EVOLUTION OF DIAGNOSTIC DELAY IN PEDIATRIC INFLAMMATORY BOWEL DISEASE AND THE IMPACT OF THE COVID-19 PANDEMIC.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) is increasingly prevalent, but diagnosis can still be challenging. Diagnostic delay is particularly deleterious in this age group. OBJECTIVE: This study explores the evolution of diagnostic delay in pediatric IBD and the influence of the COVID-19 pandemic. METHODS: Retrospective study including all pediatric IBD patients diagnosed during 2014, 2019 and 2020 in a tertiary hospital. Diagnostic delay, time to first medical visit, time to pediatric gastroenterologist (PG) visit and time to diagnosis were calculated and compared within a gap of five years (2019 and 2014) and with the year of onset of the pandemic (2020 and 2019). RESULTS: A total of 93 participants were included (2014: 32, 2019: 30, 2020: 31). No significant differences were observed in diagnostic delay, time to first medical visit in Crohn's disease (CD), time to PG visit and time to diagnosis when comparing 2019-2014 and 2020-2019. Time to first visit in ulcerative colitis (UC) and Undetermined-IBD increased in 2019 (P=0.03), with new decrease in 2020 (P=0.04). Diagnostic delay was longer in DC compared to UC plus Undetermined-IBD. CONCLUSION: Diagnostic delay is still an important matter in pediatric IBD, with no significant change over the last years. The time to the first PG visit and the time for diagnosis seem to have the greatest impact on diagnostic delay. Thus, strategies to enhance recognition of IBD symptoms among first-line physicians and to improve communication, facilitating referral, are of utmost importance. Despite the restraints in the health care system caused by the pandemic, time to diagnosis in pediatric IBD was not impaired during 2020 in our center.

Evolução do atraso diagnóstico na doença inflamatória intestinal em idade pediátrica e o impacto da pandemia COVID-19 / Evolution of diagnostic delay in pediatric inflammatory bowel disease and the impact of the covid-19 pandemic

ABSTRACT Background: Pediatric inflammatory bowel disease (IBD) is increasingly prevalent, but diagnosis can still be challenging. Diagnostic delay is particularly deleterious in this age group. Objective This study explores the evolution of diagnostic delay in pediatric IBD and the influence of the COVID-19 pandemic. Methods Retrospective study including all pediatric IBD patients diagnosed during 2014, 2019 and 2020 in a tertiary hospital. Diagnostic delay, time to first medical visit, time to pediatric gastroenterologist (PG) visit and time to diagnosis were calculated and compared within a gap of five years (2019 and 2014) and with the year of onset of the pandemic (2020 and 2019). Results A total of 93 participants were included (2014: 32, 2019: 30, 2020: 31). No significant differences were observed in diagnostic delay, time to first medical visit in Crohn's disease (CD), time to PG visit and time to diagnosis when comparing 2019-2014 and 2020-2019. Time to first visit in ulcerative colitis (UC) and Undetermined-IBD increased in 2019 (P=0.03), with new decrease in 2020 (P=0.04). Diagnostic delay was longer in DC compared to UC plus Undetermined-IBD. Conclusion Diagnostic delay is still an important matter in pediatric IBD, with no significant change over the last years. The time to the first PG visit and the time for diagnosis seem to have the greatest impact on diagnostic delay. Thus, strategies to enhance recognition of IBD symptoms among first-line physicians and to improve communication, facilitating referral, are of utmost importance. Despite the restraints in the health care system caused by the pandemic, time to diagnosis in pediatric IBD was not impaired during 2020 in our center.

