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1.
Gut ; 69(3): 411-444, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31780574

RESUMO

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Vigilância da População , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/prevenção & controle , Polipose Adenomatosa do Colo/terapia , Colonoscopia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/terapia , DNA Glicosilases/genética , Saúde da Família , Humanos , Polipose Intestinal/congênito , Polipose Intestinal/genética , Polipose Intestinal/terapia , Irlanda , Estilo de Vida , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Encaminhamento e Consulta/normas , Fatores de Risco , Reino Unido
2.
J Assoc Physicians India ; 67(10): 83-84, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571463

RESUMO

Cronkhite-Canada syndrome (CCS)is a rare non-hereditary hamartomatous polyposis syndrome of unknown aetiology. It is characterized by diffuse gastrointestinal polyps, dystrophic nail changes, alopecia, cutaneous hyperpigmentation, chronic diarrhoea, anorexia and hypogeusia. It is associated with a high incidence of gastrointestinal malignancies, mortality and morbidity. Early clinical suspicion and treatment is important. We report an elderly male with CCS who showed clinical and endoscopic improvement with long term corticosteroid therapy.


Assuntos
Diarreia , Hiperpigmentação , Polipose Intestinal , Idoso , Alopecia , Humanos , Masculino , Síndrome
4.
Pediatrics ; 144(2)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31366686

RESUMO

Juvenile polyposis syndrome is a rare autosomal dominant condition characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. Juvenile polyposis of infancy is a generalized severe form of juvenile polyposis syndrome associated with a poor prognosis. A 47-month-old female infant presented initially with gastrointestinal bleeding and protein-losing enteropathy at 4 months of age. At the age of 12 months, the condition worsened, requiring albumin infusions every 24 to 48 hours and red blood cell transfusions every 15 days. Upper gastrointestinal endoscopy, colonoscopy, and small-bowel enteroscopy revealed diffuse polyposis that was treated with multiple endoscopic polypectomies. Despite subtotal colectomy with ileorectal anastomosis, protein-losing enteropathy and bleeding persisted, requiring continued blood transfusions and albumin infusions. A chromosomal microarray revealed a single allele deletion in chromosome 10q23, involving both the PTEN and BMPR1A genes. Loss of PTEN function is associated with an increased activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway involved in cell proliferation. Treatment with sirolimus, an mTOR inhibitor, was initiated with the aim of inhibiting polyp growth. Soon after initiation of treatment with sirolimus, blood and albumin infusions were no longer needed and resulted in improved patient growth and quality of life. This case represents the first detailed report of successful drug therapy for life-threatening juvenile polyposis of infancy.


Assuntos
Imunossupressores/uso terapêutico , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Sirolimo/uso terapêutico , Pré-Escolar , Feminino , Seguimentos , Humanos , Polipose Intestinal/diagnóstico , Polipose Intestinal/tratamento farmacológico , Polipose Intestinal/cirurgia , Síndromes Neoplásicas Hereditárias/cirurgia , Resultado do Tratamento
5.
BMJ Case Rep ; 12(6)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31229977

RESUMO

We describe the case of a 16-year-old male patient with BMPR1A mutation and incidentally detected atrial septal defect (ASD). This patient was diagnosed with BMPR1A mutation through genetic testing and was attending for routine surveillance endoscopy when ASD was incidentally diagnosed. He was referred to cardiology outpatient clinic with plans for elective ASD closure. Through this case report we aim to discuss the pathophysiology of juvenile polyposis syndrome (JPS), highlight what we believe to be a novel presentation of comorbid BMPR1A mutation and ASD and hypothesise that patients with BMPR1A mutation and JPS may be at risk of previously unrecognised cardiovascular complications analogous to the previous association of SMAD4 JPS and cardiac abnormalities.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Mutação em Linhagem Germinativa/genética , Comunicação Interatrial/genética , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/genética , Adolescente , Comunicação Interatrial/fisiopatologia , Humanos , Polipose Intestinal/genética , Polipose Intestinal/fisiopatologia , Masculino , Síndromes Neoplásicas Hereditárias/fisiopatologia , Fenótipo
7.
Mol Pharmacol ; 96(1): 99-108, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31036695

RESUMO

C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic.


