Pancreatitis, Hereditary

A number sign (#) is used with this entry because of evidence that chronic pancreatitis can be caused by mutation in the cationic trypsinogen gene PRSS1 (276000) and the SPINK1 gene (167790). Furthermore, idiopathic pancreatitis has been found to be associated with mutations in the cystic fibrosis gene (CFTR; 602421). A missense variant in the PRSS2 gene (601564.0001) confers protection against chronic pancreatitis. Variants in the chymotrypsin C gene (601405) that diminish activity or secretion are associated with chronic pancreatitis.

Gross et al. (1962) described a kindred with affected persons in 4 generations. Four other families had been reported from the Mayo Clinic, including the first reported example by Comfort and Steinberg (1952). A puzzling feature was the urinary excretion of lysine and cystine by about half the members of affected kindreds (with or without pancreatitis). Cystine urinary stones had not been observed.

Singer and Cohen (1966) reported onset at about age 20 in a man whose younger sister and a cousin were similarly affected. The attacks were characterized by severe abdominal pains, fever, and marked elevation of serum amylase. Except for the last symptom, differentiation from familial Mediterranean fever (249100), also called 'familial paroxysmal peritonitis,' might be difficult. The aminoaciduria was almost certainly an incidental finding since family members without pancreatitis showed it and because other families with pancreatitis have not had this feature (Davidson et al., 1968).

Robechek (1967) observed a family in which 5 individuals had hereditary chronic relapsing pancreatitis, 3 of whom obtained symptomatic relief after sphincterotomy or section of the hypertrophied sphincter of Oddi. Robechek (1967) suggested that hypertrophy of the sphincter of Oddi together with a common ampulla of the biliary and pancreatic ducts may be the inherited factor. Mann and Rubin (1969) described a 17-month-old boy with steatorrhea whose 26-year-old brother and mother had steatorrhea and pancreatic calcification. Hereditary pancreatitis occurs with hyperparathyroidism in the multiple endocrine adenomatosis syndrome (131100). McElroy and Christiansen (1972) described a family in which 10 persons had definite pancreatitis and 16 others may have been affected. They pointed out that thrombosis in the portal or splenic vein occurs with significant frequency.

Sibert (1978) identified 72 patients in 7 families in England and Wales. Penetrance was about 80%. The mean age of onset was 13.6 years. There were 2 peaks, one at 5 years and one at 17 years. The second peak was thought to represent genetically susceptible persons with symptoms precipitated by alcohol, rather than genetic heterogeneity. In 5 of the families, members with both childhood and adult onset were identified. In most cases the attacks were of nuisance value only. Only 4 of the 72 patients had life-threatening disease. Pancreatic insufficiency (5.5%), diabetes mellitus (12.5%), pseudocysts (5.5%) and hemorrhagic pleural effusion were observed. Portal vein thrombosis occurred in 2 and was suspected in 3 others. Patients seemed to improve later in life. Attacks were precipitated by emotional upset, alcohol, or high fat intake.

Sarles et al. (1982) pointed out that chronic calcifying pancreatitis is characterized by pancreatic stones in the ducts and acini. They had shown that 'stone protein' (see 167770) inhibits in vitro calcium carbonate nucleation and decreases the rate of crystal growth, suggesting that it acts as a physiologic inhibitor of spontaneous calcium carbonate formation in supersaturated pancreatic juice. (A similar function has been suggested for statherin in human saliva (Schlesinger and Hay, 1977).) Sarles et al. (1982) found absence of stone protein in the pancreatic stones in a case of calcific pancreatitis and interpreted this as indicating that the protein was not secreted into the pancreatic juice.

Freud et al. (1992) described the cases of monozygotic twin girls of Ashkenazi origin who were admitted to hospital at the age of 9 years because of recurrent attacks of pancreatitis. Dalton-Clarke et al. (1985) found 10 definite and 4 suspected cases of pancreatitis in an English family. Lewis and Gazet (1993) reported pancreatitis in members of 4 successive generations of a second English family. A male in each of the first generations had a combination of calcific pancreatitis and pancreatic carcinoma.

