The first five-year evaluation of cystic fibrosis neonatal screening program in São Paulo State, Brazil / Uma avaliação dos primeiros cinco anos do programa de triagem neonatal da fibrose cística no Estado de São Paulo, Brasil / Una evaluación de los primeros cinco años del programa de cribado neonatal de fibrosis cística en el Estado de São Paulo, Brasil

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.

Fibrosis quística y tamizaje neonatal / Newborn screening and cystic fibrosis

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.

Pesquisa neonatal en fibrosis quística: un modelo de coordinación multidisciplinaria. ha llegado la hora de los centros de fibrosis quística / Cystic fibrosis screening: amultidisciplinary coordinationapproach. the time for cysticfibrosis centers has arrived

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.

Two cases of chronic pancreatitis associated with anomalous pancreaticobiliary ductal union and SPINK1 mutation / 소아과

Chronic pancreatitis is a progressive inflammatory disease resulting from repeated episodes of acute pancreatitis that impair exocrine function and eventually produce endocrine insufficiency. Some causes of chronic pancreatitis appear to be associated with alterations in the serine-protease inhibitor, Kazal type 1 (SPINK1), cationic trypsinogen (PRSS1), and cystic fibrosis-transmembrane conductance regulator (CFTR) genes, or with structural disorders in the pancreaticobiliary ductal system, such as pancreatic divisum or anomalous pancreaticobiliary ductal union (APBDU). However, it is unusual to observe both genetic alteration and structural anomaly. Here, we report 2 cases with both APBDU and a mutation in the SPINK1 genes, and we discuss the implications of these findings in clinical practice.

Pathogenesis of Acute Pancreatitis / 대한내과학회지

Acute pancreatitis is an inflammatory disease that is caused by various etiologies including gallstone, alcohol or hypertriglyceridemia. Although most cases of acute pancreatitis show self-limiting course, severe cases are still associated with significant morbidity and mortality. The pathogenic mechanisms of acute pancreatitis are not fully understood. However, it is a central dogma that premature intracellular activation of trypsinogen is the earliest pathologic event. Even though it remains unknown how intracellular trypsinogen activation can be caused by such diverse etiologies, this initial insult in pancreatic acinar cells lead to local inflammatory complications and a systemic response or death. Pathophysiologic mechanisms related to the progression of acute pancreatitis include microcirculatory injury, chemoattraction of inflammatory cells, release of pro-inflammatory cytokines, and bacterial translocation to pancreas and systemic circulation. Recently, several interesting transgenic mice model experiments shed a light in trypsin independent mechanism of local and systemic inflammation for progression of acute pancreatitis.

Heat Shock Proteins and Autophagy in Rats with Cerulein-Induced Acute Pancreatitis

BACKGROUND/AIMS: Heat shock proteins (HSPs) protect rats from cerulein-induced acute pancreatitis (AP) by preventing the subcellular redistribution of cathepsin B and the activation of trypsinogen. Autophagy plays a critical role in the secretion of digestive enzymes and triggering of cerulein-induced AP via the colocalization of trypsinogen and lysosomes. Therefore, using a rat cerulein-induced AP model, we investigated whether HSPs prevent AP by regulating autophagy. METHODS: Twelve hours after fed standard laboratory chow and water, the experimental groups (cerulein, water-immersion [WI]-cerulein and heat-shock [HS]-cerulein) and the control groups (control, WI, and HS) received one intraperitoneal injection of cerulein (50 microg/kg) or saline, respectively. All of the rats were sacrificed at 6 hours after injection. The severity of the AP was assessed based on the serum amylase level and the histological and electron microscopy findings. Western blotting was also performed for HSP60/70 and LC3B-II. RESULTS: WI and HS induced HSP60 and HSP70, respectively. The induced HSP60/70 effectively prevented the development of cerulein-induced AP. Autophagy developed in the rats with cerulein-induced AP and was documented by the expression of LC3-II and electron microscopy findings. The WI-stressed rats and HS-treated rats did not develop cerulein-induced autophagy. CONCLUSIONS: HSPs exert protective effects against cerulein-induced AP in rats by inhibiting autophagy.

Neonatal screening for cystic fibrosis in São Paulo State, Brazil: a pilot study

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.

