Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins.

BACKGROUND: Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identified in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modification in a Tunisian LS family. PATIENTS AND METHODS: A Tunisian family with strong colorectal cancer (CRC) history that fulfill the Amsterdam I criteria for the diagnosis of Lynch syndrome was proposed for oncogenetic counseling. The index case was a man, diagnosed at the age of 33 years with CRC. He has a monozygotic twin diagnosed at the age of 35 years with crohn disease. Forty-seven years-old was the onset age of his paternal uncle withCRC. An immunohistochemical (IHC) labeling for the four proteins (MLH1, MSH2, MSH6 and PMS2) of the MisMatchRepair (MMR) system was performed for the index case. A targeted sequencing of MSH2, MLH1 and a panel of 85 DNA repair genes was performed for the index case and for his unaffected father. RESULTS: The IHC results showed a loss of MSH2 but not MLH1, MSH6 and PMS2 proteins expression. Genomic DNA screening, by targeted DNA repair genes sequencing, revealed an MSH2 pathogenic mutation (c.1552C>T; p.Q518X), confirmed by Sanger sequencing. This mutation was suspected to be a causal mutation associated to the loss of MSH2 expression and it was found in first and second degree relatives. The index case has smoking and alcohol consumption habits. Moreover, he harbors extensive genetic variations in other DNA-repair genes not shared with his unaffected father. CONCLUSION: In our investigated Tunisian family, we confirmed the LS by IHC, molecular and in silico investigations. We identified a novel pathogenic mutation described for the first time in Tunisia. These results come enriching the previously reported pathogenic mutations in LS families. Our study brings new arguments to the interpretation of MMR expression pattern and highlights new risk modifiers genes eventually implicated in CRC. Twins discordance reported in this work underscore that disease penetrance could be influenced by both genetic background and environmental factors.

Thyroid storm-induced acute liver dysfunction and portal hypertension in a patient with Graves' disease: a case report.

Thyroid storm is a life-threatening condition associated with multiorgan dysfunction and decompensation. We report the case of a 41-year-old woman having Graves' disease presented with thyroid storm complicated with liver dysfunction and portal hypertension in the absence of congestive heart failure or known liver disease. After successful therapeutic management, all biological, clinical and morphological abnormalities regressed.

Graves' disease is an immune system disorder that results in the overproduction of thyroid hormones. We report the case of a 41-year-old woman with Graves' disease who presented with reversible liver dysfunction and high blood pressure in the portal vein (located in the abdomen) following the withdrawal of her treatment.

Impact of direct-acting antiviral on subclinical atherosclerosis in chronic hepatitis C infected patients.

INTRODUCTION: The impact of direct antiviral drugs (DAAs) on extrahepatic manifestations in chronic hepatitis C (CHC) has been poorly studied. AIM: To assess the prevalence of subclinical atherosclerosis in patients with CHC and the impact of DAAs on atherosclerotic lesions. Methods A 5-year prospective evaluative study, including patients followed for CHC at hepato-gastroenterology department. The subclinical atherosclerosis was assessed by ultrasound measurement of carotid intima-media thickness (IMTc) and the highest IMTc measurements from the left and right side defined the IMTc maximum (IMTc max). IMTc>75th percentile (IMTc75) define subclinical atherosclerosis with high cardiovascular risk. Patients were evaluated before (T0) and one year after DAAs therapy achievement (T1). RESULTS: At time T0, forty patients (median age: 55 y.; sex ratio M / F = 0.48), were included. Average value of IMTc max was 0.68 ± 0.16 mm. Subclinical atherosclerosis was noted in 82.5 %. At time T1, 28 patients were evaluated, all of whom completed sustained virological response (SVR). Compared to time T0, there was a significant increase in cholesterol (p = 0.001) and triglyceride (p = 0.009) levels. IMTc max was significantly higher at time T1 compared to T0 (0.75 Vs 0.67 mm, p = 0.04). Prevalence of IMTc75 was 82.1% at time T0 and 75% at time T1 (p=0.5). CONCLUSIONS: SVR, in CHC patients treated with DAA, was associated with worsening of carotid atherosclerotic lesions.

