérard, Bénédicte; Hugot, Jean-Pierre*,†,‡

Author Information
Journal of Pediatric Gastroenterology and Nutrition: December 2014 - Volume 59 - Issue 6 - p 779-785
doi: 10.1097/MPG.0000000000000526


Microvillous inclusion disease (MVID) represents 5% to 15% of intractable diarrhea (1–3). MVID was described for the first time by Davidson et al (4). Gestation is most often unremarkable (5–8). The diarrhea usually occurs within the first days of life or less often during the second month of life (9). MVID is characterized by a profuse, secretory, watery, severe diarrhea (up to 150 mL · kg−1 · day−1). The diarrhea persists all along the life, even under total parenteral nutrition (10). Some authors reported MVID-associated abnormalities including cardiac malformations, facial dysmorphia, transient neuronal dysplasia, aganglionic megacolon, Down syndrome, intrahepatic cholestasis, or hypochondroplasia (5,11–16).

Several treatments have been unsuccessfully tested including corticosteroids (12), loperamide (12,17), cromoglycate disodique, cimetidine (17), urogastrone/epidermal growth factor (18,19), and somatostatin (12,20). The only curative treatment is small bowel transplantation, often combined with liver transplantation (15,21,22). When transplanted, only 54% of the patients were weaned off parenteral nutrition (15). Two spontaneous healings have been reported in the literature (11,23).

The criterion standard for diagnosis is a combined histological analysis with light and transmission electron microscopy (TEM). Light microscopic examination of duodenal biopsies shows various degrees of villous atrophy, without local inflammation or crypt hyperplasia (10,12,17). Periodic acid-Schiff (PAS) staining shows decreased reactivity of the brush border and accumulation of PAS-positive staining material along the apical pole of enterocytes. This abnormal staining pattern is pathognomonic of the disease. Vacuolated epithelial cells can be observed (5,11,12,24). These alterations may also affect the colon (10) or the gastric mucosa (25). Immunostaining techniques directed against CD10 or CEA lead to similar results as PAS staining (24,26,27).

TEM shows microvillus inclusion bodies within the cytoplasm, often in the vicinity of lysosomes (28). Microvilli are rarefied, shortened, widened, clubbed, or fused. Microvilli are sometimes observed on the lateral membrane (4,9,12,17,28). These abnormalities mainly affect the mature enterocytes. Additional cell abnormalities include heterogeneous vesicles in microvilli-denuded areas and abundant secretory granules (10,28,29). All of these changes can also be found to a lesser extent in the colonic epithelium (17). In summary, MIVD is characterized by the association of loss of microvilli, microvillous inclusion, and secretory granules.

A genetic cause has been suspected (20,30), and Müller et al (31) found that MYO5B is the main MVID gene. This large-sized gene contains 40 exons and encodes for the 5b myosin motor protein, which is involved in membrane vesicle trafficking. Since the “princeps” article, mutations have been reported in most patients, suggesting low gene heterogeneity (32–34). Patients are usually mutated homozygotes or compound heterozygotes, confirming the recessive mode of inheritance. Myosin5b interacts with rab11a and Rab8a, and this interaction is essential for proper addressing of subapical vesicles and thus proper functioning of polarized cells (37). Thus, the main physiopathological hypothesis for MVID is a defect of exocytosis (29,35,36).

The aim of this study was to provide a clinical, histological, and genetic description of 8 new patients with MVID who were characterized by atypical presentations.



The 8 patients were recruited at Hôpital Robert Debré (n = 7) and Hôpital Necker-Enfants-Malades (n = 1), Assistance Publique-Hôpitaux de Paris, France. Their characteristics are summarized in Table 1. Parents of all of the included patients signed an informed consent.

Summary of the reported cases

Histological Analyses

Duodenal biopsies were fixed in formalin, embedded in paraffin, and stained by PAS. Immunohistochemistry was done according to standard protocols (mouse monoclonal antibody anti-CD10 ready to use, clone 56C6; Leica Biosystems, Wetzlar, Germany) using the BOND-MAX automat (Leica Biosystems). For TEM, biopsies were fixed in 2.5% glutaraldeyde, washed in cacodylate buffer (0.1 mol/L) (patients 1 and 2) or phosphate buffer (patients 3–8), postfixed in 1% or 2% osmic acid in the same buffer solution, dehydrated in graded alcohols, and finally embedded in an epon mixture. Thin sections were obtained with the UCT Leica ultramicrotome, submitted to a double impregnation of uranyl acetate and lead citrate and then examined with a TEM JEOL 1010 or 1011 kV (Tokyo, Japan) with a camera Gatan ES 1000W Erlangshen (Pleasanton, CA).

