Unusual case of adult familial Menetrier disease in siblings.

Menetrier disease is a rare disease characterised by hyperplasia of the gastric epithelium and large gastric folds. We present a case of a 58-year-old woman who was referred with iron deficiency anaemia, with a family history of a sibling who had undergone gastrectomy for presumed gastric malignancy. Endoscopy showed prominent gastric mucosal folds and biopsies showed hyperplastic gastric mucosa, with prominent foveolar hyperplasia suggestive of Menetrier disease. Further information about her brother's diagnosis was sought, and it was found that his pathology after gastrectomy showed diffuse glandular hyperplasia also in keeping with Menetrier disease. Adult familial Menetrier disease has so far been a rarity in the literature-review elicits five previous cases of this presentation in siblings.

A SMAD4 mutation indicative of juvenile polyposis syndrome in a family previously diagnosed with Menetrier's disease.

BACKGROUND: Menetrier's disease (MD) is a rare disease with unknown aetiology, characterized by hypertrophic folds within the fundus and body of the stomach. AIMS: We investigated mutations of the candidate genes SMAD4, BMPR1A, TGF-α, and PDX1 within a family with MD. METHODS: A large 4-generation family with MD was identified. This family had 5 cases of MD, 1 case of MD and juvenile polyposis syndrome (JPS) and 3 cases of JPS. Participants provided saliva for DNA extraction and completed a health questionnaire designed to assess conditions that may be found in patients with MD. Following pedigree analysis, we sequenced the coding regions of the SMAD4 and BMPR1A genes and the regulatory regions of the TGF-α and PDX1 genes in affected and non-affected family members. RESULTS: No mutations were identified in the sequenced regions of BMPR1A, TGF-α, or PDX1. A dominant 1244_1247delACAG mutation of SMAD4 was identified in each of the subjects with JPS as well as in each of the subjects with MD. Although this mutation segregated with disease, there were also unaffected/undiagnosed carriers. CONCLUSION: The 1244_1247delACAG mutation of SMAD4 is the cause of JPS and the likely cause of MD in a large family initially diagnosed with MD.

Generation of stomach tissue from mouse embryonic stem cells.

Successful pluripotent stem cell differentiation methods have been developed for several endoderm-derived cells, including hepatocytes, ß-cells and intestinal cells. However, stomach lineage commitment from pluripotent stem cells has remained a challenge, and only antrum specification has been demonstrated. We established a method for stomach differentiation from embryonic stem cells by inducing mesenchymal Barx1, an essential gene for in vivo stomach specification from gut endoderm. Barx1-inducing culture conditions generated stomach primordium-like spheroids, which differentiated into mature stomach tissue cells in both the corpus and antrum by three-dimensional culture. This embryonic stem cell-derived stomach tissue (e-ST) shared a similar gene expression profile with adult stomach, and secreted pepsinogen as well as gastric acid. Furthermore, TGFA overexpression in e-ST caused hypertrophic mucus and gastric anacidity, which mimicked Ménétrier disease in vitro. Thus, in vitro stomach tissue derived from pluripotent stem cells mimics in vivo development and can be used for stomach disease models.

A unifying working hypothesis for juvenile polyposis syndrome and Ménétrier's disease: specific localization or concomitant occurrence of a separate entity?

BACKGROUND: Juvenile polyposis syndrome with gastric involvement may mimic Ménétrier's disease, which is correlated to transforming growth factor (TGF)α overproduction and PDX1 upregulation in the gastric fundus. AIM: We report a family with juvenile polyposis syndrome where one member showed typical features of Ménétrier's disease and concomitant Helicobacter pylori infection. METHODS: We studied a 31-year-old woman belonging to a family with juvenile polyposis syndrome, who exhibited a particular form of hyperplastic gastropathy diagnosed as Ménétrier's disease with Helicobacter pylori infection. RESULTS: TGFα overexpression and undetectable PDX1 expression were demonstrated in the fundic gastric biopsy specimens. In all affected members of the family we identified a 4-bp deletion in exon 9 of SMAD4 gene, a mutation usually associated with a more virulent form of juvenile polyposis syndrome with a higher incidence of gastric and colonic polyposis. CONCLUSION: To explain the association of juvenile polyposis syndrome with Ménétrier's disease we hypothesized a new mechanism that involves TGFß-SMAD4 pathway inactivation and TGFα overexpression related to Helicobacter pylori infection.

Autosomal dominant Ménétrier-like disease.

