scholarly journals Gastric Adenocarcinoma in the Setting of IPEX Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
David Steffin ◽  
Saleh Bhar ◽  
Douglas S. Fishman ◽  
Nicholas L. Rider ◽  
Bindi Naik-Mathuria ◽  
...  
Keyword(s):  
Gastric Adenocarcinoma ◽  
Clinical Symptoms ◽  
Foxp3 Expression ◽  
Immune Dysregulation ◽  
Loss Of Function ◽  
Unique Case ◽  
Foxp3 Gene ◽  
Signet Ring ◽  
Risk Of Cancer

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked disorder caused by a loss of function mutation in the FOXP3 gene. It manifests early in infancy with clinical symptoms including autoimmune enteropathy, type 1 diabetes mellitus, and eczema. While aberrant FOXP3 expression has been associated with several types of cancer, little is known regarding the risk of cancer in patients with IPEX harboring the characteristic FOXP3 mutation. Here, we present a unique case of a primary signet ring gastric adenocarcinoma in a pediatric patient with IPEX syndrome.

scholarly journals Underlying IPEX Syndrome in a Patient With Idiopathic Juvenile Arthritis and Vitiligo

2021 ◽  
Author(s):  
Leonardo Oliveira Mendonça ◽  
Adriana Ptichon dos Reis Chuster ◽  
Samar Freschi Barros ◽  
Janaina Baptista Alves ◽  
Victor Lucas Gonçalves ◽  
...  
Keyword(s):  
Inborn Error ◽  
Immune Dysregulation ◽  
Juvenile Arthritis ◽  
Loss Of Function ◽  
Renal Disorders ◽  
Foxp3 Gene ◽  
Skin Manifestations ◽  
Forkhead Box ◽  
Idiopathic Juvenile Arthritis

Abstract IPEX syndrome (MIM #304790) also known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked is a monogenic inborn error of immunity due to loss-of-function mutations in the forkhead box 3 (FOXP3) gene. This gene is crucial for the development, maturation and maintenance of CD4+ regulatory T (T-reg) cells. Various phenomenon mainly of autoimmune origin are characteristics of the syndrome such as enteropathy, endocrinopathies, cytopenias, renal disorders and skin manifestations (1).

HER2 OVEREXPRESSION IN ENDOSCOPIC BIOPSY SAMPLE OF GASTRIC ADENOCARCINOMA BY IMMUNOHISTOCHEMISTRY

2012 ◽  
pp. 109-118
Author(s):  
Viet Nho Le ◽  
Van Huy Tran ◽  
Cong Thuan Dang ◽  
Van To Ta
Keyword(s):  
Gastric Adenocarcinoma ◽  
Undifferentiated Carcinoma ◽  
Signet Ring Cell Carcinoma ◽  
Signet Ring Cell ◽  
Endoscopic Biopsy ◽  
Her2 Overexpression ◽  
Tubular Adenocarcinoma ◽  
Signet Ring ◽  
Poorly Differentiated ◽  
Well Differentiated

