Congenital diarrheal disorders are a group of rare enteropathies that often present with life-threatening diarrhea in the first weeks of life. Enteric anendocrinosis, characterized by a lack of intestinal enteroendocrine cells due to recessively inherited mutations in the Neurogenin-3 (NEUROG3) gene, has been described as a cause of congenital malabsorptive diarrhea. Diabetes mellitus also is typically associated with NEUROG3 mutations, be it early onset or a later presentation. Here we report a case of a 16-year-old male patient with severe malabsorptive diarrhea from birth, who was parenteral nutrition dependent and who developed diabetes mellitus at 11 years old. To the best of our knowledge, only 9 cases of recessively inherited NEUROG3 mutations have been reported in the literature to date. Our patient presents with several remarkable differences compared with previously published cases. This report can contribute by deepening our knowledge on new aspects of such an extremely rare disease.

Congenital diarrheal disorders (CDDs) are a group of rare enteropathies that often present with life-threatening diarrhea in the first weeks of life.1 The number of well-characterized disorders attributed to CDDs has gradually increased over the past several years, and many new genes have been identified related to CDD.2,3 One of these new disorders is enteric anendocrinosis (EA), characterized by severe malabsorptive diarrhea and a lack of intestinal enteroendocrine cells (ECs) due to recessively inherited mutations in the Neurogenin-3 (NEUROG3) gene.4 Few cases that mention this disorder have been published to date.4,10 In this article, we present the 10th case reported, with several remarkable differences compared with previously published cases. This report can contribute by deepening our knowledge on new aspects of such an extremely rare disease.

An 11-day-old newborn boy presented with severe dehydration, metabolic acidosis (pH: 7.16; bicarbonate: 6.0 mmol/L; base excess: −21), and high-volume watery diarrhea (10 loose stools daily). Prenatal and natal history indicated a healthy pregnancy and delivery, with a birth weight of 3560 g. He had received regular infant formula and breast milk since birth. There was no family history of gastrointestinal disorders or immunodeficiency. Parents were not consanguineous.

Intravenous fluids were started and diarrhea ceased during fasting. Several different types of formula (casein extensive hydrolyzed, galactose and glucose-free formula, amino acid-based formula) were administered in the first months of life but did not lead to resolution of the diarrheal symptoms. He presented a malabsorptive diarrhea with fat malabsorption (fecal fat excretion of 12.3 g/d) and protein malabsorption (fecal nitrogen of 2.1 g/d). Comprehensive evaluations for infectious, allergic, immunologic, and metabolic causes of diarrhea were all negative. At the age of 4 months, biopsy of duodenum and colon revealed normal histologic features (Fig 1). Electron microscopy also was conducted without abnormal findings. The activity of mucosal disaccharidases was within the normal range. At that moment, celiac disease (CD) antibodies also were negative.

FIGURE 1

At 4 months old, (A) hematoxylin and eosin staining showed a normal crypt and villus architecture of duodenal mucosa. B, Immunohistochemical staining for CD8+ T cells showed minimal intraepithelial lymphocytosis (10/100 epithelial cells). C, Hematoxylin and eosin staining showed mild architectural changes in colorectal mucosa, without inflammatory changes (original magnification, ×200).

FIGURE 1

At 4 months old, (A) hematoxylin and eosin staining showed a normal crypt and villus architecture of duodenal mucosa. B, Immunohistochemical staining for CD8+ T cells showed minimal intraepithelial lymphocytosis (10/100 epithelial cells). C, Hematoxylin and eosin staining showed mild architectural changes in colorectal mucosa, without inflammatory changes (original magnification, ×200).

He was readmitted on several occasions during the first months of life because of these symptoms. Different treatments, including loperamide or pancreatic enzymes were administered without significant improvement. As a result of this diarrhea, he developed severe failure to thrive. Therefore, home parenteral nutrition (PN) was started finally at 32 months of life.

Over the following years, he was readmitted on several occasions because of infections related to the central venous catheter. PN was discontinued 2 times for this reason (6 months at 14 years old and 4 months at 16). Nevertheless, after these periods, PN was resumed due to weight loss and fatigue. He continued to pass 3 to 4 high-volume liquid stools daily.

