RESUMO
Introducción: la fibrosis quística (FQ) es una enfermedad genética, multisistémica, caracterizada por la disfunción de las glándulas de secreción exocrina secundaria a la mutación de una proteína transmembrana que actúa como canal de cloro. La inclusión de su búsqueda en el Sistema Nacional de Pesquisa Neonatal (SNPN) determinó un gran impacto sobre la morbimortalidad de esta enfermedad, permitiendo un diagnóstico y tratamiento precoz. El íleo meconial (IM) es la manifestación más precoz de la enfermedad, ocurriendo en un 10% a 18% de los pacientes. Objetivo: describir una forma de presentación precoz de FQ con resultado de pesquisa neonatal normal. Caso clínico: 18 meses. Sexo femenino; 33 semanas de edad gestacional. Retraso en la expulsión del meconio. Al tercer día de vida íleo meconial con oclusión intestinal, vólvulo de intestino medio y necrosis intestinal. Se realiza resección quirúrgica. Tripsina inmunorreactiva (TIR) normal a los 7 y 23 días de vida. No se solicita proteína asociada a la pancreatitis (PAP). Desnutrición crónica, bronquiolitis grave a los 3 meses, neumonías virales a los 7 y 11 meses. Ingreso con diagnóstico de neumonía aguda comunitaria con insuficiencia respiratoria. Test del sudor alterado en dos oportunidades. Elastasa pancreática insuficiente. Se aísla Staphylococcus aureus y Pseudomonas aeruginosa en exudado nasal y de secreciones respiratorias. Estudio genético: mutación Delta F508. Con diagnóstico de FQ se inició abordaje multidisciplinario, tratamiento y derivación al centro especializado. Conclusiones: la existencia de IM puede dar falsos negativos en el valor de la TIR, siendo necesaria la dosificación de la PAP. El pronóstico de estos pacientes va a depender de un diagnóstico precoz y el manejo terapéutico oportuno en centros especializados.
Introduction: cystic fibrosis (CF) is a genetic, multisystemic disease, characterized by dysfunction of the exocrine secretion glands secondary to the mutation of a transmembrane protein that acts as a chloride channel. Including its research by the National Neonatal Screening System (SNPN) caused a great impact on the morbidity and mortality of this disease, enabling early diagnosis and treatment. Meconium ileus (MI) is the earliest manifestation of the disease, occurring in 10% to 18% of patients. Objective: to describe a form of early presentation of CF with normal neonatal screening results. Clinical case: 18 months. Female, 33 weeks gestational age. Delay in the expulsion of meconium. On the third day of life, meconium ileus with intestinal obstruction, midgut volvulus and intestinal necrosis. Surgical resection is performed. Trypsin immunoreactive (TIR) normal at 7 and 23 days of age. Pancreatitis-associated protein (PAP) is not requested. Chronic malnutrition, severe bronchiolitis at 3 months, viral pneumonia at 7 and 11 months. Admission with a diagnosis of acute community pneumonia with respiratory failure. Sweat test altered on two occasions. Insufficient pancreatic elastase. Staphylococcus aureus and Pseudomonas aeruginosa were isolated in nasal exudate and respiratory secretions. Genetic study: Delta F508 mutation. With the CF diagnosis, a multidisciplinary approach, treatment and referral to a specialized center began. Conclusions: the existence of MI can provide false negatives in the IRR value, making PAP dosage necessary. The prognosis of these patients will depend on early diagnosis and timely therapeutic management at specialized centers.
