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Spontaneous and Sporadic Trypsinogen Mutations in Idiopathic Pancreatitis
To the Editor: Hereditary pancreatitis is an uncommon variety of pancreatitis. It generally follows an autosomal dominant inheritance and is associated with germline mutations in the cationic trypsinogen (PRSS1) gene.1 Thus, genetic testing is often recommended when 2 or more family members are diagnosed with idiopathic pancreatitis. However, the prevalence of trypsinogen mutations among patients with idiopathic pancreatitis and without a family history remains unknown.
Methods
Between 1998 and 2001, all outpatients referred to the pancreas clinic of Münster University Hospital with the diagnosis of recurrent or chronic pancreatitis of unknown etiology (N = 87) were screened for the study. We then excluded patients with known risk factors for pancreatitis, including biliary disease, hyperlipidemia, hypercalcemia, congenital malformations, or alcohol abuse. The remaining 50 patients were offered genetic research testing according to established guidelines2 and in accordance with regulations of our institutional ethics committee. After informed consent was obtained, leukocyte DNA from all 50 patients was prepared and tested for trypsinogen mutations using established protocols3 and sequencing of the entire coding regions of exons 2 and 3 of the PRSS1 gene. This analysis allowed the detection of all 16 previously reported PRSS1 mutations.4
To further clarify the absence of an indicative family history in patients who were found to carry a trypsinogen mutation (n = 5), we obtained informed consent for anonymous genetic testing of unaffected relatives. When inheritance from unaffected carriers was ruled out, DNA was genotyped using amplification in a multiplex system (AmpFlSTR Profiler kit, Perkin-Elmer, Foster City, Calif). This multiplex kit contains 9 short tandem repeat (STR) systems, which are amplified simultaneously in 1 reaction. It has a combined general exclusion chance for nonpaternity of 99.95%.5
Results
A trypsinogen mutation was found in 5 of 50 patients (10%) with idiopathic pancreatitis. All 5 had the R122H mutation. Patients with trypsinogen mutations were significantly younger at disease onset (mean [SD] age, 14 [3] years) than the remaining cohort (38 [2] years) and accounted for 35% of the patients younger than 25 years. Three individuals had inherited the mutation from unaffected carriers in previous generations, paternity was found to be uncertain in 1 individual, and 1 individual carried a spontaneous de novo R122H mutation. The latter patient, who had had severe pancreatitis since age 6, came from a family in which none of 38 known relatives, including the parents, had a history of pancreatitis. Moreover, neither of the parents carried the R122H mutation (confirmed by testing 3 separate DNA preparations). Testing for DNA in the STR loci resulted in complete agreement without exclusions, indicating a combined probability of parenthood for both parents of greater than 99.99%.
Comment
Our findings indicate that hereditary pancreatitis may be more common than previously assumed. Although our study was performed in the setting of a specialized tertiary referral center in which, during the period of the study, 16 extended hereditary pancreatitis kindreds (including 40 patients with confirmed trypsinogen mutations) were diagnosed, we also found that the mutation can sometimes be the etiology in patients with seemingly sporadic idiopathic pancreatitis. An early age of disease onset should raise the suspicion of hereditary pancreatitis, even in the absence of a family history. In view of the much higher risk of pancreatic cancer associated with hereditary, as opposed to idiopathic, pancreatitis,6 we believe that recommendations for genetic testing that are solely based on information regarding relatives with pancreatitis should be reconsidered. Our data further suggest that codon 122 of the cationic trypsinogen gene, where the majority of patients with hereditary pancreatitis carry a mutation,1, 3-4 may represent the most frequent locus for spontaneous genetic alterations. Inheritance from unaffected carrier parents, uncertain paternity, and spontaneous de novo mutations should be considered when patients with PRSS1 mutatations have no corresponding family history.
AUTHOR INFORMATION
Funding/Support: Funding was provided by the Münster Interdisciplinary Center for Clinical Research (IZKF) and the German Research Foundation (DFG).
Acknowledgment: Drs Simon and Weiss contributed equally. We thank S. Greiner and H. Baumhöver for providing expert technical assistance, and J. A. Cohn, Duke University, Durham, NC, for helpful comments and discussion.
Peter Simon, MD;
F. Ulrich Weiss, PhD
Department of Molecular Gastroenterology
Klaus Peter Zimmer, MD
Department of Pediatrics
Westfälische Wilhelms-Universität
Münster, Germany
Steven Rand, PhD;
Bernd Brinkmann, MD
Department of Forensic Medicine
Universitätsklinikum Münster
Münster
Wolfram Domschke, MD;
Markus M. Lerch, MD
Department of Medicine B
Westfälische Wilhelms-Universität
Münster
1. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14:141-145.
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2. Ellis I, Lerch MM, Whitcomb DC. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology. 2001;1:405-415.
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3. Simon P, Weiss FU, Sahin-Toth M, et al. Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 --> Cys) that alters autoactivation and autodegradation of cationic trypsinogen. J Biol Chem. 2002;277:5404-5410.
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4. Witt H, Becker M. Genetics of chronic pancreatitis. J Pediatr Gastroenterol Nutr. 2002;34:125-136.
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5. Brinkmann B, Pfeiffer H, Schürenkamp M, Hohoff C. The evidential value of STRs: an analysis of exclusion cases. Int J Legal Med. 2001;114:173-177.
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6. Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. J Natl Cancer Inst. 1997;89:442-446.
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JAMA. 2002;288:2122.
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