Rumenapf et al. (1994) stated that more than 50 families of hereditary pancreatitis had been reported since the first description by Comfort and Steinberg (1952). They reported on the case of a 26-year-old man from a family in which 6 of 34 members had confirmed pancreatitis and an additional 3 members had suspected pancreatitis. A great uncle had died of pancreatic cancer after suffering from pancreatitis for years. Numerous pancreatic calculi were removed surgically, and a side-to-side pancreaticojejunostomy with a Roux-Y loop was performed. Rumenapf et al. (1994) suggested that surgery may be superior to endoscopic drainage.

Sarles et al. (1996) reported 11 families with hereditary pancreatitis characterized by the presence of calculi in pancreatic ducts. The disorder in 1 family with 5 cases was classified as calcic lithiasis because the calculi were composed of more than 95% calcium salts. Protein lithiasis was present in the other 10 families, the calculi being composed of degraded amorphous residues of lithostathine (167770), the pancreatic secretory protein that inhibits salt crystallization. Average age at clinical onset of symptoms was 15 years. Clinical progression seemed to be less severe than that in alcoholic chronic pancreatitis (alcoholic calcic lithiasis).

Lowenfels et al. (1997) assembled records on 246 patients (125 males and 121 females) thought to have hereditary pancreatitis. In 218 patients the diagnosis appeared to be highly probable and in 28 patients it was thought to be less certain. The mean age of onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, 8 pancreatic adenocarcinomas developed during 8,531 person-years of follow-up. The mean age at diagnosis of pancreatic cancer was 56.9 +/- 11.2 years. Frequency of other tumors was not increased. Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort had been tested and all were found to have a mutated copy of the trypsinogen gene. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approached 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer was approximately 75%.

Le Bodic et al. (1996) analyzed the genomic segregation of highly informative microsatellite markers in a French family of 147 individuals, 47 of whom had hereditary pancreatitis. Linkage was found between HPC and 6 chromosome 7q markers. The marker D7S661 was linked to HPC with a lod score of 8.58 at theta = 0.077. Multipoint linkage analysis indicated that the HPC gene is most likely located in the region encompassed by markers D7S661 and D7S676 on 7q33-qter. Le Bodic et al. (1996) noted that the gene encoding carboxypeptidase A1 (CPA1; 114850), which is a pancreatic exopeptidase, mapped centromeric to the HPC locus.

Whitcomb et al. (1996) performed a genomewide linkage analysis on a family extensively affected with hereditary pancreatitis centered in eastern Kentucky and western Virginia. Using microsatellite markers, they established linkage between the hereditary pancreatitis phenotype and 7q. A maximal lod score of 4.73 at a recombination fraction of 0.0 was obtained with D7S684 located in the 7q35 region. Using 3 large HP families located in Virginia, West Virginia, and Tennessee, Pandya et al. (1996) confirmed the tight linkage of HP to marker D7S684. They placed the HP locus within a 16-cM interval between markers D7S495 and D7S688.

Several genes previously mapped to 7q were considered candidates for HPC because they were known to be expressed in the exocrine pancreas and to encode enzymes that could potentially activate digestive enzymes within the pancreas. The hypothesis that pancreatitis results from inappropriate activation of pancreatic proenzymes was first promulgated by Chiara (1896) and subsequently demonstrated to be an experimental model for pancreatitis (Steer and Meldolesi, 1987). However, at least 8 trypsinogen genes are located on 7q35 between markers D7S495 and D7S498 and within the V and D-C segments of the complex T-cell receptor beta chain gene (see 186930). Trypsinogen is an inactive proenzyme for trypsin, which becomes active when an 8-amino acid N-terminal peptide is removed. Of the 8 trypsinogen-like genes sequenced and identified within the TCRB locus by Rowen et al. (1996), 3 were determined by sequence analysis to be pseudogenes. Another group of 5 trypsinogen genes, including the cationic and anionic pancreatic trypsinogen genes, were found to be in a cluster located between 2 elements near the 3-prime end of the TCRB locus.

Tzetis et al. (2007) genotyped the CFTR, SPINK1, and PRSS1 genes in 25 Greek patients with chronic pancreatitis and found that 20 (80%) of 25 had a molecular defect in 1 or both of the CFTR and SPINK1 alleles, whereas no mutations were detected in PRSS11. The authors suggested that mutations or variants in CFTR plus or minus mutations in SPINK1, but not PRSS1, may confer high risk for recurrent pancreatitis.