Effect of trypsinogen 16 on phenotypic switch of airway fibroblasts into myofibroblasts / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the relation between transdifferentiation of the airway myofibroblasts and the expression level of (trypsinogen16, TG16) in vitro and explore the mechanism of airway basement membrane thickening.</p><p><b>METHODS</b>The total lung proteins were extracted from normal and OVA-induced asthmatic mice and the protein expression profiles were analyzed with SDS-PAGE. The differentially expressed proteins were isolated for analysis with liquid chromatography-mass spectrometry. TG16 was cloned from mouse lung tissue and subcloned into the expression vector pcDNA3.0 to generate a pcDNA3-TG16 plasmid. The vectors were transfected into mouse embryonic fibroblast 3T3 cells and cultured in MEM in the presence of transforming growth factor-beta1 (TGF-beta1). The mRNA levels of alpha-actin and the housekeeping GAPDH gene were analyzed with RT-PCR. Using RNA interference, TG16 expression was suppressed and the resultant alpha-actin or GAPDH protein levels were analyzed using Western blotting.</p><p><b>RESULTS</b>In the total lung proteins from OVA-induced mice, a 25 000 Da protein was significantly enhanced in comparison with the protein profiles of normal mice. The protein band was identified to represent the protein of TG16. With TGF-beta1 stimulation, transfection with the plasmid pcDNA3-TG16 significantly suppressed the mRNA expression of alpha-actin (alpha-actin/GAPDH=1.78-/+0.50) in 3T3 cells as compared with the expression in cells transfected with pcDNA3.0 (3.20-/+1.36); transfection of the cells with TG16 stealth RNAi oligonucleotide to decrease TG16 mRNA level upregulated the protein level of alpha-actin (3.60-/+0.44) as compared with the alpha-actin protein level in 3T3 cells transfected with control oligonucleotide (2.78-/+0.50).</p><p><b>CONCLUSION</b>TG16 can inhibit the expression of alpha-actin in fibroblasts, which might be a protective mechanism in the progression of airway remodeling in asthma.</p>

Novel mutation and polymorphism of PRSS1 gene in the Chinese patients with hereditary pancreatitis and chronic pancreatitis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Mutations in the cationic trypsinogen gene (PRSS1) have been detected in patients with hereditary pancreatitis (HP). This study investigated the prevalence of the R122H (c.365 G > A), A121T (c.361 G > A) and D162D (c.488 C > T) mutations or polymorphisms in the common, non-hereditary forms of chronic pancreatitis and in an HP family.</p><p><b>METHODS</b>DNA was prepared from blood samples of 54 patients with chronic pancreatitis (35 alcoholic, 17 idiopathic and 2 hereditary) and 120 normal controls. The PRSS1 genes were amplified by polymerase chain reaction (PCR) and their products were analyzed by sequencing and related clinical data were also collected.</p><p><b>RESULTS</b>A new polymorphism (c.488 C > T) of PRSS1 was found in 25 patients with chronic pancreatitis (including one affected member of the HP family) and six members of the normal controls. The C/T genotype was significantly increased in chronic pancreatitis (OR: 16.379, 95% CI: 5.7522 - 52.3663), the frequency of c.488 C > T change was in according with the Hardy-Weinberg equilibrium, but it doesn't affect the clinical phenotype. The commonly reported change of R122H (c.365 G > A) was not detected in any of the study subjects. c.361 G > A was found in 2 affected members and one unaffected carrier in an HP family. One of the affected members of an HP family had c.361 G > A mutation and polymorphism (c.488 C > T) in the PRSS1 gene at the same time. The patient's clinical values (C3, C4, CA19-9 and HbA1c) were higher than those of the other patients with chronic pancreatitis. The two patients with HP developed diabetes mellitus and their father died with pancreatic cancer.</p><p><b>CONCLUSION</b>A new polymorphism (c.488 C > T) in the PRSS1 gene is associated with chronic pancreatitis, but it did not affect the clinical phenotype while the A121T (c.361 G > A) mutation in the gene shows a significant correlation in the patients with HP.</p>

Three Cases of Hereditary Pancreatitis in Two Households in the Same Family Associated with R122H Mutation in Cationic Trypsinogen Gene / 대한소화기학회지

Hereditary pancreatitis is a rare, autosomal dominant, inherited disease characterized by recurrent attacks of acute pancreatitis with the development of chronic pancreatitis and an increased risk of pancreatic cancer. R122H or N29I mutation in cationic trypsinogen (protease serine 1, PRSS1) gene causes hereditary pancreatitis. R122H mutation is the most common mutation that causes pancreatitis by preventing deactivation of trypsin within the pancreas and prolonging its action. Three members of the family, the patient, her elder son, and her niece experienced recurrent attacks of pancreatitis. We analyzed five exons of the PRSS1 gene in DNA samples of five family members including her husband and younger son who were asymptomatic. We found out that four members of the family, the patient, her two sons, and her niece, had R122H mutation in the exon 3 of PRSS1 gene. Finally, we diagnosed hereditary pancreatitis in two households in the same family.