Background and aim: HER2 overexpression by immunohistochemistry is a prognostic maker in gastric cancer and helps to select candidates benefitted from targeted therapy with trastuzumab. This study is aimed at the assessing HER2 overexpression and its relationship with endoscopic and histopathological findings of gastric adenocarcinoma. Objectives and methods: Biopsy samples from 92 gastric cancer patients were examined for HER2 status by immunohistochemical staining. Results: 6.5% of tumors were cardia tumors and 93.5% were non-cardia tumors. Using the Lauren classification, 51.1% were intestinal type and 48.9% were diffuse type. Using WHO classification, 54.3% were tubular adenocarcinoma, 7.6% were mucinous adenocarcinoma, 15.2% were signet-ring cell carcinoma, and 22.8% were undifferentiated carcinoma. 32.6% were well-differentiated, 15.2% were moderately-differentiated, and 52.2% were poorly-differentiated carcinoma. HER2 was positive in 20.7% of gastric carcinomas, 50% cardia tumors and 18.6% non-cardia tumors. HER2 positivity among polypoid, fungating, ulcerated, and infiltrative types were 38.5%, 29.7%, 9.1% and 0%, respectively. HER2 overexpression in intestinal type was higher than that in diffuse type (31.9% vs. 8.9%, p = 0.009). HER2 overexpression in tubular adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, and undifferentiated carcinoma was 28.0%, 14.3%, 7.1% and 14.3%, respectively. HER2 overexpressions were different between differentiation degrees: 30% of well-differentiated tumors, 35.7% moderately-differentiated tumors, and 10.4% of poorly-differentiated tumors (p = 0.037). Conclusions: HER2 overexpression was found in 20.7% of endoscopic biopsy sample of gastric adenocarcinoma and was associated with endoscopic gross characteristic, Lauren histologic type and differentiation degree.

scholarly journals Clinical spectrum and pleiotropic nature of CDH1 germline mutations

2019 ◽  
Vol 56 (4) ◽  
pp. 199-208 ◽  
Author(s):  
Joana Figueiredo ◽  
Soraia Melo ◽  
Patrícia Carneiro ◽  
Ana Margarida Moreira ◽  
Maria Sofia Fernandes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Lobular Breast Cancer ◽  
Cancer Syndrome ◽  
Risk Of Cancer ◽  
E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

scholarly journals Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 268
Author(s):  
Marta Ferrari ◽  
Stefano Stagi
Keyword(s):  
Down Syndrome ◽  
Autoimmune Diseases ◽  
Normal Population ◽  
Underlying Mechanism ◽  
Short Review ◽  
Immune Dysregulation ◽  
Infectious Complications ◽  
Genetic Syndromes ◽  
Genetic Syndrome

Within immune system-related diseases, autoimmunity has always represented a field of great interest, although many aspects remain poorly understood even today. Genetic syndromes associated with immunity disorders are common and represent an interesting model for a better understanding of the underlying mechanism of autoimmunity predisposition. Among these conditions, Down syndrome (DS) certainly deserves special attention as it represents the most common genetic syndrome associated with immune dysregulation, involving both innate and adaptive immunity. Autoimmunity represents a well-known complication of DS: it is estimated that people affected by this disease present a risk four to six times higher than the normal population to develop autoimmune diseases such as celiac disease, type 1 diabetes mellitus, and hypo- or hyperthyroidism. Several factors have been considered as possible etiology, including genetic and epigenetic modifications and immune dysregulation. In times in which the life expectancy of people with DS has been extremely prolonged, thanks to improvements in the diagnosis and treatment of congenital heart disease and infectious complications, knowledge of the mechanisms and proper management of autoimmune diseases within this syndrome has become essential. In this short review, we aim to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes.

scholarly journals Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zahra Beyzaei ◽  
Fatih Ezgu ◽  
Bita Geramizadeh ◽  
Mohammad Hadi Imanieh ◽  
Mahmood Haghighat ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Gene Sequencing ◽  
Glycogen Storage ◽  
Loss Of Function ◽  
Retrospective Case ◽  
Complex Disorders ◽  
Glycogen Storage Diseases ◽  
Targeted Gene Sequencing ◽  
Retrospective Case Study