Assuntos
Oxirredutases do Álcool/química , Oxirredutases do Álcool/genética , Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Inibidores Enzimáticos/farmacologia , Polipose Intestinal/tratamento farmacológico , Triptofano/metabolismo , Oxirredutases do Álcool/antagonistas & inibidores , Animais , Antineoplásicos/química , Domínio Catalítico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores Enzimáticos/química , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Hidroxilaminas/química , Hidroxilaminas/farmacologia , Polipose Intestinal/metabolismo , Camundongos , Mutagênese Sítio-Dirigida , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Multimerização Proteica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Z Gastroenterol ; 57(4): 497-500, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30873576

RESUMO

Juvenile polyposis syndrome is a rare autosomal-dominant disorder characterized by multiple hamartomatous polyps in the gastrointestinal tract. It is associated with an increased risk of gastrointestinal cancer. We report the case of a 49-year-old woman presenting with proximal muscle weakness, weight loss, severe anemia, and melena. One year before, the diagnosis of a "fundic gland polyposis" was presumed after endoscopic evaluation for iron deficiency anemia had shown numerous polyps limited to the gastric mucosa. On admission, the diagnosis of dermatomyositis was made based on laboratory results with a marked elevated creatine kinase as well as the presence of characteristic clinical findings and muscle histology. Upper endoscopy revealed multiple pedunculated, edematous polyps in the stomach without apparent cancerous lesions intraluminally. Infiltration of the muscular layer was not detectable on endoscopic ultrasound. Histopathological examination of the polyps showed smooth outer surfaces and multiple dilated cystic glands, consistent with hamartomatous juvenile-type polyps. Magnetic resonance imaging revealed a peritoneal mass close to the greater curvature of the stomach, which was identified as a poorly differentiated adenocarcinoma by laparoscopic sampling. Immunohistochemical analysis of resected polyps was remarkable for a loss of SMAD4 expression, a finding that is very commonly observed in patients with gastric juvenile polyposis syndrome. Despite initial treatment response to glucocorticoids and chemotherapy, the patient died 5 months later due to progressive illness. Patients with gastric juvenile polyposis and SMAD4 mutations are at a high risk of developing gastric cancer; hence, early gastrectomy should be considered.


Assuntos
Dermatomiosite/complicações , Polipose Intestinal/congênito , Polipose Intestinal/diagnóstico por imagem , Síndromes Neoplásicas Hereditárias/diagnóstico por imagem , Pólipos/complicações , Pólipos/genética , Proteína Smad4/genética , Neoplasias Gástricas/complicações , Neoplasias Gástricas/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/genética , Adolescente , Dermatomiosite/patologia , Endoscopia do Sistema Digestório , Evolução Fatal , Feminino , Humanos , Polipose Intestinal/patologia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Gástricas/patologia
10.
BMC Gastroenterol ; 19(1): 36, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813906

