Ménétrier disease is a rare hypoproteinemic hypertrophic gastropathy first described in 1888. It is characterised by enlarged gastric folds, decreased acid production, excessive mucus secretion, anaemia (due to gastric blood loss and decreased iron absorption), and decreased serum albumin (due to loss of protein across the gastric mucosa) (1–3).
The diagnosis of Ménétrier disease is based on clinical, endoscopic, and pathological criteria. Although there is high clinical variability, the classic disease features include abdominal pain, nausea and vomiting, anaemia, and peripheral oedema. The upper gastrointestinal (GI) endoscopy shows diffusely enlarged folds of gastric fundus and body. Although there is typical sparing of the antrum, patients with Ménétrier disease presenting with antrum involvement have been reported (3). Pathology hallmarks of the disease are massive expansion of mucous cells, referred to as foveolar hyperplasia, and marked reduction in parietal and chief cells. Patients often show hypochlorhydria with normal serum gastrin levels and may exhibit increased transforming growth factor-α (TGF-α) immunoreactivity in the areas of abnormal gastric mucosa (3,4). In adult patients, Ménétrier disease presents with an insidious onset and progressive clinical course. Moreover, it is considered a premalignant disorder with an increased risk of gastric cancer (5,6). The few paediatric cases described (7–9) had abrupt onset, resolved spontaneously, and have been associated to cytomegalovirus (CMV) or Helicobacter pylori infections (10–12). Increased immunohistochemical staining for TGF-α has been reported in the affected gastric mucosa of adult patients with Ménétrier disease and in childhood cases associated with CMV infection (13). Interestingly, CMV infects human cells by interacting with the epidermal growth factor receptor (EGFR), the receptor of TGF-α. Therefore, given the role of EGFR signalling in the disease pathogenesis, it is speculated that CMV triggers childhood Ménétrier disease by inducing abnormal EGFR downstream signalling in genetically susceptible individuals (13,14).
Familial occurrence of Ménétrier disease is rare and has been reported only in 3 instances:
1. Lam et al (15) described 2 Chinese brothers, ages 27 and 29 years, with pachydermoperiostosis and Ménétrier disease.
2. Larsen et al (16) described Ménétrier disease in 3 affected members across a 3-generation pedigree, suggesting an autosomal dominant inheritance.
3. Marcus and Verp (17) described a case of early-onset Ménétrier disease in the son of Jordanian double-first-cousin parents, suggesting autosomal recessive inheritance.
In the present study, we describe a unique, 4-generation pedigree with multiple affected members presenting the typical clinical, endoscopic, and pathological findings of Ménétrier-like disease.
Laboratory studies including complete blood count, total serum protein, and albumin, serum iron, and ferritin were performed. Pepsinogen-I, pepsinogen-II, gastrin-17, and H pylori IgG antibodies were determined using specific enzyme immunoassays (Gastrin-17 EIA test kit, pepsinogen-I EIA test kit, and H pylori IgG test kit; Biohit Plc, Helsinki, Finland), as described previously (18). The detection of CMV DNA in plasma and biopsies was performed using real-time PCR and previously described primers and TaqMan probe that target the CMV polymerase I gene (19).
Endoscopy was carried out in the index cases (IV.2, IV.5) by standard, forward-viewing paediatric endoscope (Fujinon EG530FP, Fujinon Corp, 26–30 Nishiazabu, Chome Minato, Ku. Tokyo, Japan) (E.M., A.S.). The procedures were performed under general anaesthesia and 6 biopsies were taken from the duodenum, including bulb, antrum, corpus, and fundus, and from the oesophagus.
Control gastric specimens were collected from 3 age-matched controls who underwent upper endoscopy for diagnostic purposes and were found to have normal looking mucosa.
Formalin-fixed endoscopic biopsies were processed for conventional histology (haematoxylin & eosin) and for TGF-α immunohistochemistry with an anti-TGF-α antibody (Novus Biologicals, Littleton, CO) (G.R., F.P.D.). Immunohistochemistry was performed as previously described (20). Negative controls consisted of substituting normal sera for the primary antibodies. Formalin fixed, paraffin embedded colon cancer tissue was used as positive control for TGF-α expression at immunohistochemistry.
