RESUMO
BACKGROUND: The benefits of early cystic fibrosis (CF) detection using newborn screening (NBS) has led to widespread use in NBS programs. Since 2002, a two-stage immunoreactive trypsinogen (IRT/IRT) screening strategy has been used as a CFNBS method in all public maternity units in the City of Buenos Aires, Argentina. However, novel screening strategies may be more efficient. The aim of this study is to prospectively compare two CFNBS strategies: IRT/IRT and IRT/PAP (pancreatitis-associated protein). METHODS: A two-year prospective study was performed. IRT was measured in dried blood samples collected 48-72 h after birth. When an IRT value was abnormal, PAP was determined, and a second visit was scheduled to obtain another sample for IRT before 25 days of life. Newborns with a positive CFNBS were referred for a confirmatory sweat test. RESULTS: There were 69,827 births in the City of Buenos Aires during the period studied; 918 (1.31%) had an abnormal IRT. A total of 207 children (22.5%) failed to return for the second IRT, but only two PAP (0.2%) were not performed. IRT/IRT was more likely to lead to a referral for sweat testing than IRT/PAP (odds ratio 2.3 [95% confidence interval 1.8-2.9], p < .001). Sensitivity and specificity were: 80% and 100% and 86.5% and 82.6% for IRT/IRT and IRT/PAP strategies, respectively. CONCLUSION: The IRT/PAP strategy is more sensitive than IRT/IRT and has similar specificity; it avoids a second visit and unnecessary sweat testing, and it reduces loss to follow-up in our population.
Assuntos
Fibrose Cística/diagnóstico , Triagem Neonatal/métodos , Antígenos de Neoplasias/sangue , Argentina , Biomarcadores Tumorais/sangue , Criança , Regulador de Condutância Transmembrana em Fibrose Cística , Feminino , Humanos , Recém-Nascido , Lectinas Tipo C/sangue , Proteínas Associadas a Pancreatite/metabolismo , Gravidez , Estudos Prospectivos , Sensibilidade e Especificidade , Tripsinogênio/sangueRESUMO
Abstract Multiple studies undertaken on cord blood demonstrate analyte perturbations in infants exposed to gestational diabetes mellitus (GDM). Cord blood as a sample is influenced by maternal and placental metabolism. Newborn screening (NBS), performed after the first 24 hours of life reflects early neonatal metabolism. We compared NBS analytes between women with and without GDM with different management approaches in the Treatment of Booking of Gestational Diabetes (TOBOGM) pilot randomised controlled trial. Pregnant women with GDM risk factors were randomised to early or deferred GDM treatment following an oral glucose tolerance test (<20 weeks gestation). Women without GDM served as "decoys". From the decoy group 11 developed GDM (screened at 26-28 weeks), were analysed separately; their results were compared with the other groups. De-identified controls were chosen from NBS results from the same analytic run matched for sex, birthweight and gestational age. Results were available for 73/78 women participating in the pilot and 358 de-identified controls. Tyrosine levels (μmol/l; whole blood)were higher in the late GDM group vs early, deferred treatment, and decoy groups (medians:106.28; IQR: 96.73-151.11) (76.33; 64.64-97.90) (75.68; 66.59-110.88)(73.74; 58.32-90.36) (p=0.009) and remained elevated when compared to normal, age-matched controls (106.28; 96.73-151.11) (87.26; 68.55-111.26) (p value=0.01) Immunoreactive trypsinogen (μgm/l; whole blood)was highest in the early treatment group when compared with group-specific controls (22.30; 13.90-29.90 vs 14.00, 10.60-21.10) (p=0.02). These results provide evidence of biochemical perturbations detectable on NBS of in-utero exposure to hyperglycemia and treatment and provide data for hypothesis building.