Air embolism complicating endoscopic retrograde cholangiopancreatography.

Aim: Venous air embolism is a rare but potentially life threatening complication of endoscopic retrograde cholangiopancreatography. Diagnosis is difficult because of the lack of specific signs or symptoms. Case: A 62-year-old man underwent endoscopic retrograde cholangiopancreatography for choledocholithiasis. A cardiovascular collapse occurred during the procedure. The echocardiography showed air within the right ventricle. Aspiration of air from the right ventricle was done and saved the patient's life. Conclusion: We highlight through this case that increased awareness is essential for prompt recognition of the air embolism to allow life-saving therapy.

Endoscopic treatment is the first-line treatment for biliary stones. It may be associated with various complications. We report the case of a 62-year-old patient who underwent endoscopic treatment for biliary stone. During the procedure, he experienced disturbed cardiac function due to the passage of air bubbles into the cardiac cavities. The bubbles were aspirated with a good outcome.

Risk of metabolic syndrome in patients with chronic hepatitis C.

INTRODUCTION: Chronic hepatitis C is associated with several metabolic abnormalities including diabetes and insulin resistance. Metabolic syndrome, a major cardiovascular risk factor, may represent an additional risk of morbidity and mortality in patients with viral hepatitis C. AIM: To assess the risk of metabolic syndrome in patients with chronic hepatitis C and its impact on liver fibrosis. METHODS: Retrospective cohort study, including a group of exposed patients with untreated chronic hepatitis C and a group of unexposed patients with negative hepatitis C serology. We compared the prevalence of metabolic syndrome between the two groups and evaluated the association between metabolic syndrome and advanced fibrosis in the exposed patients. RESULTS: Forty exposed and 40 unexposed were included. The two groups were matched for age, sex and anthropometric data. Fibrosis was significant in 67.5% of the exposed group. The exposed group had a significantly higher prevalence of metabolic syndrome and insulin resistance compared to the unexposed group (37.5% VS 15%; p=0.02 VS 67.5% , 37.5%; p=0.02 VS 67.5%, 37.5%; p=0.007, respectively). The relative risk of metabolic syndrome in the exposed group was 2.5. Metabolic syndrome was not associated with significant fibrosis (p=0.7).

Performance of the ADRESS-HCC score in the assessment of the risk of hepatocellular carcinoma in viral cirrhosis in Tunisia.

INTRODUCTION: The ADRESS-HCC score allows predicting the risk of occurrence of Hepatocellular carcinoma in cirrhosis at one year of follow-up. AIM: Measuring the performance of ADRESS-HCC in predicting the risk of degeneration on post-viral cirrhosis, in a gastroenterology department in Tunisia. METHODS: Retrospective study, including patients followed for compensated viral cirrhosis in the gastroenterology department of the Mohamed Taher Maamouri hospital. The ADRESS-HCC score was calculated at diagnosis of cirrhosis. We divided patients into two groups depending on whether they developed Hepatocellular carcinoma or not. We evaluated the performance of the ADRESS-HCC score in predicting the risk of Hepatocellular carcinoma according to a threshold value. RESULTS: We enrolled 60 patients; the mean age was 62 years. Twenty-five patients developed hepatocellular carcinoma during follow-up. The mean value of ADRESS-HCC score was 5.08. To predict the occurrence of hepatocellular carcinoma at 1 year of follow-up, the area under the curve of the ADRESS-HCC score was 0.74 (p=0.01). For a threshold value of 5.63 its sensitivity was 91 % with a negative predictive value of 95.83%. CONCLUSION: The ADRESS-HCC score had an average performance in predicting degeneration in post-viral cirrhosis.

A rare case of gastric metastasis originating from primary lung adenocarcinoma: a case report.