When our patient was 11 years old, he developed type 1 diabetes with negative pancreatic autoantibodies; therefore, insulin treatment was started. At that point, a new evaluation was made. He had 1186 g of stools per day with fecal fat excretion of 58.1 g/d and fecal nitrogen of 12.8 g/d. Fecal elastase levels were decreased: 15.1 mg/g (normal, 200–500 mg/g). Both anti-gliadin and anti-transglutaminase (anti-tTG) antibodies were positive. Anti-gliadins were 110 U/mL (normal <18) and anti-tTGs were 150 U/mL (normal <10). HLA study was DR17, DR7/DQ2, DQ9.

An esophagogastroscopy and a colonoscopy were repeated. Duodenum biopsies revealed moderate villous atrophy with increased intraepithelial lymphocytes (Fig 2). Goblet cells and Paneth cells were present in a normal pattern. Staining of the small intestine with chromogranin-A, a neuroendocrine marker, showed presence of EC. With these findings, a diagnosis of CD was made and a gluten-free diet was started. He was also treated with supplemental pancreatic enzymes without improvement. Three years after starting the diet, our patient continued to have malabsorptive diarrhea. Duodenum biopsies were repeated, revealing mild to moderate villous atrophy with intraepithelial lymphocytes (Fig 3). Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome was suspected, but FOXP3 mutation analysis was negative. Mutations of NEUROG3 were investigated and a homozygous mutation (c.319C>A; p.Arg107Ser) was identified (Fig 4). After the identification of the NEUROG3 mutation, intestinal biopsy samples were reexamined for the presence of EC and compared with control subjects. We found that our patient had a significant depletion of ECs. Only 3 cells were identified per 10 crypts in the duodenum (Fig 5) and no ECs were identified in the colon, whereas 1 to 3 cells were present per crypt in normal mucosa of control patients (Fig 6).

FIGURE 2

At 11 years old, (A) hematoxylin and eosin staining showed moderate duodenal mucosa atrophy and increased number of intraepithelial lymphocytes (35/100 epithelial cells). B, Immunohistochemical staining for CD8+ T cells confirms intraepithelial lymphocytosis (35/100 epithelial cells). C, Colorectal mucosa with minimal changes. No inflammatory changes were found (original magnification, ×200).

FIGURE 2

At 11 years old, (A) hematoxylin and eosin staining showed moderate duodenal mucosa atrophy and increased number of intraepithelial lymphocytes (35/100 epithelial cells). B, Immunohistochemical staining for CD8+ T cells confirms intraepithelial lymphocytosis (35/100 epithelial cells). C, Colorectal mucosa with minimal changes. No inflammatory changes were found (original magnification, ×200).

FIGURE 3

At 14 years old, after 3 years of gluten-free diet, duodenum biopsies still revealed mild to moderate villous atrophy with heterogeneous intraepithelial lymphocytosis. A, Hematoxylin and eosin staining. B, Immunohistochemical staining for CD8+ T cells (20–30/100 epithelial cells) (original magnification, ×200).

FIGURE 3

At 14 years old, after 3 years of gluten-free diet, duodenum biopsies still revealed mild to moderate villous atrophy with heterogeneous intraepithelial lymphocytosis. A, Hematoxylin and eosin staining. B, Immunohistochemical staining for CD8+ T cells (20–30/100 epithelial cells) (original magnification, ×200).

FIGURE 4

NEUROG3 sequence of our patient. The specific mutation is indicated by the arrow.

FIGURE 4

NEUROG3 sequence of our patient. The specific mutation is indicated by the arrow.

FIGURE 5

A, Chromogranin-A staining of normal duodenal mucosa from an age-matched control, showing a normal distribution of ECs, 1 to 3 ECs per crypt. B, Chromogranin-A staining of patient with enteroendocrine dysgenesis that shows a significant depletion of ECs, 3 were identified per 10 crypts, at 11 years old. C, At 14 years old, after 3 years of gluten-free diet, chromogranin-A staining continued showing a depletion of ECs, 3 per 10 crypts. D, At 4 months old, chromogranin-A staining of duodenal mucosa shows no immunohistochemical reactivity to chromogranin-A, but the sample was considered too small to be representative (original magnification, ×200).