Real-time PCR Analysis
Gastric biopsies from antrum, fundus, and corpus of 2 index cases (IV.2, IV.5) and 3 unaffected age-matched controls were obtained during upper endoscopy, placed in TRIzol (Invitrogen, Carlsbad, CA) and stored at −80°C, until specimens from each individual were pooled and total RNA was extracted using standard phenol/chloroform method. Total cDNA was then obtained using high-capacity cDNA reverse transcription kit (Applied Biosystems, Foster City, CA) according to manufacturer's instructions. Real-time PCR reaction was carried out in triplicate using Light Cycler Faststart DNA Master SYBR Green I (Roche, Indianapolis, IN), with 1 μL of total cDNA and 0.2 μmol/L of each primer in a total volume of 15 μL. Cycling conditions were as follows: 5 minutes at 95°C; 45 cycles of 10 seconds at 95°C, 10 seconds at 60°C, and 15 seconds at 72°C. Human GAPDH was used as reference. Primer sequences were as follows: hTGFA-forward: 5-AGCATGTGTCTGCCATTCTG-3′; hTGFA-reverse: 5′-GTGATGGCCTGCTTCTTCTG-3′; hGAPDH-forward: 5′-ATGTTCGTCATGGGTGTGAA-3′; hGAPDH-reverse: 5′-GGGGTGCTAAGCAGTTGT-3′. Relative quantification analysis was performed by Light Cycler 480 software (Roche) using ΔΔCt method and fit points calculation to determine Ct. Subject control 1 was used as calibrator.
Written, informed consent was obtained from the parents of index cases. The study was approved by the institutional review board of the University of Naples “Federico II.”
CASE REPORTS AND RESULTS
Two index cases from an Italian 4-generation pedigree with at least 11 members affected with a Ménétrier like-disease were referred to the Department of Paediatrics, “Federico II” University of Naples and to the Department of Gastroenterology, “Sapienza” University of Rome (Fig. 1). The index cases, a 4-year and 6-month-old boy (IV.2) and his second-degree cousin, a 2-year and 9-month-old girl (IV.5), were both initially evaluated for chronic iron deficiency anaemia. They both complained of mild and recurrent episodes of abdominal pain that neither awakened them at night nor were related to eating or bowel habits. Index cases were not treated by proton pump inhibitors or by any other kind of antacid agents. Physical examinations revealed only pallor and there was no evidence of peripheral oedema. Laboratory findings confirmed iron deficiency anaemia in both patients and coagulation tests, serum protein, and pepsinogen were within normal ranges. Serum gastrin and pepsinogen II were both increased (91 and 93.4 pmol/L, normal range 2–10, 68 and 21, normal range 3–10). Erythrocyte sedimentation rate and C-reactive protein were within the normal range in both patients. Cellobiose/mannitol small intestinal permeability study was normal. Testing for CMV, performed by histopathology and immunochemistry in the gastric tissue and in blood, was negative in both index cases. To rule out GI bleeding, upper and lower GI endoscopies were performed in both index cases. Lower GI endoscopy was negative, whereas upper GI endoscopy showed thick mucus and massive, diffusely enlarged folds of the stomach lining of the corpus and fundus (Fig. 2A and B). Similar findings were observed in the patient III.2, mother of index case IV.2 (Fig. 2C). Gastric biopsies collected from fundus, corpus, and antrum of both index cases showed increase in the mucus-secreting portion of acidopeptic glands, massive foveolar hyperplasia, gland elongation, tortuous and focally cystic lumen, and parietal cell reduction (Fig. 3 A, B, and D, case IV.5). H pylori infection was ruled out on either a negative histopathology and negative rapid urease test in both index cases. No significant inflammation was observed. A similar picture, though at a lesser extent, was observed in the antral mucosa as well. These findings were all consistent with Ménétrier disease. Intragastric pH monitoring was not performed, because the parents of children refused it.