AbstractGlycogen storage diseases (GSDs) are known as complex disorders with overlapping manifestations. These features also preclude a specific clinical diagnosis, requiring more accurate paraclinical tests. To evaluate the patients with particular diagnosis features characterizing GSD, an observational retrospective case study was designed by performing a targeted gene sequencing (TGS) for accurate subtyping. A total of the 15 pediatric patients were admitted to our hospital and referred for molecular genetic testing using TGS. Eight genes namely SLC37A4, AGL, GBE1, PYGL, PHKB, PGAM2, and PRKAG2 were detected to be responsible for the onset of the clinical symptoms. A total number of 15 variants were identified i.e. mostly loss-of-function (LoF) variants, of which 10 variants were novel. Finally, diagnosis of GSD types Ib, III, IV, VI, IXb, IXc, X, and GSD of the heart, lethal congenital was made in 13 out of the 14 patients. Notably, GSD-IX and GSD of the heart-lethal congenital (i.e. PRKAG2 deficiency) patients have been reported in Iran for the first time which shown the development of liver cirrhosis with novel variants. These results showed that TGS, in combination with clinical, biochemical, and pathological hallmarks, could provide accurate and high-throughput results for diagnosing and sub-typing GSD and related diseases.

scholarly journals Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor

2021 ◽  
Author(s):  
Daan H. H. M. Viering ◽  
Anneke P. Bech ◽  
Jeroen H. F. de Baaij ◽  
Eric J. Steenbergen ◽  
A. H. Jan Danser ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Collecting Duct ◽  
Perinatal Period ◽  
Tubular Dysfunction ◽  
Loss Of Function ◽  
Angiotensin Ii Receptor ◽  
Salt Wasting ◽  
Truncating Mutation ◽  
Urinary Potassium

AbstractBackgroundGenetic loss of function ofAGT(angiotensinogen),REN(renin),ACE(angiotensin-converting enzyme), orAGTR1(type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age.MethodsHere, we report a 28-year-old male with a homozygous truncating mutation inAGTR1(p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone.ConclusionsThis report provides living proof that even truncating loss-of-function mutations inAGTR1are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.

The outcome of seven patients with hereditary tyrosinemia type 1

2016 ◽  
Vol 29 (10) ◽  
Author(s):  
Songul Gokay ◽  
Pembe Soylu Ustkoyuncu ◽  
Fatih Kardas ◽  
Mustafa Kendirci
Keyword(s):  
Clinical Symptoms ◽  
Age At Onset ◽  
Nodule Formation ◽  
First Year ◽  
Tyrosine Metabolism ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia ◽  
Biochemical Imaging

AbstractBackground:Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment.Methods:A retrospective study was carried out with seven HT1 patients.Results:The median age at onset of clinical symptoms was 11.2 months (range, 3–28 months) and the median age at diagnosis was 22 months (range, 6–58 months). Liver enzymes and coagulation parameters were back to normal in all symptomatic patients in about 2 weeks. Alfa-fetoprotein (AFP) levels were normalized within the first year of therapy. Hypoechoic nodule formation was detected in two of the seven patients despite drug treatment without an increase of AFP and any dysplastic changes in the biopsies. One patient died due to metastatic HCC because of the late diagnosis and the poor compliance of the follow-up.Conclusions:This study showed once again that adherence to the treatment and a follow-up schedule of the patients are very important. Also it should not be forgotten that nodule formation can occur despite nitisinone treatment without an increase of AFP. Despite nitisinone treatment, HT1 patients still carry the risk of HCC. HCC must be detected before metastasis to other organs otherwise, patients may lose the chance for liver transplantation.

Functional Hyperactivity in Long QT Syndrome Type 1 Pluripotent Stem Cell-Derived Sympathetic Neurons

2021 ◽  
Author(s):  
Annika Winbo ◽  
Suganeya Ramanan ◽  
Emily Eugster ◽  
Annika Rydberg ◽  
Stefan Jovinge ◽  
...  
Keyword(s):  
Pluripotent Stem Cell ◽  
Sympathetic Neurons ◽  
Compound Heterozygous ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Long Qt ◽  
Action Potential Frequency ◽  
Qt Syndrome ◽  
Potential Frequency

Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two LQT1 patients with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterisation of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay and whole-cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared to healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted noradrenaline. hiPSC-SNs at 60±2.2 days in vitro had healthy resting membrane potentials (-60±1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased noradrenaline release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarisation, compared to age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared to heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes.

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