MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy.

We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Ménétrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in MIB2, a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of HES1 and NOTCH3 expression reflecting alteration of NOTCH signalling. Because mutations of MIB1, the homolog of MIB2, have been found in patients with left ventricle non-compaction (LVNC), we investigated members of our family with Ménétrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the MIB2 variant. Finally, we identified an additional MIB2 variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both MIB2 variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.In conclusion, we report the first example of left ventricular hypertrabeculation/LVNC with germline MIB2 variants resulting in altered NOTCH signalling that might be associated with a gastropathy clinically overlapping with Ménétrier disease.

A case of Ménétrier's disease seemingly caused by hilar cholangiocarcinoma.

A 54-year-old man presented to our department with abdominal discomfort and anorexia and was diagnosed as having Ménétrier's disease (MD) with hilar cholangiocarcinoma. Based on his clinical examination, there was no evidence of Helicobacter pylori or cytomegalovirus (CMV) infection. Although we administered proton pump inhibitor and high-calorie enteral nutrition, hypoproteinemia did not improve, and the refractory protein-losing enteropathy persisted. However, interestingly, MD improved immediately after resection of the hilar cholangiocarcinoma. Generally, the etiology of MD is unknown, but H. pylori and CMV infections have been implicated. To our knowledge, there has been no previous report indicating that a malignant tumor could be involved in the etiology of MD. Thus, we report an extremely rare case of MD which is seemingly caused by malignancy.

[MENETRIER DISEASE].

Menetrier disease (MD) is a very rare stomach pathology of unknown etiology characterized by manifest hypertrophy of gastric mucosa. The main causes of MD are believed to be Helicobacter pylori and cytomegalovirus infections. The most frequent symptom is epigastric pain. Also common are peripheral oedema due to hypoalbuminemia and increased permeability of gastric mucosa. The main diagnostic signs of MD include diffusive enhancement of mucosal folds, foveolar hyperplasia and glandular atrophy with a decrease in the number of main and parietal cells, hypoalbuminemia and peripheral oedema. MD being a very rare condition, the optimal methodfor its treatment is unknown.

Pierre Ménétrier and his disease.

In 1888, Pierre Ménétrier first described the disease that bears his name. Many of the findings he reported then remain accepted features of the disease. Based on studies performed in our laboratory over the past 20 years, we have implicated increased transforming growth factor-α (TGFα) expression and heightened epidermal growth factor receptor (EGFR) activity in the pathogenesis of Ménétrier's disease. Herein, we provide a historical perspective of this rare disorder, review our experience with Ménétrier's disease, and discuss future challenges and opportunities posed by this disorder.

A case of Ménétrier's disease without Helicobacter pylori infection.

Ménétrier's disease (MD) is a rare, acquired, premalignant disorder of the stomach characterized by enlarged gastric folds with foveolar hyperplasia, the phenotype of antralization of gastric glands, hypochlorhydria and hypoproteinemia. The etiology of MD is unknown, but both increased signaling by transforming growth factor-α and infection with Helicobacter pylori (H. pylori) have been implicated. Here, a case involving 70-year-old man who lost weight after developing anorexia and diarrhea is reported. He was diagnosed as MD without H. pylori infection, and in spite of intensive care, he died 40 days after admission. An autopsy confirmed MD. Immunohistochemistry revealed overexpression of transforming growth factor-α in the foveolar region of the gastric mucosa. The autopsy also distinguished this H. pylori-negative MD from hyperplastic polyp of the stomach, which is important in clarifying the entity of H. pylori-negative MD.

Ménétrier's disease of the stomach: a clinical challenge.

Ménétrier's disease is a rare hyperproliferative protein-losing gastropathy of the gastric foveolar epithelium. Most common symptoms include epigastric pain with fullness and vomiting, and generalized peripheral edema with hypoalbuminemia. Radiologically, the wall of the gastric body and fundus is diffusely thickened, often with antral sparing. Giant rugal edematous folds are seen on gastroscopy, and histology of biopsy material shows diffuse foveolar hyperplasia with cystic dilatation of the glandular portion of the gastric mucosa in the absence of significant inflammatory infiltrate. The recent discovery of transforming growth factor α overexpression opens the way of epidermal growth factor receptor blockade with cetuximab as first-line treatment modality in severe cases of Ménétrier's disease.

Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach.

Ménétrier disease and gastrointestinal stromal tumors (GISTs) are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases (RTKs). In Ménétrier disease, overexpression of TGF-alpha, a ligand for the RTK EGFR, results in selective expansion of surface mucous cells in the body and fundus of the stomach. In GISTs, somatic mutations of the genes encoding the RTK KIT (or PDGFRA in a minority of cases) result in constitutive kinase activity and neoplastic transformation of gut pacemaker cells (interstitial cells of Cajal). On the basis of the involvement of these RTKs in the pathogenesis of these disorders, Ménétrier disease patients have been effectively treated with a blocking monoclonal antibody specific for EGFR and GIST patients with KIT and PDGFRA tyrosine kinase inhibitors.

Long-term gastric changes in achlorhydric H(+)/K(+)-ATPase beta subunit deficient mice.

OBJECTIVE: Hypergastrinemia is known to induce enterochromaffin-like (ECL) cell derived tumors in rodents and man. In this study, we have examined the effect of life-long gastric anacidity and secondary hypergastrinemia in H(+)/K(+)-ATPase beta subunit knockout (KO) mice. MATERIAL AND METHODS: Female H(+)/K(+)-ATPase beta subunit KO mice and controls were followed up to 20 months before being sacrificed. At termination, intragastric acidity was measured and internal organs were examined for macroscopic and histological changes. Plasma gastrin and serum albumin were measured. RESULTS: KO mice were anacidic and hypergastrinemic. The oxyntic mucosa was markedly, and with increase in age, hyperplastic with cystic dilatations resembling the changes seen in patients with Menetrier's disease. Serum albumin in KO mice did not differ from controls. KO mice had a marked ECL cell hyperplasia, but only one gastric carcinoma was found. CONCLUSION: H(+)/K(+)-ATPase beta subunit KO mice develop Menetrier-like changes in the stomach, and may be useful in studying the pathogenesis and treatment of Menetrier's disease. The reason why only one KO mice developed gastric neoplasia whereas the histamine-2 blocker loxtidine has previously been found to regularly induce ECL cell carcinoids in mice is not known.

A Rare Case of Hypertrophic Gastropathy with Adenocarcinoma Arising from a Gastric-type Adenoma.

A 60-year-old man was referred for the investigation of giant gastric folds, life-threatening anemia and hypoproteinemia. A combination of multiple endoscopic procedures derived a clinical diagnosis of protein-losing gastropathy with two gastric adenomas. After two months of alimentary therapy, the patient received total gastrectomy and fully recovered. The final pathological diagnosis was hypertrophic gastropathy of unknown origin with concomitant adenocarcinoma arising from a gastric type adenoma.

The edematous toddler: a case of pediatric Ménétrier disease.

Ménétrier disease is a protein-losing gastroenteropathy, characterized clinically by nonspecific gastrointestinal symptoms and generalized edema, biochemically by hypoalbuminemia, and pathologically by enlarged gastric folds. Distinct from its adult counterpart, Ménétrier disease of childhood usually remits spontaneously and has a very good prognosis. We present a case report of Ménétrier disease in an edematous toddler and a brief review.

Ménétrier's disease and severe gastric ulcers associated with cytomegalovirus infection in an immunocompetent child: a case report.

In pediatric patients, Ménétrier's disease is an uncommon clinical entity that has been rarely described only as sporadic cases, and the etiology is unclear. These patients usually have a self-limiting clinical course. Cytomegalovirus is an important pathogen in the immunocompromised host. However, cytomegalovirus infection can be detected in non-immunocompromised children. We discuss the possible role of cytomegalovirus infection in both Menetrier's disease and severe gastric ulcers in an immunocompetent child.

Mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disease characterized by progressive ophthalmoplegia, peripheral neuropathy, mitochondrial abnormalities and gastrointestinal involvement. We describe a 19-year-old male having chronic intestinal pseudoobstruction associated with ophthalmoplegia and proximal muscle weakness. The clinical and radiologic features suggested the diagnosis of mitochondrial neurogastrointestinal encephalomyopathy. Mitochondrial genetic defects should be considered in the differential diagnosis of unexplained chronic gastrointestinal symptoms accompanied by neurological findings, especially in families where there is more than one individual with the same kind of symptoms.

[Acetic acid-induced gastro-duodenal ulcers in experimental animals--examples of serendipity and pseudoserendipity].

Our understanding of the function and etiology of various gastric diseases has exponentially expanded over the past 40 years. In particular, several animal models had been devised and used for screening of anti-ulcer drugs and elucidation of pathogenesis. This review describes how water-immersion stress ulcer model, Helicobacter pylori ulcer model, and acetic acid ulcer models were established in experimental animals. In recent years, genetically modified mice allowed rapid accumulation of very important findings. H(2)-receptor knockout mice revealed to exhibit Menetrier's disease-like gastric mucosal changes. Gastrin-transgenic mice infected with H. pylori revealed to develop gastric cancer. The hypothesis for the origin of parietal cells was provided.

A clinicopathologic study of 42 patients with granulomatous gastritis. Is there really an "idiopathic" granulomatous gastritis?

Idiopathic granulomatous gastritis (IGG) is a diagnosis made only by excluding other causes of granulomatous gastritis, such as infection, foreign bodies, and systemic granulomatous diseases. Recently, several investigators have questioned the existence of IGG. We reviewed the slides and clinical data of all cases of granulomatous gastritis seen at the Cleveland Clinic between 1975 and 1994. In addition to routine hematoxylin and eosin stains, slides from all cases were stained with Ziehl-Neelsen, Gomori's methenamine silver, and Giemsa stains. Clinical information and follow-up were available for 42 patients. The clinicopathologic diagnoses of the 42 patients with granulomatous gastritis were as follows: Crohn's disease (n = 23), three of whom had concomitant chronic active gastritis with Helicobacter pylori infection; sarcoidosis (n = 9), four of whom had concomitant chronic active gastritis with H. pylori infection; chronic active gastritis with H. pylori infection and no other systemic illness (n = 2); distal esophageal adenocarcinoma and chronic active gastritis (n = 2); mucosa-associated lymphoid tissue (MALT) lymphoma with chronic active gastritis and presumed H. pylori infection (n = 2); peptic ulcer complications (n = 2); hypertrophic gastropathy with chronic active gastritis (n = 1); and possible Crohn's disease (n = 1). We conclude that (a) in most cases of granulomatous gastritis, a diagnosis of Crohn's disease or sarcoidosis could be established; (b) the background inflammatory pattern was helpful in suggesting a diagnostic category for granulomatous gastritis; (c) granulomatous gastritis is not associated with H. pylori per se; however, if known cases of Crohn's disease and sarcoidosis are excluded, an association between H. pylori and granulomatous gastritis cannot be ruled out; and (d) IGG, if it exists, is extremely rare.

Protein-losing gastropathy associated with cytomegalovirus: a rare and late complication of allogeneic bone marrow transplantation.

A 36-year-old women with chronic myelogenous leukemia in first chronic phase received a bone marrow transplant from her HLA-identical brother. The preparatory regimen consisted of total body irradiation (10 Gy) and cyclophosphamide (60 mg/kg for 2 days). Full engraftment was achieved and the woman was monitored as an outpatient after discharge from hospital on day 35. One year after BMT, while she was on cyclosporin A and steroids because of chronic graft-versus-host disease, the patient developed protein-losing gastropathy associated with cytomegalovirus infection (with no gastrointestinal symptoms), which regressed spontaneously in 4 weeks.

The association between tumour necrosis factor-alpha gene polymorphism and the susceptibility to rugal hyperplastic gastritis and gastric carcinoma.