RESUMO Contexto Apesar da prevalência crescente da doença inflamatória intestinal (DII) em idade pediátrica, o seu diagnóstico pode ser desafiante. Um atraso no diagnóstico é particularmente deletério nesta faixa etária. Objetivo Este estudo investiga a evolução do atraso diagnóstico na DII pediátrica e o impacto da pandemia COVID-19 no mesmo. Métodos Estudo retrospetivo que incluiu todos os doentes em idade pediátrica diagnosticados com DII durante 2014, 2019 e 2020 num hospital terciário. O atraso diagnóstico, o tempo para a primeira visita médica, o tempo para a primeira visita ao gastroenterologista pediátrico (GP) e o tempo para o diagnóstico foram calculados e comparados num intervalo de cinco anos (2019 e 2014) e com o ano marcado pelo surgimento da pandemia COVID-19 (2020 e 2019). Resultados Foram incluídos 93 participantes (2014: 32, 2019: 30, 2020: 31). Não se observou diferença significativa no atraso diagnóstico, no tempo para a primeira visita médica na doença de Crohn (DC), no tempo para a primeira visita ao GP e no tempo para o diagnóstico após comparação entre 2019-2014 e 2020-2019. Na colite ulcerosa e colite indeterminada, o tempo para a primeira visita médica aumentou em 2019 (P=0,03), com nova diminuição em 2020 (P=0,04). O atraso diagnóstico foi superior na DC comparativamente com a colite ulcerosa e colite indeterminada. Conclusão O atraso diagnóstico na DII pediátrica continua a ser um tema importante, que não sofreu alteração significativa ao longo dos últimos anos. O tempo para a primeira visita ao GP e o tempo para o diagnóstico parecem ter maior impacto no atraso diagnóstico, pelo que são necessárias estratégias para aumentar o reconhecimento dos sintomas da DII entre os médicos de primeira linha, bem como melhorar a comunicação e a referenciação. Apesar das restrições causadas pela pandemia no sistema de saúde, o tempo para o diagnóstico na DII pediátrica não foi comprometido no nosso centro em 2020.

Impact of COVID-19 in Pediatric Patients and Young Adults with Inflammatory Bowel Disease.

Introduction: Acute COVID-19 in pediatric and young adult patients tends to be milder in severity compared to adult infection. Recent studies seem to show that inflammatory bowel disease (IBD) patients are at no greater risk than the general population. We aim to describe our experience in the follow-up of pediatric and young adult patients with IBD followed in our center and determine possible risk factors of said population for severe COVID-19. Methods: We performed a retrospective study of all patients aged under 25 years followed for IBD at the Unit of Pediatric Gastroenterology in a tertiary center between December 2019 and April 2021 evaluating the incidence of COVID-19 and characterization of positive cases. Results: Of the 268 participants, 24 had COVID-19: the mean age was 19 years old and gender had an equal distribution; 75% (n = 18) had Crohn's disease, whereas only 25% (n = 6) had ulcerative colitis. Most patients were in clinical remission (n = 21). The majority of patients were under treatment with a tumor necrosis factor (TNF) antagonist (58%, n = 14), mainly infliximab, and most had no comorbidities other than IBD (83%). Regarding COVID-19, 17% of the patients were asymptomatic while the rest had only mild symptoms. There were no reported gastrointestinal complaints, no complications nor hospitalizations. Most patients did not require interruption of their IBD treatment. Conclusions: Our data suggest that pediatric and young adult IBD patients have a low risk for complications and hospitalization, regardless of IBD treatment. We believe that this experience is encouraging and allows for safe counseling regarding treatment options and school attendance in pediatric and young adult IBD patients.

Introdução: Na população pediátrica e de jovens adultos a gravidade da COVID-19 tende a ser moderada quando comparada com os doentes adultos. Os estudos mais recentes sugerem que os doentes com doença inflamatória intestinal (DII) não têm risco acrescido em relação à população geral. O objetivo do presente estudo é a descrição da nossa experiência no follow-up de crianças e jovens adultos com DII a COVID-19 e determinar a existência de possíveis fatores de risco para doença grave na referida população. Métodos: Foi realizado um estudo retrospetivo de todos os doentes com idade inferior a 25 anos, seguidos na Unidade de Gastrenterologia Pediátrico de um centro terciário por DII, com avaliação da incidência de COVID-19 entre dezembro de 2019 e abril de 2021, e caracterização dos casos postivos. Resultados: Entre os 268 participantes, 24 tiveram COVID-19. A idade média foi de 19 anos com uma distribuição por género equiparável. Destes, 75% (n = 18) tinham doença de Crohn, enquanto 25% (6) tinham colite ulcerosa. A maior parte dos doentes apresentavam-se em remissão clínica (n = 21) e, à data da doença COVID-19. A sua maioria, os doentes encontravam-se sob tratamento com antagonistas do fator de necrose tumoral (58%, n = 14), predominantemente o infliximab, e a generalidade dos doentes (83%) não apresentava outras comorbilidades além da DII. Relativamente à COVID-19, 17% eram assintomáticos enquanto os restantes apresentavam apenas sintomas ligeiros. Não houve relato de queixas gastrointestinais, complicações ou necessidade de hospitalização. Na maioria dos casos, não houve necessidade de interromper o tratamento da DII. Conclusão: Os nossos dados sugerem que doentes pediátricos e jovens adultos com DII apresentam um risco baixo de complicações ou hospitalização associados à COVID-19, independentemente do tratamento em curso para a DII. Este estudo apresenta resultados encorajadores e contribui para o aconselhamento adequado e fundamentado aos doentes e respetivos cuidadores, no que diz respeito às opções terapêuticas e frequência escolar dos doentes pediátricos e jovens adultos com DII.

