An exceptional genealogy for hereditary chronic pancreatitis

Abstract

Nearly one hundred families affected with hereditary chronic pancreatitis (HCP) have been reported in the literature. However, the fact that the disease involved only a few members of each family limits the informativeness of these reports and accounts for the infrequency and disappointing results of pathogenetic and genetic research. Our study concerned an exceptional HCP genealogy which would seem to provide an ideal model for the detection of a genetic anomaly linked to the expression of the disease. We studied 249 members of a family (214 still alive), covering eight generations born between 1800 and 1993. According to the customary criteria, 63 had definite and 17 probable HCP. Fifty-eight members under 18 years of age were still susceptible to developing the disease. This series confirms the mode of autosomal dominant heredity with variable penetrance. The clinical features and disease course were typical, except that symptoms tended to appear earlier. The series represents the most extensive HCP genealogy compiled and is one of the largest families studied in the field of genetic disease, regardless of etiology. Blood samples were taken from 146 subjects to facilitate pathogenetic and genetic research.

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

“…In contrast, mutations of anionic trypsinogen (PRSS2) or mesotrypsinogen (PRSS3) have not been found in association with chronic pancreatitis to date [Chen et al, 1999a;. Classic hereditary pancreatitis follows an autosomal dominant inheritance pattern with incomplete penetrance and highly variable disease expression [Comfort and Steinberg, 1952;Le Bodic et al, 1996a;Sossenheimer et al, 1997;Keim et al, 2001;Howes et al, 2004]. The mutations are located in three clusters within the trypsinogen sequence: in the TAP, in the N-terminal part of trypsin or in the longest peptide segment not stabilized by disulfide bonds between Cys64 and Cys139 ( Fig.…”

Molecular basis of hereditary pancreatitis

“…1,2 Apart from an early age of onset and a positive family history, HP is indistinguishable from the sporadic disease. 3,4 Although pancreatitis was hypothesised to result from inappropriate activation of pancreatic zymogens in 1896 5 and the genetic nature of HP was identified in 1952, 6 the molecular basis of HP remained elusive until 1996, when a mutation in the cationic trypsinogen gene was demonstrated as being associated with HP.…”

New insights into hereditary pancreatitis

“…However, other explanations for this must be explored because we found that the mean and median age at onset of symptoms in 128 patients from 25 kindreds with the trypsinogen R117H mutation were 13.7 years and 11 years, respectively; the age at onset ranged from 0 years to 53 years (unpublished data). Other complications, such as pseudocysts, are also seen and have been reported in 11% [7] to 17% [4] of patients in large studies and in higher proportions in smaller studies [10]. Thus, the clinical symptoms of patients with HP are similar to those of patients with other types of pancreatitis with variable age of onset and severity.…”