Mutations in the PRSS1 Gene

Whitcomb et al. (1996) noted that the 5 trypsinogen genes are highly homologous, each residing within a tandemly duplicated 10-kb segment and each composed of 5 exons. Mutational screening analyses for each of the exons from the cationic and anionic trypsinogen genes in multiple affected and unaffected family members allowed Whitcomb et al. (1996) to identify a missense mutation in the cationic trypsinogen (PRSS1; 267000) in all affected members and obligate carriers in 1 family (276000.0001). The same R122H mutation (previously designated R117H by the chymotrypsin numbering system) was identified in 5 separate kindreds, raising the possibility that these families might be distantly related and the mutation centuries old. Although no genealogic link could be found through 8 generations, subsequent haplotyping revealed that all 4 of the American families had the same high-risk haplotype over a 4-cM region encompassing 7 STR markers, confirming the likelihood that these kindreds share a common ancestor. A fifth family from Naples, Italy, displayed a unique haplotype indicating that the same mutation had occurred on at least 2 occasions. The R122H mutation created a novel restriction enzyme recognition site for AflIII that permitted facile screening for the mutation in the general population. The mutation was not found in any of 140 unrelated control individuals. X-ray crystal structure analysis, molecular modeling, and protein digest data indicated that the arg122 residue is a trypsin-sensitive site. Whitcomb et al. (1996) provided a diagram of a model of the trypsin self-destruct mechanism designed to prevent pancreatic autodigestion. Active trypsin is inhibited normally by a limited supply of trypsin inhibitor (e.g., SPINK1; 167790). If trypsin activity exceeds the inhibitory capacity of PSTI, then proenzymes, including mesotrypsin (PRSS3; 613578) and enzyme Y, are activated. The activation of these enzymes is postulated to be part of a feedback mechanism for inactivating wildtype trypsinogen, trypsin, and other zymogens. When the arg122 cleavage site for mesotrypsin, enzyme Y, and trypsin is replaced by histidine, trypsin continues to activate trypsinogen and other zymogens unabated, leading to autodigestion of the pancreas and pancreatitis.

In affected members and obligate carriers of a large family originally reported by Robechek (1967) with hereditary pancreatitis believed to be due to hypertrophy of the sphincter of Oddi, Gorry et al. (1997) identified heterozygosity for a missense mutation in the PRSS1 gene (N21I; 276000.0002). The pancreatitis in this family appeared to be a milder form of the disease, with a later onset of symptoms and fewer hospitalizations than that seen in the so-called 'S-family' in which Whitcomb et al. (1996) identified the R122H mutation. Noting that prematurely activated trypsin must pass through the sphincter of Oddi and may produce chronic inflammation, scarring, and stenosis, Gorry et al. (1997) suggested that high sphincter pressures may be an independent complication of hereditary pancreatitis rather than the cause. The authors stated that 4 of the 5 patients reporting symptomatic improvement after surgical sphincterotomy had progressed to chronic pancreatitis with insulin-dependent diabetes mellitus, supporting the hypothesis that the underlying pathophysiologic mechanism persists. Affected members of a second, unrelated family with hereditary pancreatitis were also found to have the N21I mutation, which was not found in 188 control chromosomes.

Dasouki et al. (1998) reported on the results of linkage and direct mutation analysis for the common R122H mutation (276000.0001) in the PRSS1 gene in 8 unrelated families with hereditary pancreatitis. By 2-point linkage analysis with the 7q35 marker D7S676, done initially in 4 families, positive lod scores were found in 2, a negative lod score in 1, and a weakly positive lod score in 1. Direct mutational analysis of exon 3 of the cationic trypsinogen gene in 6 families showed that all symptomatic individuals tested were heterozygous for the R122H mutation. Also, several asymptomatic but at-risk relatives were found to be heterozygous for this mutation. Affected individuals in the remaining 2 families did not have the mutation. Radiation hybrid mapping assigned the gene to 7q35 between 2 specific markers. The negative linkage and absence of the trypsinogen mutation in 2 of 8 families suggested locus heterogeneity in hereditary pancreatitis.

Ferec et al. (1999) studied 14 families with hereditary pancreatitis and found mutations in the PRSS1 gene in 8 families. In 4 of these families, the mutation (R122H; 276000.0001) had been described by Whitcomb et al. (1996). Three novel mutations were described in 4 other families (276000.0003, 276000.0004, 276000.0005).