RESUMO

BACKGROUND: Cronkhite-Canada syndrome is a rare disease of unknown etiology and the optimal treatment for this syndrome is unknown. CASE PRESENTATION: We present the case of a man who at the age of 66.0 years was diagnosed with Cronkhite-Canada syndrome (CCS). In addition to watery diarrhea, alopecia, and a complete loss of toenails and fingernails, the patient had been suffering from dysgeusia and rapid weight loss of more than 10.0 kg within a few months. The patient had recently incurred a distal radius fracture. During the initial endoscopy an extensive polyposis of the stomach and jejunum was found. The diagnosis of CCS was made and after initiation of a steroid therapy his diarrhea improved immediately. A discontinuation of the steroid therapy was not possible and mesalazine (1000 mg t.i.d.) was added to prednisolone (10.0 mg/d). This therapy led to a remission within 6.0 months with weight gain and normalization of serum albumin levels. The prednisolone dose was reduced to 7.5 mg/d. During the following year, the steroids could be further reduced and nails had regrown again. Within three years, all polyps had disappeared and the steroid therapy was finished while the dosage of mesalazine was reduced in a stepwise fashion. Four years later, the mesalazine was stopped and more than 14.0 years after the initial diagnosis the patient is still in complete remission without any treatment. CONCLUSION: The optimal treatment for CCS is unknown. In our case, the initial combination therapy of corticosteroids plus mesalazine followed by a mesalazine monotherapy has led to a remarkable long-lasting remission with complete resolution of all intestinal polyps.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Glucocorticoides/uso terapêutico , Polipose Intestinal/tratamento farmacológico , Mesalamina/uso terapêutico , Prednisolona/uso terapêutico , Idoso , Alopecia/etiologia , Diagnóstico Diferencial , Diarreia/etiologia , Esquema de Medicação , Disgeusia/etiologia , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/diagnóstico , Masculino , Desnutrição/etiologia , Desnutrição/terapia , Doenças da Unha/etiologia , Indução de Remissão , Perda de Peso
12.
13.
Clin Imaging ; 54: 37-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30521991

RESUMO

Juvenile polyposis syndrome (JPS) may coexist with hereditary hemorrhagic telangiectasia (HHT) due to implication of the SMAD4 gene in a subset of both diseases. To the best of our knowledge, we present the first case in the radiologic literature on the MRI findings in a patient with this rare combined diagnosis undergoing workup for burden of disease.


Assuntos
Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/complicações , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/complicações , Endoscopia/métodos , Humanos , Polipose Intestinal/complicações , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mutação
14.
J Pediatr Gastroenterol Nutr ; 68(3): 453-462, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30585890

RESUMO

The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Polyposis Working Group developed recommendations to assist clinicians and health care providers with appropriate management of patients with juvenile polyposis. This is the first juvenile polyposis Position Paper published by ESPGHAN with invited experts. Many of the published studies were descriptive and/or retrospective in nature, consequently after incorporating a modified version of the GRADE system many of the recommendations are based on expert opinion. This ESPGHAN Position Paper provides a guide for diagnosis, assessment, and management of juvenile polyposis syndrome in children and adolescents, and will be helpful in the appropriate management and timing of procedures in children and adolescents. The formation of international collaboration and consortia is proposed to monitor patients prospectively to advance our understanding of juvenile polyposis conditions.


Assuntos
Testes Genéticos/normas , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia , Adolescente , Criança , Colonoscopia/normas , Consenso , Medicina Baseada em Evidências , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/prevenção & controle , Testes Genéticos/métodos , Humanos , Polipose Intestinal/complicações , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Polipose Intestinal/terapia , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/genética
17.
Intern Med ; 58(3): 387-393, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30210120

RESUMO

A 52-year-old man with recurrent epistaxis and palpebral conjunctival telangiectasia visited our hospital for a follow-up checkup for gastrointestinal polyposis. At 48 years of age, he underwent Y-graft replacement for an abdominal aortic aneurysm. Arteriovenous malformation was detected in his lungs, and a genetic test revealed an SMAD4 mutation. Eventually, he was diagnosed with juvenile polyposis-hereditary hemorrhagic telangiectasia (JP-HHT) syndrome. In addition, fatty degeneration of the left ventricle and a coronary aneurysm were detected. This is the first report suggesting the possibility of an association between these manifestations and JP-HHT due to SMAD4 mutations. Examining cardiovascular disorders in JP-HHT patients is imperative.