Introdução: a fibrose cística (FC) é uma doença genética, multissistêmica, caracterizada pela disfunção das glândulas secretoras exócrinas secundária à mutação de uma proteína transmembrana que age como canal de cloreto. A inclusão da sua pesquisa no Sistema Nacional de Triagem Neonatal (SNPN) determinou grande impacto na morbimortalidade desta doença, permitindo diagnóstico e tratamento precoces. O íleo meconial (IM) é a manifestação mais precoce da doença, ocorrendo em 10 a 18% dos pacientes. Objetivo: descrever uma forma de apresentação precoce da FC com resultados normais de triagem neonatal. Caso clínico: 18 meses. Sexo feminino. 33 semanas de idade gestacional. Atraso na expulsão do mecônio. No terceiro dia de vida, íleo meconial com obstrução intestinal, vólvulo de intestino médio e necrose intestinal. A ressecção cirúrgica é realizada. Imunorreativo à tripsina (TIR) normal aos 7 e 23 dias de vida. A proteína associada à pancreatite (PAP) não é solicitada. Desnutrição crônica, bronquiolite grave aos 3 meses, pneumonia viral aos 7 e11 meses. Internação com diagnóstico de pneumonia comunitária aguda com insuficiência respiratória. Teste do suor alterado em duas ocasiões. Elastase pancreática insuficiente. Staphylococcus aureus e Pseudomonas aeruginosa foram isolados em exsudato nasal e secreções respiratórias. Estudo genético: mutação Delta F508. Com o diagnóstico de FC iniciou-se abordagem multidisciplinar, tratamento e encaminhamento para centro especializado. Conclusões: a existência de IM pode dar falsos negativos no valor da TIR, tornando necessária a dosagem de PAP. O prognóstico destes pacientes dependerá do diagnóstico precoce e do manejo terapêutico oportuno em centros especializados.
Assuntos
Humanos , Feminino , Lactente , Tripsina/análise , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Íleo Meconial/etiologia , Recém-Nascido Prematuro , Diagnóstico Precoce , Reações Falso-Negativas , Íleo Meconial/cirurgia , Obstrução Intestinal/cirurgiaRESUMO
Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR) mutations and pancreatic insufficiency (PI). D1152H is a class IV mutation that corresponds with a milder CF phenotype and pancreatic sufficiency (PS). We present the case of an infant with G542X/D1152H mutations and MI who required surgical intervention with small bowel resection. The sweat testing was normal, and this child presently remains PS, however at age 5 continues to experience short gut syndrome and failure to thrive. Eight cases were identified in the CF Registry and seven cases in the literature describing patients with D1152H and echogenic bowel (EB) or MI. Our case highlights the importance of CFTR gene sequencing in infants with EB or MI and sweat testing not suggestive of CF. It is our practice to perform full CFTR gene sequencing for infants who present with MI, recognizing protocols for newborn screening across the United States vary. Increased awareness of D1152H association with PS may also well inform both prenatal and postnatal genetic counseling.
Assuntos
Fibrose Cística , Íleus , Íleo Meconial , Recém-Nascido , Criança , Lactente , Feminino , Gravidez , Humanos , Pré-Escolar , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Íleo Meconial/etiologia , Íleo Meconial/genética , Mutação , Fenótipo , Íleus/etiologia , Íleus/genética , MecônioRESUMO
Cystic fibrosis is an autosomal-recessive defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7 that affects 1 in 2500 live White births. Defects in the gene lead to abnormally thick secretions causing chronic obstruction in the respiratory and gastrointestinal tracts. Common gastrointestinal pathology in children with cystic fibrosis includes meconium ileus in infancy and distal intestinal obstruction syndrome in childhood and exocrine pancreatic insufficiency, constipation, and rectal prolapse. This article describes the presentation, diagnosis, and management of these conditions in patients with cystic fibrosis, from birth to adulthood.
Assuntos
Fibrose Cística , Íleus , Obstrução Intestinal , Íleo Meconial , Adulto , Criança , Fibrose Cística/complicações , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Íleus/etiologia , Íleus/cirurgia , Recém-Nascido , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/etiologia , Mecônio , Íleo Meconial/complicações , Íleo Meconial/etiologiaRESUMO
BACKGROUND: Contemporary early outcome data of meconium Ileus (MI) in cystic fibrosis (CF) are lacking on a population level. We describe these and explore factors associated with successful non-operative management. METHODS: A prospective population-cohort study using an established surveillance system (BAPS-CASS) was conducted October 2012-September 2014. Live-born infants with bowel-obstruction from inspissated meconium in the terminal ileum and CF were reported. Data are described as median (interquartile range, IQR). RESULTS: 56 infants were identified. 14/56(25%) had primary laparotomy (13/23 complicated MI, 1/33 simple), the remainder underwent contrast enema. Twelve, (12/33 (36%) with simple MI) achieved decompression. 8/12 (67%) who decompressed had >1 enema vs 3/20 (15%) with simple MI who had laparotomy after enema. The number of enemas per infant (1-4), contrast agents and their concentration, were highly variable. Enterostomy was formed at 24/44(55%) of laparotomies. In infants with simple MI, time to full enteral feeds was 6 (2-10) days in those decompressing with enema vs 15 (9-19) days with laparotomy after enema. Case fatality was 4% (95% CI 0.4-12%). Two infants, both preterm died, both in the second month after birth. CONCLUSIONS: Infants with simple MI achieving successful enema decompression were more likely to have had repeat enemas than those who proceeded to laparotomy. Successful non-operative management was associated with a shorter time to full feeds. The early management of infants with MI is highly variable and not standardised across the UK and Ireland.