OBJECTIVES: Some subjects infected by Helicobacter pylori have enlarged folds in the gastric body, the precise mechanism of which remains obscure. The aim of this study was to clarify the association of tumour necrosis factor-alpha (TNFA) gene polymorphism with susceptibility to hyper-rugosity. We also examined the association of TNFA polymorphism with gastric carcinoma. SUBJECTS AND METHODS: Four hundred and seventy-two subjects (male/female = 351/121, aged 26-81 years) without gastric carcinoma (control group), and 300 patients (male/female = 218/82, aged 32-91 years) with gastric carcinoma. Barium meal roentgenograms were performed in 396 subjects in the control group and fold width was measured at the greater curvature of the middle portion of the gastric body. Fasting plasma anti-H. pylori IgG titres, pepsinogens (PGs) I and II were analysed, and TNFA -857 promoter polymorphism was distinguished by the 5' nuclease polymerase chain reaction assay and polymerase chain reaction restriction fragment length polymorphism using HincII in both groups. RESULTS: Adjusted odds ratios of TNFA -857 T/T genotype and H. pylori seropositivity for hyper-rugosity (fold width = 6.0 mm) were 6.7 (95% confidence interval (CI) 1.5-28, P < 0.01) and 18.2 (95% CI 4.2-78, P < 0.0001), respectively. There were no significant differences in any genotype or allele frequencies between the control and total gastric carcinoma group. In a subgroup of gastric carcinoma patients who were negative for the PG assay, however, the odds ratio of the T allele was 1.4 (95% CI 1.0-2.0, P < 0.05). CONCLUSION: The TNFA -857 T/T genotype and H. pylori infection were strongly associated with rugal hyperplastic gastritis. The TNFA -857 T allele may promote gastric carcinoma without severe atrophy.

[Exudative gastropathy associated with cytomegalovirus infection after allogenic bone marrow transplantation]. / Gastropathie exsudative à cytomégalovirus après greffe de moelle allogénique.

The authors report a case of protein losing gastropathy associated with cytomegalovirus. This form which is extremely rare in adults occurred alone after allogenic bone marrow transplantation and become apparent by a hypoalbuminaemia causing oedema of the lower limbs. Gastrocopy showed large red folds of approximately a centimetre covered in a whitish hypersecretion coating. Biopsy demonstrated active gastritis which appeared on a hypertrophic and hypersecretive gastritis. Outcome was favourable within 3 months without treatment.

[Menetrier disease associated with ulcerative colitis. Response to the treatment with octreotide. Review of the diagnostic criteria and etiopathogenesis]. / Enfermedad de Ménétrier asociada a colitis ulcerosa. Respuesta al tratamiento con octreótido. Revisión de los criterios diagnósticos y etiopatogenia.

The case of a patient with Ménétrier's disease in association with inactive ulcerative colitis of 7 years of evolution is presented. Diagnosis was confirmed by exploratory laparotomy and the symptoms of anemia and hypoproteinemia improved following treatment with octreotide. On review of the literature this was found to be the third case of Ménétrier's disease associated with ulcerative colitis described in the world literature. A possible relationship with an increase in alpha TGF is suggested. The diagnostic criteria and the possible etiopathogenic factors of the disease are herein reviewed.

[Resolution of Ménétrier's disease after eradication of Helicobacter pylori infection]. / Resolución de la enfermedad de Ménétrier tras la erradicación de la infección por Helicobacter pylori.

Ménétrier's disease is an infrequent clinical entity characterized by thickening of the gastric folds secondary to hyperplasia of the foveolar mucosa cells, frequently associated with loss of enteric proteins and hypoalbuminemia. Its etiology is unknown, although in the last few years it has been related to Helicobacter pylori infection. We present the case of a 38-year-old man with protein-losing gastroenteropathy caused by Ménétrier's disease, in whom eradication of H. pylori infection was followed by symptom improvement and resolution of hypoalbuminemia. In agreement with the criteria of other authors, we investigate the presence of H. pylori infection in all patients with Ménétrier's disease. When positive, the first-line treatment consists of eradication therapy.