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The Hospital of the Ribeirão Preto Medical School, University of São Paulo is one of the three screening centers in São Paulo State, Brazil, and has included a test for cystic fibrosis (CF) since February 6, 2010, by a court order. We evaluated the first five years of this CF-newborn screening program. The original immunoreactive trypsinogen (IRT)/IRT screening protocol was adopted in Brazil. A total of 173,571 newborns were screened, 1,922 (1.1%) of whom showed IRT1 ≥ 70ng/mL. Of these, 1,795 (93.4%) collected IRT2, with elevated results (IRT2 ≥ 70ng/mL) in 102 of them (5.2%). We identified a total of 26 CF cases during this period, including three CF cases that were not detected by the CF-newborn screening. The incidence of the disease among the screened babies was 1:6,675 newborns screened. Median age at the initial evaluation was 42 days, comparable to that of neonates screened with the IRT/DNA protocol. Almost all infants with CF already exhibited some manifestations of the disease during the neonatal period. The mutation most frequently detected in the CF cases was F508del. These findings suggest the early age at the beginning of treatment at our center was due to the effort of the persons involved in the program regarding an effective active search. Considering the false negative results of CF-newborn screening and the early onset of clinical manifestations of the disease in this study, pediatricians should be aware of the diagnosis of CF even in children with negative test.
O Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo é um dos três centros de triagem da fibrose cística (FC) no estado de São Paulo, tendo incluído esse teste desde 6 de fevereiro de 2010, a partir de uma liminar judicial. O estudo avalia os primeiros cinco anos desse programa de triagem neonatal da FC. O Brasil adota o protocolo de triagem original, com o tripsinogênio imunorreativo (IRT)/IRT. Foram triados um total de 173.571 recém-nascidos, dos quais 1.922 (1,1%) mostraram IRT ≥ 70ng/mL. Destes, 1.795 (93,4%) tiveram amostras coletadas para IRT2, com resultados elevados (IRT2 ≥ 70ng/mL) em 102 deles (5,2%). Identificamos um total de 26 casos de FC durante esse período, inclusive 3 casos de FC que não foram detectados com a triagem neonatal. A incidência da FC foi de 1 caso em cada 6.675 recém-nascidos triados. A idade mediana na avaliação inicial foi 42 dias, comparável à idade de recém-nascidos triados com o protocolo IRT/DNA. Quase todos os lactentes com FC já exibiam algumas manifestações da doença durante o período neonatal. A mutação mais comum nos casos de FC foi a F508del. Os resultados em nosso centro indicam que a idade precoce no início do tratamento foi devido aos esforços do programa na implementação de uma busca ativa eficaz. Considerando os resultados falsos-negativos no programa de triagem neonatal para FC e o início precoce das manifestações clínicas da doença neste estudo, os pediatras devem estar cientes da possibilidade de diagnóstico de FC, mesmo em crianças com teste negativo.
El Hospital das Clínicas de la Facultad de Medicina de Ribeirão Preto, São Paulo Universidad es uno de los tres centros de cribado de fibrosis cística (FC) en el estado de São Paulo, incluyendo este test desde el 6 de febrero de 2010, debido a una medida cautelar judicial. El estudio evalúa los primeros cinco años de este programa de cribado neonatal de FC. Brasil adopta el protocolo de cribado original, con el tripsinógeno inmunorreactivo (TIR)/IRT. Se cribaron un total de 173.571 recién nacidos, de los cuales 1.922 (1,1%) mostraron IRT ≥ 70ng/mL. De estos, se obtuvieron 1.795 (93,4%) muestras recogidas para IRT2, con resultados elevados (IRT2 ≥ 70ng/mL) en 102 de ellos (5,2%). Identificamos un total de 26 casos de FC durante ese período, inclusive 3 casos de FC que no fueron detectados con el cribado neonatal. La incidencia de la FC fue de 1 caso por cada 6.675 recién-nacidos cribados. La edad media en la evaluación inicial fue 42 días, comparable a la edad de recién nacidos cribados con el protocolo IRT/DNA. Casi todos los lactantes con FC ya manifestaban algunos síntomas de la enfermedad durante el período neonatal. La mutación más común en los casos de FC era el F508del. Los resultados en nuestro centro indican que la edad precoz en el inicio del tratamiento se debía a los esfuerzos del programa en la implementación de una búsqueda activa eficaz. Considerando los resultados falsos-negativos en el programa de cribado neonatal para FC, y el inicio precoz de las manifestaciones clínicas de la enfermedad en este estudio, los pediatras deben ser conscientes de la posibilidad de diagnóstico de FC, incluso en niños con test negativo.