Assuntos
Fibrose Cística , Íleus , Obstrução Intestinal , Íleo Meconial , Estudos de Coortes , Fibrose Cística/complicações , Fibrose Cística/terapia , Enema , Humanos , Íleus/etiologia , Íleus/terapia , Lactente , Recém-Nascido , Mecônio , Íleo Meconial/etiologia , Íleo Meconial/terapia , Estudos ProspectivosRESUMO
OBJECTIVE: Wales has an immunoreactive trypsin (IRT)-DNA cystic fibrosis (CF) newborn screening (NBS) programme. Most CF NBS false negative cases are due to an IRT concentration below the screening threshold. The accuracy of IRT results is dependent on the quality of the dried bloodspot (DBS) sample. The aim of this study was to determine the cause of false negative cases in CF NBS and their relationship to DBS quality. DESIGN: Longitudinal birth cohort. SETTING: Wales 1996-2016. PATIENTS: Children with CF. INTERVENTIONS: Identification of all CF patients with triangulation of multiple data sources to detect false negative cases. MAIN OUTCOME MEASURES: False negative cases. RESULTS: Over 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases-all were classified as small/insufficient or poor quality. CONCLUSIONS: The majority of false negatives had a low bloodspot IRT, and this was associated with poor quality DBS. The optimal means to improve the sensitivity of our CF NBS programme would be to improve DBS sample quality.
Assuntos
Fibrose Cística/diagnóstico , Teste em Amostras de Sangue Seco/estatística & dados numéricos , Triagem Neonatal/métodos , Tripsinogênio/sangue , Cloretos/análise , Fibrose Cística/sangue , Fibrose Cística/epidemiologia , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Teste em Amostras de Sangue Seco/métodos , Reações Falso-Negativas , Humanos , Incidência , Lactente , Recém-Nascido , Íleo Meconial/epidemiologia , Íleo Meconial/etiologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Viés de Seleção , Suor/química , País de Gales/epidemiologiaRESUMO
INTRODUCTION: The cystic fibrosis (CF) clinical profile and associated CFTR mutation spectrum is poorly understood in the South Asian population. This is likely due to the lack of diagnostic resources and the absence of a centralised CF database and screening programme, despite a relatively large proportion of the global population. METHODS: Following identification of a previously unreported CFTR mutation (c.2805_2810delinsTCAGA; p.(Pro936Ginfs*6)) in a newly diagnosed patient of Indian descent, we interrogated national registries for other cases. RESULTS: We identified three European-born subjects of South Asian descent with CF due to a novel CFTR mutation. All three subjects presented in infancy and each had a severe phenotype with intestinal complications as a presenting feature. Two subjects were diagnosed prior to the advent of universal screening. Preliminary genetic screening failed to identify the causative mutation in all three patients. CONCLUSION: Our work highlights the value of extended or targeted genotyping in selected populations. It also demonstrates the benefit of routine collaboration between national registries. This will promote the identification of novel mutations; leading to greater understanding of genotype-phenotype associations, improved individual prognostication and ultimately the improved availability of novel precision therapies. This collaboration is essential if we are to achieve health equality for people with CF living in resource-limited settings.