Unlike liver and lung, the stomach is rarely a metastatic location for cancers. We report a case of a 62-year-old man known to have lung adenocarcinoma poorly differentiated presented with melena 1 month after diagnosis. Upper endoscopy revealed an ulcerated tumor in the prepyloric antrum. The diagnosis of gastric metastasis from pulmonary cancer was confirmed by the immunohistochemical staining for the thyroid transcriptional factor-1 and the pattern cytokeratine CK7+/CK20-. In conclusion, gastric metastasis from primary lung cancer is a rare phenomenon that every clinician must keep in mind.

A 62-year-old man known to have lung adenocarcinoma poorly differentiated presented with melena 1 month after diagnosis. Upper endoscopy revealed an ulcerated tumor in the prepyloric antrum. The diagnosis of gastric metastasis from pulmonary cancer was confirmed by histology.

Multifocal nodular lesions in fatty liver mimicking neoplastic disease: a case report.

Usually, fatty hepatic infiltration is diffuse and homogeneous. However, in some cases, it can be localized simulating benign or malignant tumors. We present a case of a 61-year-old female patient with family history of malignancy: sister with lung cancer, an other sister with colon cancer and a mother with breast cancer; who presented with multiple hepatic nodules at the ultrasonography images. CT scan and MRI were not sufficient to pose a certain diagnosis which was later confirmed by liver biopsy.

In some cases, fatty hepatic infiltration may simulate benign or malignant tumors. We present a case of a 61-year-old female patient with family history of malignancy who presented with multiple hepatic nodules at the ultrasonography images. CT scan and MRI were not sufficient to pose a certain diagnosis which was later confirmed by liver biopsy.

A rare cause of spontaneous hemoperitoneum: intra-abdominal vein rupture.

Aim: Ruptures of the intra-abdominal vein causing a spontaneous hemoperitoneum in cirrhotic patients is a rare condition. However, diagnosis must be considered early in cirrhotic patients with hematic ascites as a delayed diagnosis with hemodynamic instability is associated with a poor prognosis. Case report: We present the case of a 54-year-old cirrhotic patient who presented a spontaneous hemoperitoneum due to the rupture of the intra-abdominal vein that was diagnosed during exploratory laparoscopy. Conclusion: Early diagnosis and management of spontaneous hemoperitoneum due to the rupture of intra-abdominal vein helps improve its prognosis.

Spontaneous hemoperitoneum is a rare but catastrophic condition caused by the rupture of the liver, spleen or abdominal vessels. In patients with cirrhosis, diagnosis of spotaneous hemoperitoneum is difficult. This is a case report of a 54-year-old cirrhotic man with a spontaneous hemoperitoneum due to the rupture of a vein within the abdomen. The diagnosis was suspected as the patient had signs of blood in the abdomen. To confirm spontaneous hemoperitoneum, the doctors performed a procedure called exploratory laparoscopy, which involves inserting a small camera into the abdomen. The laparoscopy confirmed the presence of blood and thus the diagnosis of spontaneous hemoperitoneum.

Synchronous primary gastric and renal tumors: a case report.

Synchronous multiple primary cancers of the stomach and kidney are very rare, only 45 cases of synchronous multiple primary cancers of the stomach and kidney had been reported in the literature up until 2020. Thus far, no particular risk factors have been identified. We present a case of synchronous multiple primary cancers of the stomach and kidney in a 67-year-old female presenting with a 3-month history of vomiting and abdominal pain. The diagnosis of gastric adenocarcinoma with signet ring cells was confirmed through upper endoscopy with biopsies, while CT-guided biopsies of the renal tumor confirmed the diagnosis of primary kidney neoplasm.

Having more than one cancer at the same time is known as multiple primary malignancies. Having cancers in both the stomach and kidney at the same time is even rarer, with only 45 cases reported in literature. The exact causes of such cancers occurring together are not yet known. We present a 67-year-old woman who was diagnosed with synchronous multiple primary cancers of the stomach and kidney. She presented with vomiting and abdominal pain. The diagnosis of gastric cancer was confirmed through upper endoscopy with biopsies, while biopsies of the renal tumor confirmed the diagnosis of primary kidney cancer.

Tunisian consensus on the management of Helicobacter Pylori infection.

