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SPINK1 mutations and phenotypic expression in patients with pancreatitis associated with trypsinogen mutations
  1. F U Weiss1,
  2. P Simon1,
  3. H Witt2,
  4. J Mayerle1,
  5. V Hlouschek1,
  6. K P Zimmer3,
  7. J Schnekenburger1,
  8. W Domschke1,
  9. J P Neoptolemos4,
  10. M M Lerch1
  1. 1Department of Medicine B, Westfälische Wilhelms-Universität Münster, Germany
  2. 2Department of Paediatrics, Charité, Campus Virchow-Klinikum, Humboldt Universität, Berlin, Germany
  3. 3Department of Paediatrics, Westfälische Wilhelms-Universität Münster, Germany
  4. 4Department of Surgery, University of Liverpool, Royal Liverpool University Hospital, Liverpool, UK
  1. Correspondence to:
 Dr M M Lerch, Department of Medicine B, Westfälische Wilhelms-Universität, Albert Schweitzer-Strasse 33, D-48129 Münster, Germany; 
 markus.lerch{at}uni-muenster.de

https://doi.org/10.1136/jmg.40.4.e40

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    Hereditary pancreatitis (HP) is an inborn disorder which leads to recurrent episodes of pancreatitis in children and young adults and is associated with exocrine pancreatic insufficiency and secondary diabetes.1–3 Several germline mutations in the cationic trypsinogen (PRSS1) gene have been found to be associated with the disease phenotype, the most common of which are the R122H, N29I, and A16V mutations.4–6 The clinical significance of various other PRSS1 mutations that have been reported from isolated patients or single families is as yet unclear.7,8 In many families with HP some relatives who carry the mutation relevant to the disease will never develop pancreatitis. The prevalence of these healthy carriers varies from between 20% and 30% in families with the common R122H and N29I mutations,2,5 and may rise to nearly 80% in families with the A16V mutation.6,9 The underlying cause for this variable penetrance remains unknown, but environmental as well as genetic factors might be involved.

    Key points

    • Hereditary pancreatitis (HP) is strongly associated with mutations in the cationic trypsinogen (PRSS1) gene but the phenotypic penetrance varies between 20% and 80%. Why some carriers of mutations never develop the disease phenotype is unknown.

    • In 100 patients and relatives from 40 unrelated HP kindreds with a PRSS1 mutation, we have investigated whether coinherited mutations in the serine protease inhibitor, Kazal type 1 (SPINK1) gene, affect the onset, penetrance, and clinical severity of pancreatitis.

    • Among 17 unaffected carriers of PRSS1 mutations and 70 patients with pancreatitis with a PRSS1 mutation (11 with diabetes), we found the following SPINK1 alterations distributed across six (15%) families: N34S mutations (7), 3′UTR 272 C>T polymorphisms (3), and 3′ flanking region 371 G>A polymorphisms (1). Carriers of N34S were as frequent among patients with and without diabetes (9% v 7%), …

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