Mutation Screening

DNAs were extracted from peripheral blood samples using standard methods. The MYO5B coding regions and splice sites were PCR amplified and directly sequenced using the dye terminator technique. Each sequence was examined manually and mutations were confirmed by a second round of sequences on both strains.


Patient 1 was born at 36 weeks of gestation in a meconium liquor from 2 nonconsanguineous Italian parents. Her birth weight was 2950 g. A severe watery diarrhea started on the second day of life and parenteral nutrition was quickly started. Stool output was up to 1500 mL/day when she was 21 months old. Fluid and electrolyte requirements were high, up to 220 mL · kg−1 · day−1, when she was 4 years old. Her clinical course was marked by adverse effects of parenteral nutrition including nephrocalcinosis, cholestasis, venous thrombosis, and osteoporosis. In addition to her diarrheal disease, she experienced transient humoral immunodeficiency, a dysmorphic syndrome (badly hemmed ears, chest bell, hypertelorism, left single palmar crease), an interstitial lung syndrome, severe failure to thrive (height −5 SD, weight −3 SD), and severe mental retardation. Because of these associated disorders, she was not proposed for small bowel transplantation. At present, she is 19 years old and receives a parenteral nutrition (80 mL · kg−1 · day−1, 12/24 hours every day).

At the age of 3 months, PAS staining revealed typical MVID abnormalities confined to the enterocytes of the surface epithelium and, to a lesser degree, to crypt epithelium (Fig. 1A and Supplementary Fig. 1A, Mild chorionic edema, normal intraepithelial lymphocyte counts, and frequent mitoses within the crypts were also noted. TEM showed images compatible with MVID. Two mutations were found on exons 19 and 24 (c2259-2262dup and c3163-3165dup) (Fig. 2). The first mutation was in the motor part of the protein. The second mutation (also found in patients 7 and 8) affects the part of the protein that interacts with rab proteins.

Light microscopy. Representative images are shown for patients 1 (1A), 2 (1B), 3 (1C), 4 (1D (anti-CD10 immunostaining) and (1E), 5 (1F and 1G), 6 (1H), and 8 (1I).
Schematic representation of the mutations affecting myosin 5b protein. Upper arrows indicate previously reported mutations (30–33). Lower arrows show new here reported mutations.

Patients 2 and 3 are 2 siblings from nonconsanguineous Moroccan parents. They have a sister who is affected by an agenesis of the corpus callosum. Patient 2 was born at term, after an unremarkable gestation, weighing 3290 g. Profuse secretory diarrhea began on the seventh day of life, with ionic disorders and severe dehydration. Parenteral nutrition was immediately started. At present, he is 2 years old and receives parenteral nutrition (110 mL · kg−1 · day−1, 12/24 hours, 7/7 days).

His brother was born at term (birth weight 3570 g) after a gestation marked by a hydramnios and an echogenic bowel at 34 weeks of gestation. Diarrhea began more insidiously and led to malnutrition and ionic disorders only at 6 weeks of life. He is now 1 year old and receives parenteral nutrition daily (110 mL · kg−1 · day−1). The 2 siblings developed an intrahepatic cholestasis with low γ-glutamyl transferase (GGT). Liver biopsies showed centrolobular cholestasis without fibrosis or ductular proliferation.

Histological features of the 2 siblings were similar. At the age of 2 months, duodenum biopsies (Fig. 1B and C, and Supplementary Fig. 1B and C, revealed a severe villous atrophy in duodenum, accumulation of PAS-staining material at the apex of enterocytes from the surface epithelium and the upper part of the crypts. A mild inflammatory infiltrate of the lamina propria with no increase in intraepithelial lymphocytes and an increased number of mitoses within the crypts was noted. TEM showed heterogeneous lesions of the brush border. Microvilli were shortened (<0.5 μm) and disoriented. No microvillous inclusions were seen but many secretory granules and autophagic vacuoles (Fig. 3A and B). Two MYO5B mutations were found in both siblings in exon 10 (c1222A>T) and 13 (c1582C>T). They lead to amino acid substitutions within the motor part of the protein.

Transmission electron microscopy. Representative images are shown for patients 2 (2A), 3 (2B), 5 (2C), and 8 (2D).