FIGURE 5

A, Chromogranin-A staining of normal duodenal mucosa from an age-matched control, showing a normal distribution of ECs, 1 to 3 ECs per crypt. B, Chromogranin-A staining of patient with enteroendocrine dysgenesis that shows a significant depletion of ECs, 3 were identified per 10 crypts, at 11 years old. C, At 14 years old, after 3 years of gluten-free diet, chromogranin-A staining continued showing a depletion of ECs, 3 per 10 crypts. D, At 4 months old, chromogranin-A staining of duodenal mucosa shows no immunohistochemical reactivity to chromogranin-A, but the sample was considered too small to be representative (original magnification, ×200).

FIGURE 6

A, Chromogranin-A staining of normal colonic mucosa from an age-matched control, showing a normal distribution of ECs, 1 to 3 ECs per crypt. B, Chromogranin-A staining of patient with enteroendocrine dysgenesis that shows no immunohistochemical reactivity to chromogranin-A at 11 years old (original magnification, ×100).

FIGURE 6

A, Chromogranin-A staining of normal colonic mucosa from an age-matched control, showing a normal distribution of ECs, 1 to 3 ECs per crypt. B, Chromogranin-A staining of patient with enteroendocrine dysgenesis that shows no immunohistochemical reactivity to chromogranin-A at 11 years old (original magnification, ×100).

At the time of writing, the patient was 16 years old (weight: 51 kg, −1.7 SD; height: 161.5 cm, −1.4 SD; BMI 19.55). He ate a regular home diet with no gluten and received nighttime PN 7 times a week. He had good glycemic controls with insulin in the PN.

CDDs are a group of rare enteropathies related to specific genetic defects that are generally inherited as autosomal recessive traits. Frequently, infants with these disorders present with chronic diarrhea of sufficient severity to require PN early in life. In 2010, Berni Canani et al1 suggested a new classification of CDD according to the type of defect present. This classification includes 4 groups of CDDs: defects in digestion, absorption, and transport of nutrients and electrolytes; disorders of enterocyte differentiation and polarization; defects of EC differentiation and function; and dysregulation of intestinal immune response.1,3 EA, caused by mutations in NEUROG3, is included in this classification as a defect of EC differentiation.1,3 

NEUROG3 is a basic helix-loop-helix transcriptional factor that drives endocrine cell fate in both the pancreas and intestine.11,12 Studies involving mice have shown that Neurog3−/− mice lack endocrine cells in the pancreas and intestine, which is presumably why they die of diabetes during the first few days of life.13 

The relationship between mutant NEUROG3 and congenital malabsorptive diarrhea was first described by Wang et al.4 They reported cases of 3 children with mutant NEUROG3 who lacked intestinal ECs and had malabsorptive diarrhea. This finding suggested that ECs had not only a secretory effect, as previously believed, but that they also played a critical role in augmenting nutrient absorption. Nevertheless, the mechanisms were still not completely understood. We identified the same NEUROG3 mutation as in 1 of the patients of Wang et al4 (Arg107Ser). To the best of our knowledge, 9 cases of recessively inherited NEUROG3 mutations have been reported in the literature to date.4,10 All 9 patients had congenital malabsorptive diarrhea and 4 developed diabetes; 2 of them had neonatal diabetes and 2 developed it by the age of 8. Limited clinical information has been reported on 2 patients. As can be seen, the number of patients described so far is too small to draw reliable conclusions about the typical clinical picture of this disease. A summary of the clinicopathologic, histologic, immunohistochemical, genetic, and prognostic features of the cases reported in the literature is provided in Table 1.4,10 

TABLE 1

Clinicopathologic, Histologic, Immunohistochemical, Genetic, and Prognostic Features of the Cases Reported in the Literature to Date