BACKGROUND: Familial occurrence of Ménétrier disease is rare and has been reported only in few instances. METHODS: Affected patients from a large pedigree were evaluated at the clinical, endoscopic, and pathological levels. RESULTS: Affected members presented with gastropathy of variable severity but without protein loss. Endoscopy and pathology findings were consistent with Ménétrier disease; however, gastric transforming growth factor α (TGF-α) immunohistochemistry and real-time polymerase chain reaction showed no increase in TGF-α expression. CONCLUSIONS: We describe a unique, 4-generation pedigree with autosomal dominant gastropathy exhibiting the typical clinical, endoscopic, and pathological findings of Ménétrier-like disease, though in the absence of protein loss and with no increase in the levels of gastric TGF-α. Members of this family may be affected by a novel and previously unrecognised hereditary form of gastric hyperplasia.

Helicobacter pylori isolated from a patient with Ménétrier's disease increases hepatocyte growth factor mRNA expression in gastric fibroblasts: comparison with Helicobacter pylori isolated from other gastric diseases.

Ménétrier's disease has been reported to be associated with Helicobacter pylori infection. The aim of this study was to investigate the genetic characteristics of various virulence factors and cytokine expression profiles in Helicobacter pylori isolated from patients with Ménétrier's disease. The genotyping of virulence factors was accomplished by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Induction of various cytokines in MKN45 cells or gastric fibroblasts by Helicobacter pylori stimulus was measured by real-time reverse transcription-PCR. We found that the Helicobacter pylori strain isolated from a patient with Ménétrier's disease was different from other strains in the MseI-RFLP pattern of the ureC gene. Helicobacter pylori isolated from a patient with Ménétrier's disease showed the highest hepatocyte growth factor (HGF) and TNF-alpha mRNA expressions from gastric fibroblasts, and the highest TNF-alpha expression from MKN45 cells. The results in this study suggest that the difference in cytokine production, depending on the difference in bacteria components, plays an important role in the development of Ménétrier's disease.

Different pathological phenotypes of autoimmune gastritis induced by neonatal thymectomy between BALB/c and (BALB/c x DBA/2) F1 mice: role of eosinophils in hypertrophic autoimmune gastritis.

BACKGROUND: A unique pathological feature of murine autoimmune gastritis (AIG) is its pronounced mucosal hypertrophy, which is different from human type A chronic atrophic gastritis with pernicious anemia. The aim of this study was to clarify the mechanism of gastric hypertrophy in murine AIG, especially in relation to inflammatory cells infiltrating the gastric mucosa. METHODS: Neonatally thymectomized (NTx) BALB/c and (BALB/c x DBA/2) F1 mice with gastritis were examined histologically and serologically. The T-helper (Th1/Th2) immune balance in the spleen was evaluated by intracellular cytokine staining for interferon-gamma and a flow-cytometric beads array for several cytokines. Additionally, NTx AIG BALB/c mice were orally administered an H(2)-blocker to decrease eosinophils. RESULTS: NTx AIG BALB/c mice exhibited gastritis without stomach hypertrophy at 2 months of age, and developed gastritis with mucous gland hypertrophy accompanied by eosinophil infiltration at 6 months of age. In contrast, NTx AIG (BALB/c x DBA/2) F1 mice displayed gastritis with neither stomach hypertrophy nor eosinophil infiltration even at the age of 6 months. Upregulation of interleukin-4 and granulocyte-macrophage colony-stimulating factor in the spleen was observed in BALB/c mice but not in (BALB/c x DBA/2) F1 mice. Additionally, some NTx AIG BALB/c mice did not show gastric hypertrophy or eosinophil infiltration owing to the administration of an H(2)-blocker. CONCLUSIONS: There are two different pathological phenotypes of murine AIG, chronic gastritis and hypertrophic gastritis, in NTx AIG BALB/c mice. Furthermore, eosinophil infiltration and the Th2 immune response might play a key role in the phenotypic shift from chronic gastritis to hypertrophic gastritis in these mice.

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.

[Immunoglobulin rearrangement in the differential diagnosis of primary gastric lymphoma]. / Reordenamiento de inmunoglobulinas en el diagnóstico diferencial del linfoma gástrico primario.

BACKGROUND: The traditional methods to distinguish Chronic Follicular Gastritis and Primary Gastric Lymphoma do not allow an adequate definitive diagnosis in a significant number of cases. The molecular Biology diagnostic methods are based on the rearrangement of immunoglobulin genes. The polymerase chain reaction (PCR) specifically amplifies this rearrangement and allows molecular analysis of minimal tissue samples obtained with endoscopical biopsies. AIM: To test the usefulness of this PCR method in the differential diagnosis between Chronic Follicular Gastritis and Primary Gastric Lymphoma. MATERIAL AND METHODS: We analyzed the endoscopical biopsies of six Chronic Follicular Gastritis cases and eight surgically treated Primary Gastric Lymphoma cases, six with the correct diagnosis in the endoscopical biopsies and two with a diagnosis of Chronic Follicular Gastritis. RESULTS: A policlonal immunoglobulin rearrangement was found in the six cases with Chronic Follicular Gastritis. A monoclonal arrangement was found in 5 of 6 biopsies with the diagnosis of Primary Gastric Lymphoma. The same monoclonal rearrangement was observed in the two biopsies incorrectly diagnosed as Chronic Follicular Gastritis. CONCLUSIONS: PCR analysis of immunoglobulin rearrangement is a useful method in the differential diagnosis between Chronic Follicular Gastritis and Primary Gastric Lymphoma.