Assuntos
Humanos , Recém-Nascido , Lactente , Criança , Triagem Neonatal , Fibrose Cística/diagnóstico , Fibrose Cística/epidemiologia , Tripsinogênio , Brasil/epidemiologia , Regulador de Condutância Transmembrana em Fibrose CísticaRESUMO
Trypsinogens are the inactive precursors of trypsins (EC 3.4.21.4), which are digestive serine proteases. Despite knowing the properties of trypsins from Pacific white shrimp, Penaeus vannamei, the biochemical properties of shrimp trypsinogens including activation mechanisms and kinetics are unknown, due to difficulties isolating them from natural sources. In the present work, we describe the purification and biochemical characterization of four trypsinogen-like isoforms from recombinant P. vannamei trypsinogen, with a special emphasis on understanding its activation kinetics. The major trypsinogen-like isoform had an apparent molecular mass of 29â¯kDa. The other three forms of recombinant trypsinogen were: an N-glycosylated form of 32â¯kDa, a possibly O-glycosylated form of 41â¯kDa, and a likely double-chain form with a subunit of 23â¯kDa. The autoactivation profile of three-recombinant trypsinogen-like isoforms showed increased trypsin activity at a rate that was higher than that of bovine trypsinogen. This confirms the hypothesis proposed in the literature of a rapid trypsinogen autoactivation in the absence of aspartates in the activation peptide as it is for P. vannamei trypsinogen.
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Proteínas de Artrópodes/química , Penaeidae/enzimologia , Tripsinogênio/química , Animais , Proteínas de Artrópodes/genética , Ativação Enzimática , Isoenzimas/química , Isoenzimas/genética , Penaeidae/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Tripsinogênio/genéticaRESUMO
OBJECTIVE: To use the results of the first five years of a cystic fibrosis newborn screening program to estimate the cystic fibrosis birth prevalence and spectrum of cystic fibrosis transmembrane conductance regulator ( CFTR) gene variants in Yucatan, Mexico. METHODS: Screening was performed from 2010 to 2015, using two-tier immunoreactive trypsinogen testing, followed by a sweat test. When sweat test values were >30 mmol/L, the CFTR gene was analyzed. RESULTS: Of 96,071 newborns screened, a second sample was requested in 119 cases. A sweat test was performed in 30 newborns, and 9 possible cases were detected (seven confirmed cystic fibrosis and two inconclusive). The most frequently detected CFTR pathogenic variant (5/14 cystic fibrosis alleles, 35.7%) was p.(Phe508del); novel p.(Ala559Pro) and p.(Thr1299Hisfs*29) pathogenic variants were found. CONCLUSIONS: Cystic fibrosis birth prevalence in southeastern Mexico is 1:13,724 newborns. Immunoreactive trypsinogen blood concentration is influenced by gestational age and by the time of sampling. The spectrum of CFTR gene variants in Yucatan is heterogeneous.