Helicobacter pylori infection is the most common infectious disease worldwide. It is associated with duodenal and gastric ulcer disease and the risk of gastric neoplasia. The management of helicobacter pylori infection currently represents a real challenge for clinicians, given the ever-increasing rate of resistance of Helicobacter pyolori to various antibiotics. In this consensus document, we present recommendations adapted to the Tunisian context, including indications for the detection of helicobacter pylori infection, indications for the use of different diagnostic methods, and a therapeutic strategy for the management of Helicobacter pylori infection.

Esophageal hirudiniasis: an unusual cause of upper gastrointestinal bleeding.

Leeches are carnivorous, hermaphroditic, segmented worms mainly found in fresh water. The majority of leech attachments are external and short-lasting. Internal surfaces can be involved. Yet, esophageal attachment is very rare. We report a case of a 59-year-old female who presented with hematemesis, melena and chest pain. Upper gastrointestinal endoscopy revealed a round black foreign body in the mid-third of the esophagus identified as a leech. We carefully extracted the worm with a forceps applied to the middle of its body. The diagnosis of leech infestation should be kept in mind when exploring gastrointestinal bleeding in patients living in rural areas and those with poor living conditions.

[Predictors of hepatic encephalopathy in patients with severe acute liver injury]. / Facteurs prédictifs de l'encéphalopathie hépatique au cours de l'atteinte hépatique aiguë sévère.

Introduction: severe acute liver injury (SALI) formerly known as severe acute hepatitis is an acute inflammation of the liver with markers of liver injury (elevated transaminases) and signs of hepatocellular failure (jaundice and INR greater than 1.5) according to the latest definition of the European Association for the Study of the Liver (EASL). An important prognostic factor in SALI is the development of hepatic encephalopathy (HE) and thus its progression to acute liver failure (ALF), formerly known as acute severe hepatitis. The purpose of this study is to investigate factors predicting the development of hepatic encephalopathy during SALI. Methods: we conducted a retrospective study of patients treated for SALI between January 2000 and December 2019. We divided patients into two groups depending on whether hepatic encephalopathy occurred. We performed an analytical study comparing the two groups according to their epidemiological, biological and evolutionary data. Results: data from the medical records of fifty-nine patients were collected. A virus was the most frequent cause (63%). Hepatic encephalopathy occurred in 15 patients (25.4%). Factors predicting the development of HE in univariate analysis were a delay in consultation of more than 9 days, an INR level of more than 2.45, a bilirubin level of more than 230 µmol/l, creatinine greater than 60.5 µmol/l, urea greater than 5.5 mmol/l and MELD score greater than 26.5 (p=0.023, p=0.017, p=0.0001, p=0.049, p=0.0001, p=0.0001 respectively). Autoimmune hepatitis and an undetermined cause were associated with the development of HE (p=0,003 and p=0,044, respectively). In multivariate analysis, autoimmune aetiology and a urea level above 5.5 mmol/l were significantly associated with the occurrence of HE. No statistically significant differences were found between the two groups with regard to age, sex and diabetes. Conclusion: SALI is a rare disease, mainly due to a virus in our country. Predictive factors of HE are important for early identification of patients at risk of adverse outcomes.

Esophageal tuberculosis as an unusual cause of dysphagia: a case report.

Esophageal tuberculosis is a rare cause of infectious esophagitis, even in countries with endemic tuberculosis. This impairment is often secondary. We report a case of secondary esophageal tuberculosis in an immunocompetent patient, clinically revealed by dysphagia. Esophagogastroduodenoscopy showed a large ulcer in the middle third of the esophagus with a fistula opening in the center of the ulcer. Histopathological examination of multiple esophageal tissue biopsies revealed epithelioid cell granulomas without caseous necrosis. We completed with Computed Tomography (CT) scan of the chest which revealed a fistula of the middle third of the esophagus, multiple mediastinal necrotic adenopathies and diffuse pulmonary micronodules suggesting miliary tuberculosis. Sputum examination for acid-fast-bacilli was positive. Anti-tuberculosis treatment resulted in a good response with complete remission. It is therefore important to recognize and include this entity in the differential diagnosis of patients with dysphagia particularly in countries with a high incidence of tuberculosis.