Assuntos
Povo Asiático/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Adolescente , Adulto , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/patologia , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/etiologia , Feminino , Estudos de Associação Genética , Testes Genéticos/normas , Genótipo , Humanos , Lactente , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Masculino , Íleo Meconial/diagnóstico , Íleo Meconial/etiologia , Íleo Meconial/cirurgia , Mutação , Fenótipo , Suor/químicaRESUMO
BACKGROUND: Meconium ileus (MI) affects up to 20% of newborns with cystic fibrosis (CF). We compared clinical outcomes between Australian paediatric CF patients with and without meconium ileus (non-MI). METHODS: This was a retrospective case-control study of MI and non-MI patients in New South Wales, Australia, from 1988 to 2010. MI patients were matched 1:1 with pancreatic insufficient non-MI patients for age, sex and CF clinic. Clinical measurements, nutrition and gastrointestinal outcomes over this period were compared between groups using linear mixed models for continuous variables to account for age. RESULTS: There were 162 matched pairs (N=324, 52% female) with mean (SD) age of 15.3 (8.2) and 14.9 (7.9) years for MI and non-MI patients respectively (P=0.6). MI patients aged 5-23 had poorer FEV1% compared to non-MI patients (estimate -0.070 SE [0.02], P=0.003). There were no significant differences in P. aeruginosa isolation rates; however S. aureus isolation rates were lower in MI patients (72%) compared to non-MI (82%) (OR 0.6 [0.3-1.0], P=0.03). Chronic colonisation rates for P. aeruginosa and S. aureus were not significantly different between groups. MI patients aged 2-20 had significantly lower BMI Z-scores over time (estimate -0.25 SE [0.1], P=0.02). MI patients were more likely to receive oral feed supplements (OR 2.8 [1.4-6.1], P=0.003) and gastrostomy formation (OR 4.4 [1.1-24.6], P=0.02). CONCLUSIONS: CF patients with MI may have worse lung function, growth and nutrition than non-MI patients over time. Meconium ileus may be an early poor prognostic factor for CF.
Assuntos
Fibrose Cística , Insuficiência Pancreática Exócrina , Transtornos do Crescimento , Desnutrição , Íleo Meconial , Infecções Respiratórias , Adolescente , Austrália/epidemiologia , Estudos de Casos e Controles , Fibrose Cística/diagnóstico , Fibrose Cística/epidemiologia , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Diagnóstico Precoce , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/etiologia , Feminino , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/etiologia , Humanos , Recém-Nascido , Masculino , Desnutrição/diagnóstico , Desnutrição/etiologia , Íleo Meconial/diagnóstico , Íleo Meconial/etiologia , Estado Nutricional , Prognóstico , Pseudomonas aeruginosa/isolamento & purificação , Testes de Função Respiratória/métodos , Testes de Função Respiratória/estatística & dados numéricos , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , Estudos Retrospectivos , Staphylococcus aureus/isolamento & purificaçãoAssuntos
Fibrose Cística , Diagnóstico Tardio , Íleo Meconial , Administração dos Cuidados ao Paciente , Estudos de Coortes , Correlação de Dados , Fibrose Cística/diagnóstico , Fibrose Cística/epidemiologia , Fibrose Cística/fisiopatologia , Fibrose Cística/terapia , Diagnóstico Tardio/mortalidade , Diagnóstico Tardio/estatística & dados numéricos , Humanos , Recém-Nascido , Íleo Meconial/epidemiologia , Íleo Meconial/etiologia , Íleo Meconial/terapia , Mortalidade , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/tendências , Prognóstico , Índice de Gravidade de DoençaRESUMO
Gastrointestinal, pancreatic, and hepatic signs and symptoms represent the most common presentation of early disease among patients with cystic fibrosis and may be the initial indication of disease. Regardless of whether cystic fibrosis is diagnosed early by newborn screening or later by clinical course, the impact of gastrointestinal, pancreatic, and hepatic manifestations on early life is nearly ubiquitous. Conditions strongly linked with cystic fibrosis, such as meconium ileus and pancreatic insufficiency, must be recognized and treated early to optimize both short- and long-term care. Similarly, less specific conditions such as reflux, poor weight gain, and cholestasis are frequently encountered in infants with cystic fibrosis. In this population, these conditions may present unique challenges in which early interventions may have significant influence on both short- and long-term morbidity and mortality outcomes.