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Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/sangue , Fibrose Cística/diagnóstico , Mutação , Triagem Neonatal/métodos , Alelos , Fibrose Cística/genética , Feminino , Humanos , Recém-Nascido , Masculino , México/epidemiologia , Prevalência , Reprodutibilidade dos Testes , Suor , Tripsinogênio/sangueRESUMO
BACKGROUND: Hereditary pancreatitis is a rare inherited form of pancreatitis, characterized by recurrent episodes of acute pancreatitis with early onset and/or chronic pancreatitis, and presenting brittle diabetes, composed of episodes of nonketotic hyperglycemia and severe hypoglycemia. The existing literature regarding this form of diabetes is scarce. In this report, clinical features of pancreatogenic diabetes secondary to hereditary pancreatitis are presented along with recommendations for appropriate medical treatment. RESULTS: Clinical data from five patients of a family with pancreatogenic diabetes secondary to hereditary pancreatitis were analyzed. The average time between hereditary pancreatitis and diabetes diagnosis was 80 ± 24 months (range: 60-180 months) with a mean age of 25.6 ± 14.7 years (range: 8-42 years), four patients used antidiabetic agents for 46 ± 45 months and all progressed to insulin therapy with a mean dose of 0.71 ± 0.63 IU/kg (range: 0.3-1.76 IU/kg). The glycemic control had a high variability with average capillary blood glucose of 217.00 ± 69.44 mg/dl (range: 145-306 mg/dl) and the average HbA1c was 9.9 ± 1.9% (range: 7.6-11.6%). No ketoacidosis episodes occurred and there were several episodes of hospitalization for severe hypoglycemia. CONCLUSIONS: Diabetes mellitus secondary to hereditary pancreatitis presents with early onset, diverse clinical presentation and with extremely labile glycemic control. Diabetes treatment varies according to the presentation and insulin is frequently necessary for glycemic control.
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OBJECTIVE: Because cystic fibrosis (CF) can be difficult to diagnose, and because information about the genetic complexities and pathologic basis of the disease has grown so rapidly over the decades, several consensus conferences have been held by the US CF Foundation, and a variety of other efforts to improve diagnostic practices have been organized by the European CF Society. Despite these efforts, the application of diagnostic criteria has been variable and caused confusion. STUDY DESIGN: To improve diagnosis and achieve standardization in terms and definitions worldwide, the CF Foundation in 2015 convened a committee of 32 experts in the diagnosis of CF from 9 countries. As part of the process, all previous consensus-seeking exercises sponsored by the CF Foundation, along with the important efforts of the European CF Society, were comprehensively and critically reviewed. The goal was to better understand why consensus conferences and their publications have not led to the desired results. RESULTS: Lessons learned from previous diagnosis consensus processes and products were identified. It was decided that participation in developing a consensus was generally not inclusive enough for global impact. It was also found that many efforts to address sweat test issues were valuable but did not always improve clinical practices as CF diagnostic testing evolved. It also became clear from this review that premature applications of potential diagnostic tests such as nasal potential difference and intestinal current measurement should be avoided until validation and standardization occur. Finally, we have learned that due to the significant and growing number of cases that are challenging to diagnose, an associated continuing medical education program is both desirable and necessary. CONCLUSIONS: It is necessary but not sufficient to organize and publish CF diagnosis consensus processes. Follow-up implementation efforts and monitoring practices seem essential.
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Fibrose Cística/história , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Testes Genéticos , História do Século XX , Humanos , Recém-Nascido , Triagem Neonatal , Guias de Prática Clínica como AssuntoRESUMO
OBJECTIVE: Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. STUDY DESIGN: To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. RESULTS: After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. CONCLUSIONS: It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.
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Fibrose Cística/diagnóstico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística , Testes Genéticos , Humanos , Recém-Nascido , Mutação , Triagem Neonatal , Proteínas Associadas a Pancreatite , Guias de Prática Clínica como AssuntoRESUMO
OBJECTIVE: Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. STUDY DESIGN: To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. RESULTS: After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. CONCLUSIONS: It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.
