PRSS1-Related Hereditary Pancreatitis

Clinical characteristics: PRSS1-related hereditary pancreatitis (HP) is characterized by episodes of acute pancreatitis (AP) and recurrent acute pancreatitis (RAP: >1 episode of AP), with frequent progression to chronic pancreatitis (CP). Manifestations of acute pancreatitis can range from vague abdominal pain lasting one to three days to severe abdominal pain lasting days to weeks and requiring hospitalization.

Diagnosis/testing: The diagnosis of PRSS1-related hereditary pancreatitis is established in a proband with episodes of AP, RAP, and/or CP and a heterozygous pathogenic gain-of-function variant in PRSS1 identified by molecular genetic testing. Note that, because of incomplete penetrance, identification of a disease-associated PRSS1 variant in an asymptomatic individual is not sufficient for a clinical diagnosis.

High-penetrance PRSS1 pathogenic variants include p.Asn29Ile and p.Arg122His, and lower-penetrance pathogenic variants include p.Arg16Val and p.Arg122Cys. Other pathogenic PRSS1 variants are recognized; these latter variants typically require additional risk factors to cause disease and do not cause autosomal dominant hereditary pancreatitis.

Management: Treatment of manifestations: AP episodes are treated with rapid assessment of severity and fluid resuscitation as needed. Individuals with HP should be counseled not to delay in being assessed for AP since hypovolemia and shock leads to serious organ dysfunction and failure. For chronic pancreatitis, continue strategies to prevent RAP attacks. Antioxidants may have some benefit. Pancreatic enzyme replacement therapy to improve digestion in those with pancreatic insufficiency and bloating, steatorrhea, diarrhea, unexplained weight loss, and/or micronutrient deficiencies (e.g., vitamins A, D, B₁₂); treatment of glucose intolerance with a regimen typically including metformin. Management of pain can be challenging but should begin with medical therapy, with endoscopic therapies for obstructions and surgery for more severe pain – including total pancreatectomy with islet autotransplantation in selected individuals.

Prevention of primary manifestations: Avoid smoking, alcohol abuse. Recommended: a healthy diet that is low in red meat, multiple small meals if it improves symptoms, good hydration (especially during exercise), vitamins, and antioxidants. Some individuals report that moderate exercise helps control episodes of pain and reduce pain severity.

Surveillance: Referral to a surveillance program.

Agents/circumstances to avoid: Alcohol and tobacco use; dehydration; physical and emotional stress.

Evaluation of relatives at risk: Molecular genetic testing for the family-specific germline PRSS1 pathogenic variant to allow early diagnosis and prevention and/or management of symptoms.

Genetic counseling: HP caused by gain-of-function PRSS1 pathogenic variants is inherited in an autosomal dominant manner. The proportion of PRSS1-related HP caused by a de novo pathogenic variant is unknown. Each child of an individual with autosomal dominant PRSS1-related HP has a 50% chance of inheriting the variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant of an affected family member has been identified. A number of other variants in the coding and noncoding regions of the PRSS1 locus are associated with risk for pancreatitis, but they typically do not cause autosomal dominant hereditary pancreatitis.