Mutations in the CFTR Gene

Sharer et al. (1998) and Cohn et al. (1998) demonstrated that mutations in the cystic fibrosis gene (CFTR; 602421) can cause idiopathic pancreatitis when present in heterozygous state in association with the variable number of thymidines in intron 8 of the CFTR gene, specifically the 5T allele (602421.0086).

Chang et al. (2007) identified mutations in the CFTR gene in 14.1% of total alleles and 24.4% of 78 Chinese/Taiwanese patients with idiopathic chronic pancreatitis compared to 4.8% of total alleles and 9.5% of 200 matched controls. The findings indicated that heterozygous carriers of CFTR mutations have an increased risk of developing ICP. The mutations identified were different from those usually observed in Western countries. The T5 allele with 12 or 13 TG repeats was significantly associated with earlier age at onset in patients with ICP, although the frequency of this allele did not differ between patients and controls.

Mutations in the SPINK1 Gene

Witt et al. (2000) demonstrated mutations in the SPINK1 protease inhibitor gene (N34S, 167790.0001; L14P, 167790.0005) in children and adolescents with chronic pancreatitis. The N34S mutation was found in 18 of 96 patients.

Chen et al. (2000) reported mutation analysis in the PSTI (SPINK1) gene in 14 families with hereditary pancreatitis and in 30 individuals with sporadic chronic pancreatitis. A total of 7 polymorphisms, but no pathogenic mutations, were detected.

Audrezet et al. (2002) analyzed systematically the entire coding sequence and exon/intron junctions of the PRSS1 (276000), SPINK1 (167790), and CFTR genes in 39 white French patients with idiopathic chronic pancreatitis. One patient had a missense mutation (R122H; 276000.0001) in the PRSS1 gene; 4 patients had the same missense mutation in the SPINK1 gene, 3 in heterozygosity and 1 in homozygosity (N34S; 167790.0001); and 8 patients carried 1 of the most common mutations of the CFTR gene. A trans-heterozygous state with sequence variations in the SPINK1/CFTR genes was found in 3 patients. The results demonstrated that about one-third of the patients labeled as having idiopathic chronic pancreatitis had, in fact, a genetic defect. Audrezet et al. (2002) noted that long-term follow-up of these patients, including heterozygotes, homozygotes, compound heterozygotes, and trans-heterozygotes, would improve the understanding of the complex nature of idiopathic chronic pancreatitis.

In affected members of 2 unrelated families with autosomal dominant chronic pancreatitis, Kiraly et al. (2007) identified a heterozygous mutation in the SPINK1 gene (L14R; 167790.0006). The proband of the Bulgarian family was diagnosed at age 10 years. His father had died of acute pancreatitis, and his paternal grandmother developing pancreatitis at age 59 years. The second family was German and had 3 affected members. Kiraly et al. (2007) noted that the N34S mutation had not to date been demonstrated to result in a functional defect. By expression studies, they demonstrated that the L14P and L14R mutations markedly reduce SPINK1 expression and result in loss of function.

Variation in the CTRC Gene

Rosendahl et al. (2008) found that 2 alterations in the CTRC gene, R254W (601405.0001) and K247_R254del (601405.0002), were significantly overrepresented among German patients with idiopathic or hereditary chronic pancreatitis. A replication study identified overrepresentation of these variants among German patients with alcoholic chronic pancreatitis versus control subjects with alcoholic liver disease without pancreatitis. Functional analysis of these and other associated CTRC variants showed impaired chymotrypsin C activity and or reduced secretion. Rosendahl et al. (2008) concluded that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.

Masson et al. (2008) sequenced the CTRC gene in 287 white French patients with idiopathic chronic pancreatitis and 350 controls and identified 2 common variants and 19 rare variants. The combined frequency of the rare variants in patients with sporadic chronic pancreatitis was significantly higher than that of controls (12% versus 1.1%; OR, 11.8; p less than 10(-6)).

Variation in the CPA1 Gene

For a discussion of a possible association between variation in the CPA1 gene and susceptibility to nonalcoholic chronic pancreatitis, see 114850.

The 'S.' family used by Whitcomb et al. (1996) in their map-based gene discovery in hereditary pancreatitis had the name Slone, according to an editorial accompanying the paper of Whitcomb et al. (1996) (Anonymous, 1996). This family had been reported by McElroy and Christiansen (1972). Whitcomb (1997) indicated that the family with the R122H mutation in the PRSS1 gene (276000.0001) was identified as the S-family, but the 'S.' did not stand for Slone.