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Fibrose Cística/diagnóstico , Humanos , Recém-Nascido , Triagem Neonatal , Proteínas Associadas a PancreatiteRESUMO
OBJECTIVE: An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Diagnostic and management decisions of these infants are challenges for CF healthcare professionals and stressful situations for families. As CF NBS has become more widespread across the world, increased information about the epidemiology and outcomes of these infants is becoming available. These data were reviewed at the 2015 CF Foundation Diagnosis Consensus Conference, and a harmonized definition of CRMS and CFSPID was developed. STUDY DESIGN: At the consensus conference, participants reviewed published and unpublished studies of CRMS/CFSPID and used a modified Delphi methodology to develop a harmonized approach to the definition of CRMS/CFSPID. RESULTS: Several studies of CRMS/CFSPID from populations around the world have been published in the past year. Although the studies vary in the number of infants studied, study design, and outcome measures, there have been some consistent findings. CRMS/CFSPID occurs relatively frequently, with CF:CRMS that ranges from 3 to 5 cases of CF for every 1 case of CRMS/CFSPID in regions where gene sequencing is not used. The incidence varies by NBS protocol used, and in some regions more cases of CRMS/CFSPID are detected than cases of CF. The majority of individuals with CRMS/CFSPID do not develop CF disease or progress to a diagnosis of CF. However, between 10% and 20% of asymptomatic infants can develop clinical features concerning for CF, such as a respiratory culture positive for Pseudomonas aeruginosa. Most studies have only reported short-term outcomes in the first 1-3 years of life; the long-term outcomes of CRMS/CFSPID remain unknown. The European CF Society definition of CFSPID and the CF Foundation definition of CRMS differ only slightly, and the consensus conference was able to create a unified definition of CRMS/CFSPID. CONCLUSIONS: CRMS/CFSPID is a relatively common outcome of CF NBS, and clinicians need to be prepared to counsel families whose NBS test falls into this classification. The vast majority of infants with CRMS/CFSPID will remain free from disease manifestations early in life. However, a small proportion may develop clinical features concerning for CF or demonstrate progression to a clinical phenotype compatible with a CF diagnosis, and their long-term outcomes are not known. A consistent international definition of CRMS/CFSPID will allow for better data collection for study of outcomes and result in improved patient care.
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Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/etiologia , Regulador de Condutância Transmembrana em Fibrose Cística , Testes Genéticos , Humanos , Recém-Nascido , Triagem NeonatalRESUMO
OBJECTIVES: To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation. STUDY DESIGN: We followed 89 children with severe acute malnutrition admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Stool and blood samples were taken on admission and 3 days after initial stabilization to determine exocrine pancreatic function via fecal elastase-1 (FE-1) and serum trypsinogen and amylase levels. RESULTS: A total of 33 children (37.1%) had nonedematous severe acute malnutrition, whereas 56 (62.9%) had edematous severe acute malnutrition. On admission, 92% of patients showed evidence of pancreatic insufficiency as measured by FE-1 <200 µg/g of stool. Patients with edematous severe acute malnutrition were more likely to have low FE-1 (98% vs 82.8%, P = .026). FE-1 levels remained low in these individuals throughout the assessment period. Serum trypsinogen was elevated (>57 ng/mL) in 28% and amylase in 21% (>110 U/L) of children, suggesting pancreatic inflammation. CONCLUSION: Exocrine pancreatic insufficiency is prevalent in children with severe acute malnutrition and especially in children with edematous severe acute malnutrition. In addition, biochemical signs suggestive of pancreatitis are common in children with severe acute malnutrition. These results have implications for standard rehabilitation treatment of children with severe acute malnutrition who may benefit from pancreatic enzyme replacement therapy. TRIAL REGISTRATION: ISRCTN.com: 13916953.
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Insuficiência Pancreática Exócrina/epidemiologia , Pancreatite/epidemiologia , Desnutrição Aguda Grave/complicações , Amilases/sangue , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Tempo de Internação , Masculino , Elastase Pancreática/metabolismo , Testes de Função Pancreática , Prevalência , Tripsinogênio/sangueRESUMO
Newborn screening for cystic fibrosis is a public health strategy that as been associated with early improved nutrition and survival, and the potential for preventing severe health problems. Various protocols have been employed, being the measurement of immunoreactive trypsynogen (IRT) in the first few days of life the first step in all of them. The second tier can include IRT/IRT, IRT/DNA, IRT/PAP (pancreatitis associated protein). Protocol selection depends on the priorities for each country but at present there is no optimal strategy.
El tamizaje neonatal para fibrosis quística es una estrategia de salud pública que ha demostrado beneficios nutricionales, aumento de la sobrevida y potencialmente prevención de problemas severos de salud. En el mundo se usan variados protocolos, sin embargo en todos el primer paso es la determinación de tripsinógeno inmunorreactivo (IRT) en sangre, tomado del talón del recién nacido. El segundo paso incluye la determinación de un segundo IRT o determinación de DNA o PAP (Proteína asociada a pancreatitis). La selección del protocolo a seguir depende de cada país pero hasta ahora no hay una estrategia óptima.