Could Commercial Formulations Replace Individualized Prescription in Pediatric Home Parenteral Nutrition?

OBJECTIVES: Standard parenteral nutrition (PN) solutions are safe and can meet the nutritional requirements of a significant number of pediatric patients. However, they may not always be adequate for those on long term PN. We aimed to compare the composition of individually tailored prescriptions in a pediatric population on home PN with that of available commercial PN formulations. METHODS: Retrospective analysis of the individual prescriptions of metabolically stable pediatric patients on home PN over a 1-year period (March 2019 to March 2020). These were compared with commercially available solutions with electrolytes, and replacement was considered adequate if three successive criteria were met: non-protein calorie to volume ratio (maximum variation 15%); non-protein calorie to nitrogen ratio (NPC:N) (maximum variation either 20% for long term use or 35% for possible short term use); electrolyte concentration (maximum increase 20%). RESULTS: Twenty-four patients were included (67% male; median age 7.5 years). The most common diagnosis was short bowel syndrome (58%). Replacement with a standard formulation was considered appropriate for possible short term use (maximum variation of 35% in NPC:N) in 16 (67%) patients and for long term use (maximum variation of 20% in NPC:N), the number of patients decreased to 10 (42%). CONCLUSIONS: Standard PN solutions can be adequate for a significant proportion of pediatric patients on home PN. Their use in the short term may also be appropriate in holiday periods or in settings of limited resources or restricted access to hospital facilities, such as those imposed by the COVID-19 pandemic.

Systemic steroids have a role in treating esophageal strictures in pediatric eosinophilic esophagitis.

BACKGROUND: The role of systemic steroids in the treatment of esophageal strictures in children with Eosinophilic Esophagitis (EoE) is poorly defined. AIMS: To describe a cohort of children with EoE-associated esophageal strictures responding to systemic steroids. METHODS: Retrospective review of medical records of children with EoE and moderate (<9 mm) to severe (<6 mm) strictures, who responded clinically and endoscopically to systemic steroids. RESULTS: Twenty children (median age 10.6 ±â€¯4.2 years; 17 males) from nine centers in six countries were included in the analysis; 16 had moderate and four, severe strictures; 18 had dysphagia or bolus impaction; median diagnostic delay was 8 months (IQR 3.5-35). Eighteen patients received oral systemic steroids (mean dose 1.4 mg/kg/day) for a median of 4 weeks, while two initially received IV steroids. All patients showed clinical improvement and 15/20 became asymptomatic. Stricture resolution at endoscopy was found in 19/20, while histological resolution of EoE (<15 eos/hpf) in 13/20. Only minor side effects were reported: hyperphagia (10/20); weight gain (5/20); hyperactivity (2/20) and acne (1/20). Esophageal dilation was required in 3/20 patients during a median follow-up of 48.5 months (IQR 26.7-73.2). CONCLUSION: Children with EoE and esophageal strictures, may benefit from the use of a short course of systemic steroids, avoiding mechanical dilation.

Diagnostic Yield of Endoscopic Procedures in Children: Experience of a Portuguese Center.