Patient 4 had a heavy medically charged family history: Berger disease in his father, severe deafness in his mother, and epilepsy in 2 brothers and 1 aunt. One of his brothers died in infancy owing to a similar disease (intestinal failure, facial dysmorphy, retinitis pigmentosa, severe epilepsy, cortical atrophy, mental retardation, and failure to thrive). There was no consanguinity in the family. He was born at term, after an unremarkable gestation, weighting 3360 g. Diarrhea began on the fifth day of life, with severe dehydration and parenteral nutrition requirement (160 mL · kg−1 · day−1). He also experienced hypothalamic hamartoma, sensorial deficiencies (blindness, optical atrophy, nystagmus, unilateral deafness), and severe mental retardation. At present, he is 12 years old and receives parenteral nutrition (65 mL · kg−1 · day−1 every day). He has mild growth retardation (size at −2 SD) and nephrocalcinosis.

MVID was diagnosed on the first duodenal biopsy when he was 22 days old (Fig. 1D and E and Supplementary Figs. 1D and E, Microscopic observations revealed mild partial villous atrophy. PAS-positive material accumulated at the luminal pole of upper crypt enterocytes whereas surface enterocytes were less affected. CD10—which is normally expressed at the surface of the brush border—also accumulated in the cytoplasm of the enterocytes. There was a mild inflammatory infiltrate within the lamina propria, but no increase in intraepithelial lymphocytes. Colonic biopsies were normal. TEM showed rare microvilli and vacuolization of the cytoplasm. We failed to detect MYO5B mutations (30–33).

Patient 5 was born at 40 weeks of gestation from nonconsanguineous French parents after a pregnancy marked by an intrauterine failure to thrive. He weighed 2380 g. Diarrhea began in the neonatal period in the context of a Staphylococcus aureus and an Escherichia coli K1 sepsis and severe ionic disorders. Parenteral nutrition was quickly started but could be stopped at 4 months and replaced by enteral nutrition. He presented with cholestasis with low GGT and pruritus, which were only partially improved by ursodesoxycolic acid supplementation. Liver biopsy showed mild intrahepatocyte cholestasis without biliary paucity. He had a polymalformative syndrome with facial dysmorphy, blindness (right anophthalmia, iris coloboma, left cataract, optic nerve atrophy), dolichocephaly, laryngeal palsy, deafness, brainstem hypoplasia, and mental retardation. A high-resolution karyotype was normal. Otherwise, he experienced cow's-milk–protein allergy and gastroesophagal reflux disease. At present, he is 13 years old and has a gastrostomy for nocturnal enteral nutrition (60 mL · kg−1 · day−1). He has growth retardation (height −3 SD).

Patient 5 underwent 3 duodenal biopsies showing discrete partial villous atrophy. PAS staining showed focal accumulation at the luminal pole of the enterocytes of the low villous region without inflammatory infiltrate or increased intraepithelial lymphocyte count (Fig. 1F–G and Supplementary Fig. 1F–H, TEM showed rare and isolated microvilli, with filamentous core rootlets under the terminal web, possible microvillous inclusions, vacuolization of the cytoplasm, and electron-dense vesicles (Fig. 3C and Supplementary Fig. 3, No MYO5B mutations were found.

Patient 6 was born premature at 31 weeks of gestation (weight 1645 g) from Israeli nonconsanguineous parents. Diarrhea began later, at 14 months of life, characterized by significant steatorrhea (23 g/day when he was 11 years old, 7–14 g/day when he was 14 years old). Parenteral nutrition was started only when he was 3 years old (approximately 60 mL/kg, 6/7 days). He also experienced a neonatal hydrocephaly that was treated surgically. He had normal neurological development. At present, he is 24 years old. At his last visit, when he was 20 years old, he needed parenteral nutrition 4 days/week. He had normal growth.

The diagnosis of MVID was made when he was 4 years old. Standard histology showed mild villous atrophy. Some surface enterocytes were vacuolated and a mild inflammatory infiltrate within the lamina propria was noted. PAS staining showed a focal accumulation pattern in the crypt enterocytes. The last biopsy, when he was 19 years old, showed the same abnormalities (Fig. 1H and Supplementary Fig. 2A and B, At TEM examination, microvilli were rare and shortened. There were possible microvillous inclusions and lots of secretory granules. Two MYO5B mutations were found. The first one (c656G>A) was located on the sixth exon and was already described in a Turkish patient and the second one was located on the 31st exon (c4028T>C). The mutations affect the motor part and the rab binding domain of the protein.

Patients 7 and 8 are offsprings of French nonconsanguineous parents. Diarrhea began when they were 5 months old, insidiously, with high steatorrhea levels (between 7 and 12 g/day), but low sodium excretion (15 mmol/L for the girl). Parenteral nutrition was started at 8 months for the boy (patient 7) and at 18 months for his younger sister (patient 8). After a few months, it moved for enteral nutrition and then for normal feeding. At the beginning, gluten intolerance was suspected: gluten antibodies were negative for the boy, whereas antigliadin immunoglobulin G levels were elevated for the girl. The boy is now 28 years old and the girl is 11 years old.

