Clinical Information

Hereditary pancreatitis (HP) is defined as 2 or more individuals in a family affected with pancreatitis involving at least 2 generations.(1) Variants in several genes, including PRSS1, CFTR, CTRC, and SPINK1 have demonstrated genetic susceptibility to chronic pancreatitis. Disease susceptibility may be monogenic, as is the case with PRSS1, digenic or multigenic, and multifactorial in which multiple genes and environmental factors play a role in disease expression.

PRSS1:

The most common monogenic cause of HP is the presence of a variant in the cationic trypsinogen (PRSS1) gene. Variants in the PRSS1 gene are inherited in an autosomal dominant manner. It has been reported that as many as 80% of patients with symptomatic hereditary pancreatitis have a causative PRSS1 variant.(1) HP cannot be clinically distinguished from other forms of pancreatitis. However, PRSS1 variants are generally restricted to individuals with a family history of pancreatitis and are infrequently found in patients with alcohol-induced pancreatitis. Although several variants have been identified, the p.R122H, p.N29I, and p.A16V variants are the most common disease-causing variants in PRSS1 associated with HP.(2) Patients with HP are also at an increased risk for developing pancreatic cancer. Studies have estimated the lifetime risk of developing pancreatic cancer to be as high as 40%.(3)

SPINK1:

Biallelic variants in the SPINK1 gene have been associated with increased susceptibility to chronic pancreatitis especially in families without PRSS1 variants; however, it is unknown if biallelic variants alone are sufficient to cause chronic pancreatitis. Additionally, heterozygous SPINK1 variants appear to modify disease severity when observed in combination with variants in other genes.(1,2,4) Unlike PRSS1 variants, SPINK1 variants have been associated with alcohol-induced pancreatitis.(4)

CFTR:

Pancreatitis is a known manifestation of an atypical CFTR-related disorder, which results from biallelic disease-causing variants in the CFTR gene. However, CFTR variants can also cooccur with variants in CTRC, SPINK1, or CASR to confer pancreatitis disease susceptibility.(1-4) When observed in the context of a SPINK1 variant, for example, heterozygous variants in CFTR are associated with a 2- to 5-fold increased risk for pancreatitis as compared to the general population.(4)

CTRC:

Variants in CTRC have been observed in individuals with chronic pancreatitis in association with other risk factors, such as variants in CFTR or SPINK1 or specific environmental risk factors. Thus, chronic pancreatitis may be attributable to the presence of CTRC variants in the context of other risk factors as opposed to CTRC variants alone.(1)