CFTR:F508d/A613T Mutation Is Associated With Recurrent Episodes of Pancreatitis

**Background:** Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene, with over 2000 mutations identified. Pancreatic insufficiency (PI) occurs in 85% of individuals with CF. Among the 15% who are pancreatic sufficient (PS), approximately 20% develop pancreatitis. This case report presents an adolescent female with a delayed CF diagnosis due to presentation with recurrent pancreatitis and absence of typical respiratory or gastrointestinal symptoms.

**Methods:** This is a single case report of a 17.5-year-old female with a history of acute recurrent pancreatitis (ARP) seen at an outpatient GI clinic. She was referred from the emergency department after presenting with a 1-week history of abdominal pain, nausea, steatorrhea, and low-grade fever. Diagnostic evaluation included laboratory tests (amylase, lipase, calcium, triglycerides, CRP, vitamin D, IgG4, fecal elastase), abdominal ultrasound, magnetic resonance cholangiopancreatography (MRCP), sweat chloride testing, and CFTR genetic sequencing. Pulmonary function tests and lung CT were also performed.

**Key Results:** The patient had a prior episode of pancreatitis requiring hospitalization at age 7 years with elevated lipase and amylase. Over 10 years, she experienced monthly episodes of abdominal pain and steatorrhea self-managed with Tylenol and clear fluids, averaging 6 missed school days per semester. Triggers included high-fat foods and alcohol. At presentation, BMI was 25 kg/m² (85th centile). Laboratory findings showed elevated amylase (494 U/L; normal 28–100) and lipase (345 U/L; normal 13–60) in the ED. IgG4 was slightly elevated at 2.25 g/L (normal 0.11–1.57). Fecal elastase was normal (>500 mcg/L; normal >200). Sweat chloride was elevated at 104 mmol/L initially and 98 mmol/L on repeat (normal <30 mmol/L). Initial CFTR testing revealed a single F508d mutation; further sequencing identified a second variant: CFTR p.A613T (c.1837G>A). Pulmonary function tests were normal (FEV1 99%, FVC 95%, FEV1/FVC 92%). Abdominal ultrasound showed no gallstones or pancreatitis signs. MRCP showed no pancreatic divisum or annular pancreas. The time from initial pancreatitis presentation to CF diagnosis was 10 years, compared to an average delay of 4 years (range 0–15 years) reported in a literature review of 19 similar cases.

**Clinical Implications:** This is the first reported case of ARP in an individual with a CFTR:F508d/A613T genotype. The CFTR p.A613T mutation, a class II missense mutation, has only been reported in 6 other individuals and appears to be associated with a mild phenotype despite class II mutations typically causing severe disease. The case highlights that mild CFTR genotypes can present with recurrent pancreatitis without overt respiratory symptoms. The authors recommend CFTR function testing be included in all patients with recurrent pancreatitis of unclear etiology. Individuals with mutations predicted to be responsive to CFTR modulation may benefit from CFTR modulators to reduce pancreatitis episodes. Early detection would enable timely involvement of an interprofessional health team, reduced hospital visits, and improved quality of life. The patient also had additional risk factors for ARP including alcohol consumption and overweight BMI (85th centile).