Assuntos
Aneurisma da Aorta Abdominal/genética , Aneurisma Coronário/genética , Polipose Intestinal/genética , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética , Aneurisma da Aorta Abdominal/complicações , Aneurisma Coronário/complicações , Cardiopatias/complicações , Ventrículos do Coração/patologia , Humanos , Polipose Intestinal/complicações , Masculino , Pessoa de Meia-Idade , Telangiectasia Hemorrágica Hereditária/complicações
18.
Fam Cancer ; 18(2): 165-172, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30196345

RESUMO

Relatively little is known on the genotype-phenotype correlations between SMAD4 gene mutations, juvenile polyposis of the intestine and Hereditary Hemorrhagic Teleangectasia. We describe a family in which the proband (a 46-year old woman) had massive polyposis of the stomach-leading to surgery-with high-grade dysplasia at histology. Molecular analysis was carried out using Next Generation sequencing techniques with Miseq Illumina Platforms and a minimal coverage of 40 reads. In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia). The same mutation was detected in two other members of the family (father and brother of the proband), who showed massive polypoid involvement of the stomach at gastroscopy. By taking the family history, subtle evidence of Hereditary Teleangectasia was found (nasal bleeding and arterovenous malformations) in the three gene carriers. Colonoscopy showed polyp occurrence in all three affected members with SMAD4 mutation, with prevalence of adenomatous lesions in one (father), of hamartomas in the brother, and of a mix of histological types in the proband. The main features of the family can be summarized as follows: (A) In hereditary juvenile polyposis, lesions of different histology can be detected at colonoscopy; (B) In the gene carriers of SMAD4 mutations, lesions of the stomach require careful surveillance and, when necessary, surgical interventions; (C) Signs and symptoms of Hereditary Hemorrhagic Teleangectasia should be suspected (and searched) in individuals with SMAD4 constitutional mutations.


Assuntos
Adenocarcinoma/genética , Pólipos Adenomatosos/genética , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/genética , Proteína Smad4/genética , Neoplasias Gástricas/genética , Telangiectasia Hemorrágica Hereditária/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/cirurgia , Feminino , Gastrectomia , Gastroscopia , Heterozigoto , Humanos , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Polipose Intestinal/patologia , Polipose Intestinal/cirurgia , Masculino , Anamnese , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/cirurgia , Fenótipo , Estômago/diagnóstico por imagem , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Telangiectasia Hemorrágica Hereditária/diagnóstico
20.
Virchows Arch ; 474(2): 259-264, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30276464

RESUMO

Gastrointestinal "juvenile-like (inflammatory/hyperplastic) mucosal polyps" (JLIHMPs) have been proposed as a neurofibromatosis type 1 (NF1)-specific gastrointestinal manifestation. Juvenile polyposis syndrome (JPS) has also been reported in a NF1 patient, harboring concurrent NF1 and SMAD4 germline mutations. Additionally, NF1-like cafe-au-lait spots have been described in biallelic mismatch repair deficiency, another condition featuring gastrointestinal polyps. The SMAD4 and BMPR1A genes that are involved in 50-60% of JPS cases have not been investigated in the ~ 20 published cases of NF1-associated JLIHMPs with the exception of the abovementioned patient with concomitant JPS and NF1. NF1 defects have been found in the only two cases exhaustively tested. Therefore, JLIHMP has been questioned as an independent, NF1-specific entity. Incidental associations between NF1 and gastrointestinal polyposes at risk for gastrointestinal carcinoma should not be overlooked, given their implications in terms of clinical surveillance. We describe two patients featuring JLIHMPs in clinically/genetically proven NF1, in the absence of SMAD4 and BMPR1A mutations. In one case, the intervening mucosa was markedly inflamed, unlike JPS. We suggest that JLIHMP probably represents a gastrointestinal lesion specific to NF1.


Assuntos
Pólipos Intestinais/patologia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Feminino , Humanos , Hiperplasia/patologia , Polipose Intestinal/congênito , Polipose Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Mutação , Síndromes Neoplásicas Hereditárias/patologia , Neurofibromatoses/diagnóstico , Neurofibromatose 1/complicações , Fenótipo , Pólipos/patologia , Proteína Smad4/genética
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