BACKGROUND: Over the last decades, the use of gastrointestinal (GI) endoscopic procedures has been increased in children worldwide, allowing the early diagnosis and therapeutic intervention in multiple GI diseases. AIMS AND METHODS: In order to evaluate the appropriateness and the diagnostic yield of initial GI endoscopic techniques in children in a Portuguese tertiary hospital, we performed a retrospective cohort study during a 12-month period. RESULTS: A total of 308 procedures were performed in 276 patients; the median age was 11 years and 50.4% were males. Esophago-gastro-duodenoscopy (EGD) corresponded to 81.8% of the procedures and ileo-colonoscopy (IC) to the remaining; 11.6% of the patients underwent both EGD and IC. Overall, 51.3% of the exams showed abnormal macroscopic findings, and 69.6% showed histopathological signs of disease, with IC showing significantly more positive results than EGD (p < 0.05). Considering the different indications independently, abnormal serology for celiac disease, suspected ingestion of foreign bodies, suspected inflammatory bowel disease, and food impaction were frequent in our population; and in the majority of the cases, the suspected diagnosis was confirmed: celiac disease, ingestion of foreign bodies, inflammatory bowel disease, and eosinophilic esophagitis, respectively. On the other hand, despite the high frequency of epigastric pain in this population, only nearly one-third of the patients showed abnormal histological findings. The final diagnosis was established in 63% of the patients, and 39.1% initiated the new treatment. DISCUSSION: Our results emphasize the importance of endoscopic procedures, especially IC, in the diagnosis of GI diseases in pediatric patients, as well as the careful choice of the endoscopic techniques in those with less specific symptoms, as chronic abdominal pain. In this particular situation, given the proportion of cases that may be due to functional disease, good characterization of the clinical context is needed, and endoscopy should be reserved for a second-line approach. CONCLUSION: It is important to monitor and examine the endoscopic techniques as an index of quality criteria for clinical practice.

INTRODUÇÃO: Ao longo das últimas décadas, a utilização dos procedimentos endoscópicos gastrointestinais (GI) nas crianças tem aumentado globalmente, permitindo o diagnóstico precoce e a intervenção terapêutica em múltiplas doenças GI. OBJETIVOS E MÉTODOS: Por forma a avaliar a adequabilidade e a rentabilidade diagnóstica na utilização de técnicas endoscópicas GI iniciais em crianças, realizamos um estudo retrospetivo de coorte durante um período de 12 meses num hospital terciário Português. RESULTADOS: Foram realizados 308 procedimentos em 276 doentes, a idade mediana foi 11 anos e 50.4% eram do sexo masculino. As esófago-gastro-duodenoscopias (EGD) corresponderam a 81.8% dos procedimentos e as ileocolonoscopias (IC) aos restantes; 11.6% dos doentes foram submetidos aos dois exames. No total, 51.3% dos exames mostraram alterações macroscópicas e 69.6% mostraram sinais histopatológicos de doença, com as IC a mostrar significativamente mais resultados positivos que as EGD (p < 0.05). Considerando as diferentes indicações independentemente, a presença de serologias positivas para doença celíaca, a suspeita de ingestão de corpos estranhos, a suspeita de doença inflamatória intestinal e a impactação alimentar foram frequentes na nossa população, e na maioria dos casos a suspeita diagnóstica foi confirmada: doença celíaca, ingestão de corpo estranho, doença inflamatória intestinal e esofagite eosinofílica, respetivamente. Por outro lado, apesar da elevada frequência de doentes com dor epigástrica a motivar o estudo endoscópico, apenas em perto de um terço dos mesmos encontrou-se alterações histológicas. O diagnóstico final foi estabelecido em 63, e 39.1% dos doentes iniciaram novo tratamento. DISCUSSÃO: Os resultados obtidos enfatizam a importância da utilização de técnicas endoscópicas, particularmente a IC, no diagnóstico de doenças GI nos doentes pediátricos, e da escolha criteriosa das mesmas nos doentes com sintomas menos específicos como dor abdominal crónica. Nesta situação particular, dada a proporção de casos que podem dever-se a doença funcional, uma boa caracterização do contexto clínico é essencial, e a endoscopia deve ser reservada para uma segunda linha de abordagem diagnóstica. CONCLUSÃO: A monitorização e a auditoria dos exames endoscópicos são importantes, como um índice de qualidade para a prática clínica.

Epstein-Barr Virus Infection and Thiopurine Therapy in a Pediatric Population with Inflammatory Bowel Disease.

