Expression and penetrance of the hereditary pancreatitis phenotype in monozygotic twins

Abstract

Background-Hereditary pancreatitis (HP) is a rare autosomal dominant disorder with variable expression and an overall lifetime penetrance of 80%. We hypothesised that (1) monozygotic twins within similar environments would develop the typical signs of HP at a similar age, and (2) if penetrance were due to modifier genes or environment, all twin pairs would be concordant for expression of HP. Aim-Identify monozygotic twins with HP and determine the penetrance, concordance, and age of onset of symptoms. Methods-Twins from HP kindreds were identified from the Midwest Multicenter Pancreatic Study group database, referrals, and literature searches. Each twin set was assessed for phenotypic expression, concordance, and diVerence in age of phenotypic onset of pancreatitis. The diVerence in onset of symptoms for symptomatic aVected non-twin sibling pairs as well as non-twin pairs that were mutation, sex, and age matched were calculated as two comparison groups. Results-Seven of 11 monozygotic pairs identified were suitable for evaluation and four were concordant for pancreatitis. Forty eight aVected sibling pairs and 33 pairs of mutation, sex, and age matched (cationic trypsinogen R122H (30 pairs) and N29I (three pairs)) subjects were identified for comparison groups. The median (quartiles Q1, Q3) diVerence in the age of phenotypic onset in the concordant twins was 1 (0, 2.4) years, 2 (1, 6) for the aVected siblings, and 7 (2, 15) years in the comparison control group. Three of the seven sets of twins (43%) were discordant for phenotypic expression of pancreatitis. The overall penetrance in the seven pairs of monozygotic twins was 78.6%. Conclusions-Genetic and/or environmental factors contribute to expression and age of onset of HP. Nuclear genes or general environmental factors alone cannot explain the 80% penetrance. Determining the mechanism of non-penetrance may help in developing a strategy to prevent the phenotypic expression of pancreatitis in individuals with an underlying genetic predisposition. (Gut 2001;48:542-547)

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

“…The cause of this incomplete penetrance is uncertain. In addition to further genetic factors, smoking, alcohol consumption, or the lack of antioxidants were assumed as manifestation factors [Sibert, 1978;Sossenheimer et al, 1997;Amann et al, 2001;Keim et al, 2001]. On the basis of a study of 60 affected and 25 nonaffected persons carrying the PRSS1 mutations N29I or R122H, we suggested that the TNFa-238A promoter variant could be a relevant manifestation factor for chronic pancreatitis in hereditary pancreatitis-families.…”

Hereditary pancreatitis

“…The penetrance of cationic trypsinogen gene mutations remains at approximately 80 % in the majority of studies. To investigate factors contributing to this, a study of monozygotic twins with HP was carried out [17] . Of 11 sets of twins, seven were suitable for this study.…”

Hereditary pancreatitis: A model for understanding the genetic basis of acute and chronic pancreatitis

“…Indeed, there must be other genetic, epigenetic or environmental factors that are critical in protecting the pancreas of these individuals. Studies on identical twins and specific investigations of obligate carriers have emphasized this fact without bringing any clear answers [29]. Additional questions surround the families that have been thoroughly investigated and all known mutations excluded [10].…”