Gastric mucosal phospholipids in dogs with familial stomatocytosis-hypertrophic gastritis.

In dogs, hypertrophic gastritis, which resembles Ménétrier's disease in man, has been demonstrated to be part of a hereditary syndrome called familial stomatocytosis-hypertrophic gastritis. In addition to hypertrophic gastritis, affected dogs exhibit abnormal blood phospholipid composition. Phospholipids may play a role in maintaining gastric mucosal integrity, and this may be compromised in gastritis. The question arises whether the differences in blood phospholipids may result from a disorder that might also be revealed in the composition of gastric mucosal phospholipids. We analysed the phospholipid composition of gastric mucosa from four dogs with familial stomatocytosis-hypertrophic gastritis. The general phospholipid composition and the molecular composition of phosphatidylcholine from mucosal tissue in the corpus of the stomach where hypertrophic gastritis was evident were not different from that of the antrum, where the tissue was normal. These results do not corroborate a relation between the gastric mucosal phospholipid composition and hypertrophic gastritis.

Pigmentary retinopathy with nephrotic syndrome, Ménétrier's disease, and diabetes mellitus.

A patient with pigmentary retinopathy, nephrotic syndrome, Ménétrier's disease, and diabetes mellitus is presented. Other complications were congestive heart failure, hypothyroidism, hypertension, and hypertriglyceridemia. Hypogenitalism was also suspected. Pigmentary retinopathy is known to associate with many systemic diseases, which are classified into several syndromes. This case superficially resembles Alström's disease due to the common characteristics of pigmentary retinopathy, diabetes mellitus, renal disease, and hypogenitalism. But clinically and histologically, there are distinct differences. To our knowledge, this association has never been reported.

Familial stomatocytosis--hypertrophic gastritis (FSHG), a newly recognised disease in the dog (Drentse patrijshond).

A newly recognised disease, which we have given the provisional name of familial stomatocytosis-hypertrophic gastritis (FSHG), is described in two families of dogs of the Drentse partrijshond breed. The affected dogs consisted of 3 females and 5 males, 3 to 19 (mean 9.5) months of age at admission. The main clinical problems were diarrhoea, icterus, and ataxia and paresis of the pelvic limbs. Laboratory evaluation revealed abnormal red cell shape (stomatocytosis), increased osmotic fragility, haemolytic anaemia, and increased liver enzymes and serum bilirubin. Gastroscopic and histopathologic examination of the gastric mucosa revealed hypertrophic gastritis resembling Ménétrier's disease in man. Histologic findings in the liver were suggestive of progressive liver disease. Cysts were found in the kidneys of the five oldest patients. Electroneurography in 2 dogs revealed polyneuropathy. In the parents of 2 patients (sister and brother), there were no clinical or laboratory abnormalities. An autosomal recessive hereditary defect of lipid metabolism is suspected.

Familial giant hypertrophic gastritis (Ménétrier's disease).

Familial giant hypertrophic gastritis involving three generations is reported. A review of the literature, where approximately 200 cases are described, showed only few cases of familial occurrence of this disease, and only in siblings. Our findings suggest dominant heredity, but considering the sparsity of familial occurrence reported earlier, heredity seems to be of only minor pathogenetic significance.

Pachydermoperiostosis, hypertrophic gastropathy, and peptic ulcer.

Two brothers with pachydermoperiostosis, an autosomal dominant syndrome characterized by digital clubbing, periosteal new bone formation, coarse facial features with thick, furrowed, and oily skin, presented in their twenties with severe complicated duodenal ulcer disease requiring multiple operations. Their father and one paternal uncle also had pachydermoperiostosis and a past history of ulcer dyspepsia. The mother, one sister, two maternal aunts, and one other paternal uncle were healthy. Both brothers had giant hypertrophic gastritis (Ménétrier's disease). Their pentagastrin-stimulated acid output and fasting and meal-stimulated serum gastrin levels were normal, but their serum pepsinogen I and II levels were markedly elevated. The father had hypochlorhydria and a low serum pepsinogen I/II ratio, suggesting atrophic gastritis. This family study raises the possibility that pachydermoperiostosis, hypertrophic gastropathy, and peptic ulcer may be genetically related.