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Pankreatitis - PRSS1, SPINK1, CFTR

Clinical Features

Approx. 80 % of all cases of chronic pancreatitis have an immunological or exogenous cause; for the remaining part, hereditary predisposition is responsible. The clinical course of hereditary pancreatitis is indistinguishable from other forms of recurrent pancreatitis, but begins in many patients in childhood and leads to a hard, calcifying pancreatitis with exocrine and endocrine insufficiency. In rare cases, a gradual pancreatitis can remain undetected. If mutations in the PRSS1 gene are present, there is considerable risk of developing pancreas carcinoma. This risk is further elevated by exogenous noxae (nicotine and alcohol).

Genetic Information

Hereditary pancreatitis follows different patterns of inheritance:
Autosomal dominant:
Specific mutations in PRSS1 lead to a premature activation of cationic trypsinogen (Serin-Protease-1) in the pancreas and cause a chronic pancreatitis which ultimately results in a significant increased risk of pancreas carcinoma (20-40%), particularly in combination with alcohol and nicotine consumption. The disease shows an autosomal dominant pattern of inheritance; offspring will have a 50% risk of having inherited the disease.
Autosomal recessive:
Mutations in SPINK1 (Serin-Protease inhibitor, Kazal Type 1) affect the gene's 79 amino acid protein that acts as a specifically intrapancreatic trypsin inhibitor. This results in insufficient inactivation of active trypsinogen in the pancreas (failure of protective function). The risk for developing chronic pancreatitis is significantly enhanced, especially by additional noxae; however, the risk of pancreatic cancer is not (or only marginally) elevated. In these cases, the disease shows an autosomal recessive pattern of inheritance (mutations in both gene copies); parents are normally asymptomatic carriers. Offspring will thus have a 25% risk of carrying both mutations (one from each parent) in the SPINK1 gene.
Monoallelic SPINK1 mutations only lead to an elevated risk of pancreatitis in combination with noxae. The carrier frequency for the most common SPINK1 mutation (p.Asn43Ser) is about 1% in the general population.
Mutations in CFTR: Pathogenic mutations in the CFTR gene normally cause cystic fibrosis, but mutations in CFTR that permit residual gene function lead to a very mild form of the disease, which can give rise to an isolated pancreatitis. The cancer risk is not considerably increased. Cystic fibrosis is an autosomal recessive disease with an increased risk for children of two healthy carriers.
Approximately 80 % of patients suspected of having an inherited predisposition to pancreatitis (immunological and exogenous causes excluded) carry a genetic mutation in one of the three genes PRSS1, SPINK1 or CFTR. Furthermore, patients with mutations in PRSS1 will have a considerably increased risk of developing pancreatic cancer. The pancreas carcinoma risk of family members is varies greatly, depending on the affected gene.

Prevalence

< 1 : 10 000

Diagnostic