AuthorAge at DiagnosisSexClinical OnsetDiabetesHistopathologic FeaturesStaining for Chromogranin-AMutationClinical Course
Wang et al4  35 mo Boy Malabsorptive diarrhea the first weeks of life No Normal intestinal mucosa structure 1 EC in the >350 small-bowel crypts examined and none in the colon Homozygous missense change, p.R107S He died after a liver-intestine transplant because of sepsis 
Wang et al4  8 y Boy Malabsorptive diarrhea the first weeks of life Yes, at 8 y Normal intestinal mucosa structure 1 EC in 100 crypts in the duodenum and 8 in 100 crypts in the jejunum Homozygous missense change, p.R93L - PN until 24 mo of age 
- Diarrhea continues 
- Growth retardation 
Wang et al4  9 y Boy Malabsorptive diarrhea the first weeks of life Yes, at 8 y Normal intestinal mucosa structure 1 EC in 100 crypts in the duodenum and 8 in 100 crypts in the jejunum Homozygous missense change, p.R93L - PN during 2 mo 
- Diarrhea continues 
- Growth retardation 
Rubio-Cabezas et al5  5 y Girl Diabetes and severe malabsorptive diarrhea since birth Yes, neonatal Normal intestinal mucosa structure Complete absence of ECs in small bowel and colon Two heterozygous mutations: p.E28×, p.L135P - Nighttime PN 3 times a wk 
- Diarrhea persists 
- Normal growth 
Pinney et al6  10 mo Girl Malabsorptive diarrhea since birth Yes, at 5.5 mo Moderate to severe villous blunting and atrophy Complete absence of ECs in small bowel Homozygous nonsense mutation, p.E123× She died at 10 mo from chronic liver failure secondary to PN 
Ohsie et al7  3 mo Girl Malabsorptive diarrhea since birth No NR Rare ECs in small bowel; none per 50 crypts in colon NR NR 
Sayar et al8  20 mo Girl Malabsorptive diarrhea started on the 20th day of life No Normal intestinal mucosa structure No ECs in the duodenum; 3 ECs per 50 crypts in the colon Homozygous frameshift mutation, p.S171fs - Home PN 2 d per week 
- Diarrhea persists 
- Normal growth 
Treetipsatit et al9  10 wk Girl Intractable watery diarrhea No No significant histologic abnormalities of colon Complete absence of ECs in colon NR NR 
No available small bowel biopsy 
Ünlüsoy Aksu et al10  2 y, 5 mo Boy Malabsorptive diarrhea since birth No Normal intestinal mucosa structure 1 EC per crypt in the small bowel Homozygous missense change, p.R93L - PN until 18 mo of life 
- Partial response to cholestyramine 
- Normal growth 
AuthorAge at DiagnosisSexClinical OnsetDiabetesHistopathologic FeaturesStaining for Chromogranin-AMutationClinical Course
Wang et al4  35 mo Boy Malabsorptive diarrhea the first weeks of life No Normal intestinal mucosa structure 1 EC in the >350 small-bowel crypts examined and none in the colon Homozygous missense change, p.R107S He died after a liver-intestine transplant because of sepsis 
Wang et al4  8 y Boy Malabsorptive diarrhea the first weeks of life Yes, at 8 y Normal intestinal mucosa structure 1 EC in 100 crypts in the duodenum and 8 in 100 crypts in the jejunum Homozygous missense change, p.R93L - PN until 24 mo of age 
- Diarrhea continues 
- Growth retardation 
Wang et al4  9 y Boy Malabsorptive diarrhea the first weeks of life Yes, at 8 y Normal intestinal mucosa structure 1 EC in 100 crypts in the duodenum and 8 in 100 crypts in the jejunum Homozygous missense change, p.R93L - PN during 2 mo 
- Diarrhea continues 
- Growth retardation 
Rubio-Cabezas et al5  5 y Girl Diabetes and severe malabsorptive diarrhea since birth Yes, neonatal Normal intestinal mucosa structure Complete absence of ECs in small bowel and colon Two heterozygous mutations: p.E28×, p.L135P - Nighttime PN 3 times a wk 
- Diarrhea persists 
- Normal growth 
Pinney et al6  10 mo Girl Malabsorptive diarrhea since birth Yes, at 5.5 mo Moderate to severe villous blunting and atrophy Complete absence of ECs in small bowel Homozygous nonsense mutation, p.E123× She died at 10 mo from chronic liver failure secondary to PN 
Ohsie et al7  3 mo Girl Malabsorptive diarrhea since birth No NR Rare ECs in small bowel; none per 50 crypts in colon NR NR 
Sayar et al8  20 mo Girl Malabsorptive diarrhea started on the 20th day of life No Normal intestinal mucosa structure No ECs in the duodenum; 3 ECs per 50 crypts in the colon Homozygous frameshift mutation, p.S171fs - Home PN 2 d per week 
- Diarrhea persists 
- Normal growth 
Treetipsatit et al9  10 wk Girl Intractable watery diarrhea No No significant histologic abnormalities of colon Complete absence of ECs in colon NR NR 
No available small bowel biopsy 
Ünlüsoy Aksu et al10  2 y, 5 mo Boy Malabsorptive diarrhea since birth No Normal intestinal mucosa structure 1 EC per crypt in the small bowel Homozygous missense change, p.R93L - PN until 18 mo of life 
- Partial response to cholestyramine 
- Normal growth 

NR, not reported.