Solitary gastric Peutz-Jeghers polyp: a case report.

Peutz-Jeghers syndrome is an inherited condition that is characterized by mucocutaneous pigmentation and hamartomatous polyposis in the gastrointestinal tract. It increases significantly the risk for developing of several cancers such as breast, colon, rectum, pancreas and stomach. Solitary Peutz-Jeghers polyp is defined as a unique hamartomatous polyp having the same histological features as Peutz-Jeghers syndrome polyps without associated intestinal polyposis, mucocutaneous pigmentation and family history of Peutz-Jeghers syndrome. Gastric solitary Peutz-Jeghers polyp is extremely rare. We found only 13 cases in the literature. We report a new case of solitary gastric Peutz-Jeghers polyp associated with a branch duct intraductal papillary mucinous neoplasm revealed by an acute pancreatitis. Computed tomography of the abdomen found a branch duct intraductal papillary mucinous neoplasm with a pedicled polypoid formation in the greater gastric curvature. Endoscopic resection was performed without complications. Histologic examination showed Peutz-Jeghers hamartomatous polyp. The risk of cancer remains unclear in this entity. Therefore, the follow-up of these patients is necessary because of the possible risk of malignancy.

Acquired double pylorus presenting as a gastrointestinal bleeding.

We present the case of a 65-year-old man without a past medical history who was admitted for gastrointestinal bleeding. The case shows an acquired double pylorus due to probable pre pyloric ulcer.

Fatal invasive gastric mucormycosis: Two case reports.

Mucormycosis is a fungal infection affecting most commonly immunocompromised patients. Hereby, we report two cases: the first one is about a 61-year-old female with diabetes who presented with vomiting. The upper gastrointestinal endoscopy showed a budding grayish process which corresponded to an invasive mucormycosis in histology. As laboratory tests showed renal dysfunction, conventional amphotericin B was started at low doses since liposomal form was unavailable in Tunisia. Evolution was marked by a worsening of renal function leading to drug therapy withdrawal. Total gastrectomy was delayed because of a pulmonary embolism and was practiced 2 months later. The patient passed away 10 days after surgery. The second patient was a 59-year-old man who presented with vomiting and fast worsening of general state. At admission, he had a septic shock. Explorations revealed an invasive gastric mucormycosis. He died few days after admission. Thus, prompt diagnosis of mucormycosis and rapid initiation of treatment based on amphotericin B and surgical debridement is necessary to improve prognosis.

Osteopetrosis: a rare case of portal hypertension.

Osteopetrosis is a rare genetic bone disorder characterized by a defect in osteoclasts recruitment and function. Its manifestations are numerous and they mainly include skeletal and dental deformities, cranial nerve entrapment and infections. Over time, osteoclastic expansion invades bone marrow leaving little space for hematopoietic cells. As a result, extramedullary hematopoiesis takes place in the reticular system mainly in the spleen and liver. In these patients, portal hypertension can occur as a result of extramedullary hematopoiesis associated splenomegaly. We are reporting in this article a rare case of spontaneous bacterial peritonitis associated with portal hypertension in a patient with osteopetrosis.

A case of gastric metastasis originating from right-sided colon cancer 4 years after colectomy.

The stomach is rarely a metastatic site of other primary cancers. Gastric metastasis from colonic cancer is exceptional. We hereby report a case of a 54-year-old male patient who underwent a right hemicolectomy for right-sided colon cancer. The pathology exam revealed well differentiated adenocarcinoma, it was classified stage IIb. Regular controls performed including colonoscopy were normal. Four years after colectomy, the patient was admitted for hematemesis with epigastric pain with detoriation of general condition . Gastroscopy revealed a large ulceroproliferative mass in the antropyloric region. Histology showed that this tumor was an adenocarcinoma similar to the primary right colon cancer, which led to the diagnosis of metastatic gastric cancer originating from colon cancer.

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma.

Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.