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Humanos , Recém-Nascido , Fibrose Cística/diagnóstico , Fibrose Cística/epidemiologia , Triagem Neonatal/métodos , Chile , Protocolos Clínicos , Reações Falso-Negativas , Saúde Global , TripsinogênioRESUMO
Introducción. La pesquisa neonatal para fibrosis quística ha demostrado su utilidad en el diagnóstico precoz con mejoría en nutrición, función pulmonar y cognición. Se coordinaron dos centros para la medición de los valores de TIR y diagnóstico de fibrosis quística, usando un algoritmo tradicional y uno adaptado para mejorar resultados previos sin coordinación. Método. Se presentan datos del período pre-coordinación donde no hubo diagnósticos de FQ a partir de TIR. Se detallan datos del período coordinado, que aun no siendo cronológica ni numéricamente igual al anterior, muestran resultados totalmente distintos. Para TIR se utilizó DELFIA y para test de sudor iontoforesis por pilocarpina. Resultados. Período pre-coordinación entre centros (enero de 2005 a febrero de 2010): se realizaron 18.732 determinaciones de TIR. 74 fueron TIR (+). No hubo diagnósticos de FQ por problemas de seguimiento. Período coordinado: desde el 1° de marzo de 2010 hasta el 31 de diciembre de 2011. Se realizaron 41.142 determinaciones de TIR. Se encontró TIR elevado en la 1ª muestra en 91 niños (0,22%). Se diagnosticaron 4 fibroquísticos por medio de los algoritmos presentados. Conclusiones. En 71 RN seguidos efectivamente con TIR positivo, se diagnosticaron 4 FQ en el período coordinado. Disminuyó la edad media al diagnóstico de 4,54 años a 2,5 meses (aún pocos casos) y la cantidad de perdidos al seguimiento bajó de 36,95 % a 15,90%. Estas cifras sugieren un resultado positivo producto de la integración y centralización de los sistemas como lo cita toda la literatura.
Introduction. Neonatal screening in cystic fibrosis has shown to be an important tool for early diagnosis, better nutrition, diminished lung function and cognitive development. Our laboratory and CF Center were coordinated for IRT screening and diagnosis. We used a standard and a modified algorithm to improve previous results of an uncoordinated period. Method. IRT-IRT-sweat test algorithms was implemented using Dissociation-Enhanced Lanthanide Fluroimmunoassay (DELFIA) for IRT, and pilocarpine iontophoresis for sweat test. Pre-coordination period data are also presented (January 2005 - February 2010) when follow up was difficult .Details for the coordinated period are presented although no statistical comparisons are intended since the number of patients and time-periods studied were completely different. Results. a) pre-coordination period: 18,732 IRT measurements were done. 74 positive IRT tests were detected. No CF diagnosis was made by IRT screening due to problems with follow-up. Only 3 CF patients were diagnosed by genetic studies requested only due to clinical symptoms. b) Coordinated period (March 2010 to December 2011): 41,142 IRT samples were analized. 91 positive first sample IRT detected (0.22%). 71 patients remained for effective follow-up. Four CF diagnosis were made by the algorithm IRT screening-sweat test. Conclusions. In 71 remaining patients after first IRT positive result, CF was diagnosed in four patients. Mean age of diagnosis diminished from 4.54 years to 2.5 months although numbers are small for definitive conclusions. These figures suggest that positive results are the result of coordination and centralization in the CF Center as suggested by many references.