For patient 7, until 4 years of age, duodenal biopsies showed total or subtotal villous atrophy with crypt hyperplasia and mild inflammatory infiltrate; however, when he was 18 years old, a duodenal biopsy revealed almost normal villi but a focal PAS-positive pattern, mostly on the apical pole of surface enterocytes. The number of intraepithelial lymphocytes was at the upper limit of normal. TEM showed rare microvilli abnormalities, some electron-dense vesicles, and a mild degree of cellular sickness. For patient 8, the diagnosis was made at 18 months. Focal accumulation of PAS-positive material at the luminal pole of surface and crypt enterocytes was seen. There was only a mild villous atrophy. Histological data improved at 4 years of age, with an almost normal villous relief but the persistence of the abnormal PAS-staining pattern (Fig. 1I and Supplementary Fig. 2C and D). TEM analyses were done earlier for patient 8, when she still had digestive symptoms, and revealed rarefied microvilli, possible microvillous inclusions and electron-dense vesicles (Fig. 3D). Genetic screening found the same 2 mutations in the 2 children. One in the 14th exon (C1347delC) led to a truncated protein. The other one, located on the 24th exon (c3163-3165dup), was also found in patient 1.


In summary, all 8 reported patients were characterized by a typical abnormal PAS staining on light microscopy, which made us discuss the diagnosis of MVID. All of them exhibited atypical clinical presentations, but 4 exhibited 1 or more TEM diagnostic hallmarks proposed by Davidson et al (4), including loss of microvilli, microvillus inclusions, and secretory granules. Finally, 6 patients, corresponding to 4 distinct pedigrees, were mutated for MYO5B.

Gestations were unremarkable, except for patient 3. In fact, only 4 cases from the literature had antenatal symptoms consisting of hydramnios or echogenic bowel. Among these 4 cases, 2 mothers had a strict follow-up because of health problems, whereas the third baby had a neuronal intestinal dysplasia with bowel dilatation (5–8). Antenatal echography therefore seems to have a limited role for prenatal diagnostic here and in the literature.

Three patients experienced malformations. All of them had dysmorphy and severe mental retardation. To our knowledge, there are only a few patients described in the literature with malformations (11–13), and none with sensory defects. Only 2 patients with no MYO5B mutations had the most severe malformations, suggesting another genetic cause of their disease. Three patients were small, with height values under −2 SD despite nutritional assistance and sometimes despite a treatment with growth hormone. These data suggest that in some cases MVID may be a component of a more complete syndrome.

In the reported cases, digestive symptoms were milder than in the classical presentation. Either they had a delayed starting date (patients 6, 7, and 8) or outputs were less considerable than in classic MVID. Parenteral nutrition could even be stopped in 3 patients. To our knowledge, these are the third and fourth spontaneous cures described to date (11,23).

Three patients had a cholestasis with low GGT levels whose evolution was fluctuant with medical treatment. One still had severe pruritus. In a previous study, cholestasis was described in 25% of the patients, before or even after isolated small bowel transplantation (15). It is known that myosin 5b is important for hepatocyte polarization (38). It is therefore possible that a dysfunction of myosin 5b leads to a defect of hepatocyte apical transporters (39).

All but 2 patients had MYO5B mutations. For the remaining 2 patients, the genetic defect remains to be identified. The exome sequencing strategy used here did not allow discarding genetic changes such as exon deletions or mutations within the MYO5B promotor region; however, immunohistochemical analyses of myosin 5b showed a normal signal, and thus did not argue for MYO5B gene abnormalities. For these patients, it should be more interesting to study alternative genes involved in the transport of apical proteins such as Rab8a, Rab11a, or FIP5. Because mutations in syntaxine 3 have been reported for 2 patients with MIVD, this gene should also be tested (40).

In patients with mutations, the functional impact of the mutations was not further examined with functional studies; however, among the mutations identified here, one was present in 2 families (patients 1, 7, and 8) and another one was already reported in a typical Turkish patient (31). More important, mutated patients carried 2 mutations as expected for a Mendelian recessive disorder. Thus, we conclude that patients’ mutations likely contribute to their histological and clinical findings.

MIVD is a rare pathology, with well-recognized clinical and histological aspects in its classic form. Most of the patients exhibit MYO5B mutations. This study suggests to extend the clinical spectrum of MVID to patients with less severe diarrhea and/or associated diseases.


The authors thank Alain Grodet for technical support.


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intractable diarrhea; microvillous atrophy; microvillous inclusion disease; myosin 5b

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