Epstein Barr virus (EBV) primoinfection may contribute to the development of post-mononucleosis lymphomas in EBV-seronegative adult males with inflammatory bowel disease (IBD) under thiopurine therapy, but data on children are sparse. Knowledge of the EBV status may influence the type of surveillance and therapy in a group particularly vulnerable to the occurrence of EBV primoinfection. We aimed to determine the EBV status at diagnosis, the primoinfection rate, and complications in a pediatric Portuguese population with IBD. METHOD: This was a retrospective analysis of clinical records of pediatric patients with IBD. Demographic data, EBV status, as well as clinical and therapeutic data on primoinfection were collected. RESULTS: Of the 250 patients evaluated, 229 (91.6%) had documented EBV screening and 50.8% were male. Mean age ± SD was 13.0 ± 2.8 years at diagnosis and 14.7 ± 2.3 years at EBV screening. EBV IgG serology was positive in 76.0% of patients. A total of 218 patients had been on therapy with azathioprine at some point. The average length of exposure to azathioprine was 4 years, and 91 patients (39.7%) were on azathioprine at EBV assessment. EBV primoinfection was documented in 4 patients (1.6%), all females, 2 of whom were on azathioprine. Two presented clinical signs of infection and 2 were identified at diagnostic screening; the first 2 suspended azathioprine and the other 2 did not initiate it. CONCLUSIONS: A significant proportion of pediatric Portuguese IBD patients are EBV-naïve. Systematic screening of EBV status enables the identification of patients at risk of primoinfection, and the occurrence of symptoms suggestive of acute EBV infection in seronegative patients should lead to rapid confirmation of the diagnosis. Timely diagnosis may allow the adjustment of therapeutic strategy sparing patients from potentially severe iatrogeny.

A primoinfecção pelo virus Epstein Barr (EBV) pode contribuir para o desenvolvimento de linfomas pós-mononucleose infecciosa em homens adultos EBV-seronegativos com doença inflamatória intestinal (Dll), sob terapéutica com tiopurinas. Os dados em crianças são escassos. O conhecimento do perfil serológico do EBV pode influenciar o tipo de vigilancia e terapéutica em doentes particularmente vulneráveis á ocorréncia de primoinfecção por EBV. Os autores têm como objetivo conhecer o perfil serológico do EBV ao diagnóstico de Dll, a taxa de primoinfecção e complicações numa população pediátrica portuguesa com Dll. MÉTODO: Análise retrospectiva dos processos de doentes em idade pediátrica com Dll. Foram recolhidos dados demográficos, o perfil serológico do EBV e dados clínicos e terapéuticos aquando da primoinfecção. RESULTADOS: Dos 250 doentes avaliados, 229 (91.6%) tinham rastreio do EBV documentado, 50.8% dos quais do sexo masculino. A idade média (DP) ao diagnóstico de Dll foi de 13.0 ± 2.8 anos e no momento do rastreio do EBV de 14.7 ± 2.3 anos. A serologia para EBV foi IgG positiva em 76.0% dos doentes. 218 efetuaram terapéutica com azatioprina, com exposição média de quatro anos. 91 doentes (39.7%) estavam sob azatioprina aquando da avaliação do perfil serológico do EBV. A primoinfecção por EBV foi documentada em quatro doentes (1.6%), todos do sexo feminino, dois dos quais sob azatioprina. Dois doentes apresentaram sinais clínicos de infecção, dois foram identificados no rastreio infeccioso ao diagnóstico de Dll; os dois primeiros suspenderam a terapéutica com azatioprina, os outros dois não a iniciaram. CONCLUSÕES: Uma proporção significativa de crianças portuguesas com Dll é na'ïve para o EBV. Aavaliação sistemática do perfil serológico do EBV permite a identificação de doentes com risco de primoinfecção e a ocorréncia de sintomas sugestivos de infecção aguda pelo EBV em doentes soronegativos deve levar á rápida confirmação do diagnóstico. O diagnóstico oportuno permite o ajuste da estratégia terapêutica, evitando potencial iatrogenia grave.

Laparoscopic sleeve gastrectomy in morbidly obese adolescents: Initial experience of a Pediatric Multidisciplinary Unit.