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Humanos , Recém-Nascido , Diagnóstico Precoce , Fibrose Cística/diagnóstico , Triagem Neonatal , Argentina , Diagnóstico Diferencial , Testes Obrigatórios , Tripsinogênio/sangueRESUMO
AIM: To identify gene mutations in PRSS1 and SPINK1 in individuals with early onset idiopathic chronic or recurrent acute pancreatitis. METHODS: The cationic trypsinogen gene (PRSS1; exons 2 and 3) and the serine protease inhibitor Kazal 1 gene (SPINK1; exon 3) were selectively amplified and sequenced from blood samples of 19 patients admitted to the Pancreas Clinic at our institution with chronic pancreatitis and/or idiopathic recurrent acute pancreatitis that were diagnosed or with onset before age 35. Fifty healthy volunteers served as controls. Whole blood samples were collected and gene specific sequences were amplified by polymerase chain reaction (PCR). All PCR products were subsequently sequenced in order to identify the presence of any mutations. RESULTS: Nineteen patients with pancreatitis (14 males; median age 24 years, range 15-48 years) were included in this study, of which five showed the presence of gene mutations. Direct sequencing results indicated the presence of two previously unidentified mutations in exon 2 of PRSS1 (V39E and N42S) in two patients with recurrent acute pancreatitis. Two cases had the N34S SPINK1 mutation. Analysis of the relatives of one patient homozygous for this mutation showed that five of the six family members carried the N34S SPINK1 mutation. Of these members, three were healthy heterozygous carriers and two were homozygotes (one sibling had diabetes, the other was healthy). Another patient was heterozygous for a novel SPINK1 mutation located on exon 3 (V46D). All members from this patient's family had normal genotypes, indicating that it was a de novo mutation. No mutations in either gene were present in the control subjects. CONCLUSION: Two novel PRSS1 mutations and one novel SPINK1 mutation were identified in Mexican patients with early onset idiopathic recurrent acute pancreatitis.
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Proteínas de Transporte/genética , Mutação , Pancreatite Crônica/genética , Pancreatite/genética , Tripsina/genética , Doença Aguda , Adolescente , Adulto , Idade de Início , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Pancreatite/enzimologia , Pancreatite/epidemiologia , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/enzimologia , Pancreatite Crônica/epidemiologia , Fenótipo , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Inibidor da Tripsina Pancreática de Kazal , Adulto JovemRESUMO
In recent years many studies have examined the genetic predisposition to pancreatic diseases. Pancreatic disease of an alcoholic etiology was determined to be a multi-factorial disease, where environmental factors interact with the genetic profile of the individual. In this review we discuss the main results from studies examining the frequency of genetic mutations in alcoholic chronic pancreatitis.
Assuntos
Alcoolismo/complicações , Pancreatite Alcoólica/genética , Etanol/metabolismo , Etanol/toxicidade , Humanos , Mutação , Pancreatite Alcoólica/epidemiologia , Pancreatite Alcoólica/metabolismoRESUMO
Cystic fibrosis is one of the most common autosomal recessive hereditary diseases in the Caucasian population, with an incidence of 1:2000 to 1:3500 liveborns. More than 1000 mutations have been described with the most common being F508del. It has a prevalence of 23-55 percent within the Brazilian population. The lack of population-based studies evaluating the incidence of cystic fibrosis in São Paulo State, Brazil, and an analysis concerning the costs of implantation of a screening program motivated the present study. A total of 60,000 dried blood samples from Guthrie cards obtained from April 2005 to January 2006 for neonatal screening at 4 reference centers in São Paulo State were analyzed. The immunoreactive trypsinogen (IRT)/IRT protocol was used with the cut-off value being 70 ng/mL. A total of 532 children (0.9 percent) showed IRT >70 ng/mL and a 2nd sample was collected from 418 (80.3 percent) of these patients. Four affected children were detected at two centers, corresponding to an incidence of 1:8403. The average age at diagnosis was 69 days, and 3 of the children already showed severe symptoms of the disease. The rate of false-positive results was 95.2 percent and the positive predictive value for the test was 8 percent. The cost of detecting an affected subject was approximately US$8,000.00 when this cystic fibrosis program was added to an existing neonatal screening program. The present study clearly shows the difficulties involved in cystic fibrosis screening using the IRT/IRT protocol, particularly in a population with no long-term tradition of neonatal screening.