There are several differences between our patient and those reported previously. Initial biopsies taken at the onset of the condition showed normal mucosa both in the small intestine and colon. However, when the biopsies were repeated years later, the patient showed moderate to severe villous atrophy. After testing positive for anti-tTG antibodies and HLA (DQ2), gluten was eliminated from the diet. In spite of these actions, when new biopsies were performed 3 years later, results still showed moderate atrophy and high levels of antibodies. We verified that the diet was being strictly followed. Failure to respond to the diet and the clinical data cast doubt on the CD hypothesis. Specificity of the anti-tTG antibodies is high, but high levels can be found in other conditions, such as when there is inflammation at the intestinal mucosa level or in the presence of other coexisting autoimmune disorders.14 On the other hand, other causes of villous atrophy, such as hypogammaglobulinemia, immunodeficiency, bacterial overgrowth, and infections, were ruled out.15 In the cases described so far, only 1 presented with villous atrophy at the time of diagnosis.9 In our case, there was no atrophy at the time of diagnosis either, but it could have potentially appeared as the disease evolved aided by prolonged mucosa damage. It must be kept in mind that our patient is the oldest reported patient to date, which could help us understand the behavior of the disease in the long run.

It is important to note that in view of the reported data, the degree of EC depletion at the intestinal level can vary. In our case, a chromogranin-A stain biopsy confirmed the presence of ECs; however, the quantity of these cells was not taken into account, which resulted in diagnostic delay. Once the genetic diagnosis was obtained, the results from the biopsies were reevaluated, comparing with age-matched controls revealing that the quantity of ECs was much lower than normal (1–3 for every 10 crypts, as opposed to 1–3 per crypt as is observed in healthy individuals). Therefore, the presence of this type of cell in the intestinal mucosa does not rule out the diagnosis, making quantitative precise counting of the cells necessary, by using age-matched controls. The quantity of EC does not seem to be related to the prognosis of the disease. In fact, the physiopathological mechanism behind the diarrhea remains unclear. Different hypotheses have been presented (eg, accelerated intestinal transit, exocrine pancreatic insufficiency, EC involvement in nutrient absorption). To date, there are no effective treatments available for these patients. Among the reported cases, only 1 partial response to the use of cholestyramine was reported. Our patient had low elastase levels, prompting the use of a trial treatment with pancreatic enzymes that had no results and was stopped.

EA should be considered in all patients with unexplained congenital malabsorptive diarrhea. This diagnosis should be further investigated with chromogranin-A staining of intestinal biopsies and a mutation analysis of the NEUROG3 gene.

     
  • anti-tTG

    anti-transglutaminase

  •  
  • CD

    celiac disease

  •  
  • CDD

    congenital diarrheal disorder

  •  
  • EA

    enteric anendocrinosis

  •  
  • EC

    enteroendocrine cell

  •  
  • NEUROG3

    neurogenin-3

  •  
  • PN

    parenteral nutrition

Dr Germán-Díaz was involved in the clinical management and follow-up of the patient and wrote and revised the manuscript; Dr Rodriguez-Gil provided images and descriptions of pathology slides and provided critical revisions for intellectual content; Drs Cruz-Rojo and Manzanares-López Manzanares were involved in the clinical management and follow-up of the patient and revised the manuscript; Drs Charbit-Henrion and Cerf-Bensussan performed the genetic testing and revised the manuscript; Dr Moreno-Villares was involved in the clinical management and follow-up of the patient and provided critical revisions for intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Genetic analysis was supported by institutional grants from INSERM, by the European grant ERC-2013-AdG-339407-IMMUNOBIOTA, by the Investissement d’Avenir grant ANR-10-IAHU-01, and by the Fondation Princesse Grace.

We thank Professor Frank Ruemmele, MD, PhD, of the Department of Pediatric Gastroenterology, Hôpital Necker-Enfants Malades, in Paris; and Fabienne Charbit-Henrion, MD, Institut IMAGINE-INSERM, UMR 1163, Université Paris Descartes-Sorbonne, in Paris, for providing mutation analysis of the NEUROG3 gene.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.