Assuntos
Colestase/etiologia , Fibrose Cística/complicações , Insuficiência Pancreática Exócrina/etiologia , Refluxo Gastroesofágico/etiologia , Insuficiência Hepática/etiologia , Doenças do Recém-Nascido , Íleo Meconial/etiologia , Colestase/diagnóstico , Colestase/terapia , Fibrose Cística/diagnóstico , Fibrose Cística/terapia , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/terapia , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/terapia , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/terapia , Íleo Meconial/diagnóstico , Íleo Meconial/terapiaRESUMO
Introduction Meconium Ileus (MI) is the presenting feature of CF in approximately 10-15% of cases. This report outlines the clinical presentation, imaging and management of two neonates with MI and subsequent diagnosis of Cystic Fibrosis (CF). Methods A retrospective chart review was performed to evaluate the clinical course of two neonates with MI. Results Case 1 and 2 presented clinically with signs of abdominal obstruction. Subsequent laparotomies confirmed MI. MI is strongly associated with CF and CF is the most common genetically inherited disease in Ireland. Genetic testing was positive for a homozygous ∆ F508 mutation in both case 1 and 2, securing a diagnosis of MI secondary to CF. Conclusion Our cases highlight that all infants born in Ireland with MI should be considered as CF positive until proven otherwise.
Assuntos
Fibrose Cística/complicações , Íleo Meconial/diagnóstico , Íleo Meconial/etiologia , Fibrose Cística/genética , Diatrizoato de Meglumina , Feminino , Homozigoto , Humanos , Ileostomia , Recém-Nascido , Intubação Gastrointestinal , Irlanda , Laparotomia , Masculino , Íleo Meconial/genética , Íleo Meconial/terapia , Mutação , Estudos RetrospectivosRESUMO
BACKGROUND: A clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF. METHODS: We investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis. RESULTS: Severe lung disease had a 22.2% concordance in sib-pairs, occurred early and the FEV1% at 12 years was predictive of the severity of lung disease in the adulthood. Similarly, CF liver disease occurred early (median: 15 years) and showed a concordance of 27.8% in sib-pairs suggesting a scarce contribution of genetic factors; in fact, only 2/15 patients with liver disease in discordant sib-pairs had a deficiency of alpha-1-antitrypsin (a known modifier gene of CF liver phenotype). CF related diabetes was found in 22 pairs (in 6 in both the siblings). It occurred later (median: 32.5 years) and is strongly associated with liver disease. Colonization by P. aeruginosa and nasal polyposis that required surgery had a concordance > 50% in sib-pairs and were poorly correlated to other clinical parameters. The pancreatic status was highly concordant in pairs of siblings (i.e., 95.1%) but a different pancreatic status was observed in patients with the same CFTR mutations. This suggests a close relationship of the pancreatic status with the "whole" CFTR genotype, including mutations in regulatory regions that may modulate the levels of CFTR expression. Finally, a severe course of CF was evident in a number of patients with pancreatic sufficiency. CONCLUSIONS: Physicians involved in care of patients with CF and in genetic counseling must be aware of the clinical heterogeneity of CF even in sib-pairs that, at the state of the art, is difficult to explain.
Assuntos
Portador Sadio/microbiologia , Fibrose Cística/fisiopatologia , Diabetes Mellitus/etiologia , Insuficiência Pancreática Exócrina/etiologia , Hepatopatias/etiologia , Íleo Meconial/etiologia , Irmãos , Adolescente , Adulto , Criança , Fibrose Cística/complicações , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Lactente , Recém-Nascido , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Pólipos Nasais/complicações , Pólipos Nasais/cirurgia , Orofaringe/microbiologia , Fenótipo , Pseudomonas aeruginosa , Índice de Gravidade de Doença , Escarro/microbiologia , Adulto Jovem , alfa 1-Antitripsina/genéticaRESUMO
Meconium ileus (MI) is often the first manifestation of cystic fibrosis (CF) and occurs in approximately 20% of patients diagnosed with CF. This article reviews the pathophysiology of MI and its clinical presentation. It focuses on the medical and surgical management emphasizing the importance of nutrition and a multidisciplinary approach to improve both short-term and long-term outcomes for CF patients with MI.