INTRODUCTION: Childhood obesity is a significant health problem worldwide, associated with significant metabolic and cardiovascular morbidity. Recent evidence points to metabolic and bariatric surgery as a safe and effective treatment for morbidly obese adolescents. We aim to report the initial results after laparoscopic sleeve gastrectomy (LSG) for adolescent patients in a pediatric center. MATERIAL AND METHODS: Retrospective data review of patients younger than 19 years who underwent LSG for treatment of morbid obesity between 2013 and 2019. RESULTS: A total of 16 adolescents (12 female, 4 male) with a median age of 17.5 years underwent LSG. Median preoperative weight and body mass index were 129kg and 48.6kg/m-2, respectively. All patients had at least one comorbidity. Median follow-up was 18.5 months. The overall percent total weight loss was 32.5% and percent excess weight loss was 68%. Resolution of comorbidities was noted in the majority of patients. No perioperative complications were reported. CONCLUSIONS: Laparoscopic sleeve gastrectomy is a safe and effective option for treatment of morbidly obese adolescents, resulting in significant weight loss and comorbidity resolution with a low risk of complications.

Perianal Disease and Granulomas: Think Out of the Box .

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a malfunction of NADPH oxidase. It is characterized by recurrent and severe infections caused by catalase-positive microorganisms and autoinflammatory manifestations. Recently, there has been described an NCF4 gene variant that causes a deficiency of p40phox, a subunit of NADPH oxidase. Patients with this deficiency appear to have a less severe clinical form as compared to classic CGD. CASE: A 15-year-old girl with vulvar lichen planus since she was 2 years old and suspected Crohn's disease (CD) was first seen at our hospital. At the age of 12 years, she had been submitted to sacrococcygeal cyst exeresis, without cicatrization of the surgical wound and extension of the lesion to the perianal area. The diagnosis of CD was questioned, and the patient underwent an endoscopic and radiologic assessment, which was normal. A skin biopsy from the perianal area revealed a granuloma; thus, CD with isolated perianal disease was assumed. After several different treatments including antibiotics, infliximab, and adalimumab, the perianal lesion persisted, with no associated gastrointestinal symptoms. Therefore, the hypothesis of an immunodeficiency was considered. An immunologic and genetic study revealed reduced oxidative burst in the phorbol myristate acetate test, with diminished reactive oxygen species production and a homozygous mutation in the NCF4 gene. The adolescent started prophylactic trimethoprim-sulfamethoxazole and became asymptomatic. CONCLUSIONS: The present case highlights that alternative diagnoses to CD must be considered in the presence of isolated perianal disease with granulomatous inflammation, especially when the disease is refractory to conventional CD therapy.

INTRODUÇÃO: A doença granulomatosa crônica (DGC) é uma imunodeficiência primária devido a uma disfunção da NADPH oxidase. É caracterizada por infeções recorrentes e graves causadas por microrganismos catalase positivos e manifestações auto-inflamatórias. Recentemente, foi identificada uma variante do gene NCF4 responsável por deficiência de p40 phox , uma proteína constituinte da NADPH oxidase e clinicamente esta doença manifesta-se como uma imunodeficiência menos grave quando comparada com a DGC clássica. CASO: Adolescente de 15 anos, com líquen planovulvardesdeos2 anos. Aos 12anos, submetida a exérese de quisto sacrococcígeo não tendo ocorrido cicatrização da ferida cirúrgica e com extensão da lesão para a região perianal. Perante a suspeita de doença Crohn (DC), realizada investigação endoscópica e radiológica que foi normal. A biópsia de pele da lesão perianal identificou granuloma, tendo sido admitido o diagnóstico de DC com apresentação perianal. Foi submetida a vários tratamentos sem resolução da lesão. Aos 15 anos, colocada a hipótese de imunodeficiência primária; o estudo imunológico mostrou diminuição da explosão oxidativa no teste de imunidade com acetato miristato de forbol, com produção reduzida de radicais livres de oxigénio (RLO). Geneticamente identificada mutação homozigótica no gene NCF4. Atualmente, sob antibiótico profilático e clinicamente assintomática. CONCLUSÃO: Este caso permite alertar para a investigação de diagnósticos alternativos à DC perante doença perianal isolada com inflamação granulomatosa, em particular quando é refratária à terapêutica dirigida.

Phenotypic heterogeneity of hereditary diffuse gastric cancer: report of a family with early-onset disease.