The family history was striking for several members with hypertrophic gastropathy and chronic anaemia in the absence of protein loss, consistent with an autosomal dominant pattern of inheritance (Fig. 1). The maternal great-grandmother of 1 of the index cases (I.1) died of gastric cancer; the maternal grandfather (II.2) and both granduncle and grandaunt (II.3 and II.4) had an endoscopic and pathologic diagnosis of hypertrophic gastropathy and one of them underwent subtotal gastrectomy for abundant GI bleeding; the mother (III.2), sister (III.5), and 2 first-degree cousins (III.6 and III.7) had a confirmed diagnosis of Ménétrier disease (Figs. 1 and 2).
Upon pathology evaluation, all examined cases showed a similar picture as the index cases (Fig. 3). The immunohistochemistry showed low-moderate TGF-α immunoreactivity (Fig. 3C) consistent with the real-time PCR analysis, which demonstrated no increase in TGF-α expression in 2 index cases as compared with age-matched control specimens from the same gastric segments (Fig. 4).
Despite being described more than 1 century ago, the aetiology of Ménétrier disease remains unknown and so far environmental agents have been preferred as responsible factors. We report a large pedigree with several members affected exhibiting findings that largely overlap with classic Ménétrier disease; however, the lack of protein loss observed in our family is not typically reported in classic Ménétrier disease. The pattern of inheritance of the disease in the family reported herein is autosomal dominant because both male and female members are affected, members of each generation are affected, and there is male-to-male transmission (Fig. 1).
Serum gastrin-17 and chomogranin A were only slightly increased in 2 index cases. The clinical presentation (absence of heartburn), the endoscopic appearance (presence of giant rugal folds, lack of ulcers), and the pathological findings (Ménétrier disease) rule out the diagnosis of Zollinger-Ellison syndrome (21,22). Moreover, patients with Ménétrier disease often present with elevation of serum gastrin to levels similar to those observed in our index cases (3). The most common mimics of Ménétrier disease are various forms of polyps and polyposis syndromes. These are better differentiated from one another and from Ménétrier disease by family history, manifestations outside of the stomach, genetic testing, appearance at endoscopy, and histological presentation. On pathological examination, Ménétrier disease can be distinguished from hyperplastic polyps and juvenile polyps by the preservation of tissue architecture and parallelism of gastric glands, and the presence of prominent lamina propria smooth muscle fibres. Hyperplastic polyps and juvenile polyps will appear more disorganised and oedematous, because they show a lower gland-to-stroma ratio (23). In both index cases, however, family history, clinical, laboratory, imaging, and pathological findings do not suggest this disorder.
Classic Ménétrier disease is believed to result from enhanced EGFR signalling in the gastric mucosa due to local overproduction of TGF-α (13,24). TGF-α is a potent mitogen that binds and activates the tyrosine kinase of EGFR that stimulates gastric growth and inhibits gastric acid secretion. Both TGF-α and EGFR are expressed in the normal gastric mucosa (25), with TGF-α being found predominantly in parietal cells and at the luminal surface of mucous cells in the corpus and fundus of the stomach. Patients with Ménétrier disease exhibit enhanced immunoreactivity for TGF-α in their expanded surface mucous cell compartment, despite a marked reduction in number of parietal cells (26). Moreover, transgenic mice overexpressing TGF-α in the stomach show virtually all features of Ménétrier disease (27–30). On the basis of the recognised role of TGF-α in the disease pathogenesis, patients with Ménétrier disease have been successfully treated with cetuximab, a monoclonal antibody that blocks EGFR signalling (31). Nevertheless, the underlying molecular defect that results in upregulation of TGF-α in Ménétrier disease is not known and TGF-α is not overexpressed elsewhere in the bodies of individuals with Ménétrier disease (30).
On the basis of this well-recognised role in disease pathogenesis, we have investigated TGF-α expression in the gastric mucosa of our index cases IV.2 and IV.5 by immunostaining and real-time PCR. No increase in TGF-α was noted by immunohistochemistry and real-time PCR (Figs. 3C and 4). On the basis of these findings, the patients herein reported do not appear to be candidates for therapy with cetuximab.
The lack of protein loss and the normal levels of gastric TGF-α expression in the view of macroscopic and microscopic gastric findings overlapping with Ménétrier disease suggest that the disease observed in our family may represent a novel and previously unrecognised form of gastric hyperplasia.
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