New PRSS1 and common CFTR mutations in a child with acute recurrent pancreatitis, could be considered an "Hereditary" form of pancreatitis ?

<p>Abstract</p> <p>Background</p> <p>acute recurrent pancreatitis is a complex multigenic disease, the diagnosis is even more difficult when this disease develops in a child.</p> <p>Case Presentation</p> <p>a 6-years old boy, hospitalized with epigastric pain radiating to the back showed high serum levels of serum amylase, lipase, CRP and erythrosedimentation rate. Several similar milder episodes of pain, followed by quick recovery and complete disappearance of symptoms were reported during the previous 13 months. The child was medically treated and after 7 days with normal clinic and laboratory tests was discharged with a hypolipidic diet. All the known aetiologic hypotheses were excluded by anamnestic investigation, clinical observation and biochemical evaluation, whereas, anatomic abnormality were excluded by a secretin stimulated magnetic resonance (MRI). At the last follow-up visit, (11 months later), the child showed a normal body weight and anthropometric profile, without further abdominal pain. Mutation screening for coding regions of <it>PRSS1, SPINK1, CFTR </it>and the new hereditary pancreatitis-associated chymotrypsin C (<it>CTRC</it>) genes showed a novel variation, c.541A > G (p.S181G), in the exon 4 of PRSS1 gene and the classical CF p.F508del mutation in the <it>CFTR. </it>Both mutations were present in his clinically normal mother and absent in the patient's father.</p> <p>Conclusions</p> <p>this report extend the spectrum of PRSS1 mutations, however, the absence of family history of pancreatitis leaves the present case without the hallmark of the hereditary origin of pancreatitis. At the present knowledge it can be only stated that the combined genotype CFTR (F508del)/PRSS1 (S181G) is associated to a mild phenotype of acute recurrent pancreatitis in this child without any further conclusion on its pathogenetic role or prediction on the course of the disease.</p

Pathways to Injury in Chronic Pancreatitis: Decoding the Role of the High-Risk SPINK1 N34S Haplotype Using Meta-Analysis

Background: The complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP) are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways) that are initiated by different metabolic or environmental factors (etiologies) and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis. Methods and Findings: The Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls) using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59-15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16-7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09-24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83-41.56). Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I2 = 80.95%. Conclusion: The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint. © 2008 Aoun MD et al

Prostaglandin-endoperoxide synthase genes COX1 and COX2 - novel modifiers of disease severity in cystic fibrosis patients.

Cystic fibrosis (CF) is one of the most common autosomal recessive diseases among Caucasians caused by a mutation in the CFTR gene. However, the clinical outcome of CF pulmonary disease varies remarkably even in patients with the same CFTR genotype. This has led to a search for genetic modifiers located outside the CFTR gene. The aim of this study was to evaluate the effect of functional variants in prostaglandin-endoperoxide synthase genes (COX1 and COX2) on the severity of lung disease in CF patients. To the best of our knowledge, it is the first time when analysis of COX1 and COX2 as potential CF modifiers is provided. The study included 94 CF patients homozygous for F508del mutation of CFTR. To compare their clinical condition, several parameters were recorded, e.g. a unique clinical score: disease severity status (DSS). To analyse the effect of non-CFTR genetic polymorphisms on the clinical course of CF patients, the whole coding region of COX1 and selected COX2 polymorphisms were analysed. Statistical analysis of genotype-phenotype associations revealed a relationship between the heterozygosity status of identified polymorphisms and better lung function. These results mainly concern COX2 polymorphisms: -765G>C and 8473T>C. The COX1 and COX2 polymorphisms reducing COX protein levels had a positive effect on all analysed clinical parameters. This suggests an important role of these genes as protective modifiers of pulmonary disease in CF patients, due to inhibition of arachidonic acid conversion into prostaglandins, which probably reduces the inflammatory process