Relationship between carbachol hyperstimulation-induced pancreatic acinar cellular injury and trypsinogen or NF-kappaB activation in rats in vitro / 华中科技大学学报（医学）（英德文版）

The relationship between M3 cholinergic receptor agonist (carbachol) hyperstimulation-induced pancreatic acinar cellular injury and trypsinogen activation or NF-kappaB activation in rats was studied in vitro. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc), and NF-kappaB inhibitor (PDTC) in vitro. Intracellular trypsin activity was measured by using a fluorogenic substrate. The cellular injury was evaluated by measuring the leakage of LDH from pancreatic acinar cells. The results showed that as compared with control group, 10(-3) mol/L carbachol induced a significant increase of the intracellular trypsin activity and the leakage of LDH from pancreatic acinar cells. Pretreatment with 2 mmol/L pefabloc could significantly decrease the activity of trypsin and the leakage of LDH from pancreatic acinar cells (P 0.05). It was concluded that intracellular trypsinogen activation is likely involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro. NF-kappaB activation may not be involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro.

A case of hereditary pancreatitis with a N29I mutation in the cationic trypsinogen gene / 소아과

Hereditary pancreatitis is an autosomal dominant disease characterized by recurrent episodes of pancreatitis, often beginning in childhood, with a positive family history involving at least two other affected family members with no known other precipitating factors. Most forms of hereditary pancreatitis are caused by one of two common mutations, i.e., R122H in exon 3 and N29I in exon 2 of the cationic trypsinogen (CT) (PRSS1) gene, located on chromosome 7. The authors describe the case of a 15-year-old boy who had suffered from recurrent attacks of pancreatitis since age three. His mother and grandmother had chronic pancreatitis and diabetes mellitus. Mutation analysis was performed on the family due to the suspicion of hereditary pancreatitis. The CT gene was analyzed in DNA samples extracted from the peripheral blood of three family members, the mother, the proband, and the proband's sister. Two members of the family, the mother and the proband, were found to have a N29I mutation in the CT gene. The authors document the first family with hereditary pancreatitis associated with the N29I mutation in Korea.

Hereditary Pancreatitis: Report of a Kindred

Hereditary pancreatitis (HP) appears as an autosomal dominant trait. If the patient has (1) more than 2 affected relatives in different generations and (2) no known etiological factors such as alcohol or gallstones, or has R122H or N29I mutation in the cationic trypsinogen (CT) gene, the diagnosis of HP can be applied. Risk of pancreatic cancer is estimated to be 53-fold higher than in a general population after the age of 50 years. We report a kindredof HP, involving three of its family together; two siblings (14 years old, 13 years old) and cousin (26 years old). The patient had complicating chronic pancreatitis and pancreatic stone, and was treated with amodified Puestow-Gillesby procedure. Her sisters showed chronic pancreatitis. Her cousin underwent a drainage procedure of the pancreatic duct for chronic pancreatitis during the high school period. All the three members showed the R122H mutation of the CT gene.

Hereditary Pancreatitis: Report of a Kindred

Hereditary pancreatitis (HP) appears as an autosomal dominant trait. If the patient has (1) more than 2 affected relatives in different generations and (2) no known etiological factors such as alcohol or gallstones, or has R122H or N29I mutation in the cationic trypsinogen (CT) gene, the diagnosis of HP can be applied. Risk of pancreatic cancer is estimated to be 53-fold higher than in a general population after the age of 50 years. We report a kindredof HP, involving three of its family together; two siblings (14 years old, 13 years old) and cousin (26 years old). The patient had complicating chronic pancreatitis and pancreatic stone, and was treated with amodified Puestow-Gillesby procedure. Her sisters showed chronic pancreatitis. Her cousin underwent a drainage procedure of the pancreatic duct for chronic pancreatitis during the high school period. All the three members showed the R122H mutation of the CT gene.

Hereditary Pancreatitis / 대한소화기학회지

The first family of hereditary pancreatitis was described in 1952. The mode of inheritance is autosomal dominant trait with an 80% of penetrance rate. Although hereditary pancreatitis is rare, this disorder has provided valuable insights in understanding the pathophysiology of pancreatitis and pancreatic cancer. The causative gene of hereditary pancreatitis was identified in 1996 through mutational analysis of genes within chromosome 7q35. Most forms of hereditary pancreatitis are caused by one of two common mutations, R122H in the third exon or N29I in the second exon of the cationic trypsinogen gene (protease serine 1, PRSS1). R122H mutation is the most common PRSS1 mutation. Additional mutations of the cationic trypsinogen gene have been described. In Korea, first family of hereditary pancreatitis with cationic trypsinogen gene mutation revealed an arginine to histidine amino acid substitution at the residue 122. Patients with hereditary pancreatitis present with symptoms at an early age and have significant risk for the development of chronic pancreatitis and pancreatic cancer. The risk of pancreatic cancer is estimated to be 53-fold higher after the age of 50 years than the general population. The risk of pancreatic cancer is not related to the type of mutation. Since hereditary pancreatitis is a strong risk factor for pancreatic cancer, it is important to establish a diagnostic criteria for diagnosis and surveillance. However, there are potential benefits, risks and limitations in genetic testing for hereditary pancreatitis. It is difficult to provide the proper treatment, but recent developments in therapeutic approaches may be helpful in caring hereditary pancreatitis. This article includes the current status, pathogenesis, clinical features, and management of hereditary pancreatitis including the aspects of pancreatic cancer.