BACKGROUND AND AIMS: The time course for the development of clinically significant hereditary diffuse gastric cancer (HDGC) is unpredictable. Little is known about the progression from preclinical, indolent lesions to widely invasive, aggressive phenotypes. Gastroendoscopy often fails to detect early lesions, and risk-reducing/prophylactic total gastrectomy (PTG) is the only curative approach. We present an HDGC family with early-onset disease in which clinical and histologic findings provided insight into the understanding of different HDGC phenotypes. METHODS: The proband was diagnosed at age 18 years with widely invasive, metastatic DGC. CDH1 genetic testing identified a pathogenic, germline CDH1 variant (c.1901C>T, p.Ala634Val). Thirty family members were tested, and 15 CDH1 carriers were identified. RESULTS: Six family members had PTG, with negative preoperative workup. The proband's 14-year-old sister is the youngest patient, reported to date, to have PTG after negative preoperative biopsy sampling. Intramucosal HDGC foci were detected in all PTG specimens (1-33). In contrast to the "indolent" phenotype of these foci, the aggressive DGC from the proband showed pleomorphic cells, absent E-cadherin expression, increased proliferation (Ki-67 index), and activation of oncogenic events (p53, pSrc and pStat3 overexpression). All family members had Helicobacter pylori gastritis. Cag-A-positive strains were detected in all specimens, except in the proband's sister. CONCLUSIONS: HDGC is a heterogeneous disease regarding clinical behavior, endoscopic findings, histopathologic features, and immunophenotypic/molecular profile. The presence of bizarre, pleomorphic cells in endoscopic biopsy specimens is suggestive of advanced disease and should prompt clinical intervention. The involvement of a full multidisciplinary team is essential for the management of these patients.

Hypercholesterolemia--a disease with expression from childhood.

INTRODUCTION: Hypercholesterolemia results from an alteration, genetic or acquired, in lipoprotein metabolism. Evidence that hypercholesterolemia is associated with the atherosclerotic process from childhood justifies the screening of high-risk children and initiation of therapy at preschool ages. OBJECTIVE: To assess children referred for pediatric consultations due to hypercholesterolemia. METHODS: Children and adolescents referred for pediatric consultations with a diagnosis of hypercholesterolemia were enrolled. Information on family history and clinical, anthropometric and biochemical parameters was recorded and, when appropriate, molecular study was performed. RESULTS: A total of 168 children were assessed. Forty-six presented a familial hypercholesterolemia phenotype and in 22 of these, a mutation in the low-density lipoprotein (LDL) receptor gene was identified. The lipid profile of the group with mutations showed significantly higher values of total and non-high-density lipoprotein (HDL) cholesterol compared to the group without mutations (total cholesterol 316.5±75.9 mg/dl vs. 260.9±42,0 mg/dl; non-HDL cholesterol 268.3±72.6 mg/dl vs. 203.5±43.9 mg/dl; p<0.05). Of the total, 55 were prescribed pharmacological therapy and the others underwent diet and exercise interventions only. A greater reduction in LDL cholesterol was observed in individuals under pharmacological therapy compared to those prescribed diet and exercise only (30.3% vs. 18.1%). Drug side effects were insignificant. CONCLUSION: It is possible to maintain a normal lipid profile in most individuals with familial hypercholesterolemia in order to reduce the risk of early onset of atherosclerosis, which is associated with serious cardiovascular complications from childhood.

A novel splicing mutation causes analbuminemia in a Portuguese boy.

Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. It is an allelic heterogeneous defect, caused by a variety of mutations within the albumin gene. The analbuminemic condition was suspected in a Portuguese boy who presented with low albumin level (about 3.8 g/L) and a significant hypercholesterolemia, but with no clinical findings. The albumin gene was screened by single strand conformational polymorphism and heteroduplex analysis and submitted to direct DNA sequencing. The proband was found to be homozygous for a previously unreported G>A change at position c.1289+1, the first base of intron 10, which inactivates the strongly conserved GT dinucleotide at the 5' splice site consensus sequence of the intron. The effect of this mutation was evaluated by examining the cDNA obtained by RT-PCR from the albumin mRNA extracted from proband's leukocytes. The splicing defect results in the skipping of the preceding exon. The subsequent reading frame-shift in exon 11 produces a premature stop codon located 33 codons downstream the 5' end of the exon. This extensive cDNA alteration is responsible for the analbuminemic trait. Both parents were found to be heterozygous for the same mutation. DNA and cDNA sequence analysis established the diagnosis of congenital analbuminemia in the proband. The effects of the so far identified splice-site mutations in the albumin gene are discussed.