A Case of R122H Mutation of Cationic Trypsinogen Gene in a Pediatric Patient with Hereditary Pancreatitis Complicated by Pseudocyst and Hemosuccus Pancreaticus / 대한소화기학회지

Hereditary pancreatitis is a rare autosomal dominant inherited disease with 80% penetration rate. The disease is characterized by recurrent episodes of pancreatitis often beginning in childhood, positive family history with at least two other affected members and no known precipitating factors. Most forms of hereditary pancreatitis are caused by one of two commoner mutations, R122H in exon 3 and N29I in exon 2 of the cationic trypsinogen (CT) (PRSS1) gene, located on chromosome 7. These genetic defects are speculated to cause excessive trypsin activity or to prevent inactivation of prematurely activated trypsin, resulting in pancreatitis. We performed mutation analysis of a Korean family with two members having clinically suspicious hereditary pancreatitis. We analyzed the CT gene in DNA samples extracted from peripheral blood of five family members. First of all, polymerase chain reaction and restriction enzyme digestion were performed in exon 3 of the CT gene. And then DNA products were purified and sequenced. We found out that three members of the family, the mother and two daughters, had a R122H mutation of the CT gene. We report the first family of hereditary pancreatitis associated with the CT gene mutation, an arginine to histidine amino acid substitution at residue 122, in Korea.

Hereditary Pancreatitis / 대한소화기학회지

Hereditary pancreatitis (HP) is an autosomal dominant inherited disease characterized by recurrent episodes of pancreatitis often beginning in childhood, a family history of at least 2 other affected members, and the absence of known etiologic factors. The discovery of mutations in cationic trypsinogen gene (PRSS1) in HP not only provided insights into the molecular mechanisms of pancreatitis, but also opened a new era in the field of chronic pancreatitis. The detection of mutations in serine protease inhibitor, Kazal type 1 (SPINK1) and CFTR in patients with hereditary or idiopathic chronic pancreatitis has placed the emphasis on the importance of genetic mutations in pancreatitis. Because the estimated cumulative risk of pancreatic cancer developement in hereditary pancreatitis is nearly 40%, screening tests are important in selected cases. There are no specific medical therapies recommended in patients with HP. Registration of patients with Nationwise Registries is essential if management strategies are to be improved and genetic research to be continued.

Mutations of SPINK1 and PRSS1 Gene in Korean Patients with Chronic Pancreatitis / 대한소화기학회지

BACKGROUND/AIMS: It has been found that mutations of cationic trypsinogen gene (PRSS1) and serine protease inhibitor, Kazal type 1 gene (SPINK1) increase the susceptibility of chronic pancreatitis (CP). Specifically, mutations in the PRSS1 gene are related to the occurrences of hereditary and idiopathic pancreatitis while SPINK1 mutations are known to act as a disease modifier and are associated with idiopathic CP. However, the association of SPINK1 mutations with alcoholic CP is still controversial. We investigated the prevalence of PRSS1 and SPINK1 mutations in idiopathic and alcoholic CP in Korea. METHODS: Seventy-one Korean patients with CP (alcoholic: 47, idiopathic: 22 and familial: 2) and 19 controls were included in this studies. Genomic DNA was extracted from peripheral blood of the patients. Mutations of SPINK1 (exon 3: N34S) and PRSS1 (exon 2: N29I, exon 3: R122H) genes were detected by PCR-RFLP methods. For the detection of SPINK1 mutation, restriction endonuclease PstI and BsrDI were used, while Sau3A and AflIII were used for the defection of PRSS1 mutation. RESUTLS: Only one patient (2.1%) with alcoholic CP was a heterozygote for SPINK1 (N34S) mutation. Mutation in the PRSS1 (N29I, R122H) gene was not found in any group of CP patients. Additionally, we could not find any mutations of SPINK1 or PRSS1 in the control group. CONCLUSIONS: SPINK1 and PRSS1 mutations are not related to the development of CP in Korea.