**Introduction:** Cystic Fibrosis (CF) is a genetic disorder characterized by various pathogenic mutations in the CFTR gene, typically diagnosed by newborn screening. We present a case in which two rare CFTR mutations eluded routine newborn screening but were identified during the investigation of multiple nasal polyps, emphasizing the importance of remaining vigilant in the face of atypical clinical presentations. **Case Presentation:** A previously healthy 14-year-old Caucasian adolescent presented with congestion refractory to conventional treatment. Physical exam revealed a large, right nasal polyp. The adolescent was referred to ENT and started on dupilumab. After dupilumab failed to improve symptoms, a CT sinus without contrast revealed multiple sinonasal polyps involving the bilateral maxillary sinuses and nasal cavity prompting work up for CF. Newborn metabolic screen revealed an elevated IRT of 204.5 ng/mL with a subsequent reflex genetic panel being negative for common CF mutations, and therefore, sweat chloride testing was deferred at that time. For concern of CF given nasal polyposis with history of abnormal newborn metabolic screen, further CF expanded variant panel analysis was completed and revealed two rare CFTR mutations, p.Ser492Phe and c.2490+1G>A, that have never been reported to be occurring simultaneously in one individual. Sweat chloride values of 76 mmol/L and 90 mmol/L on the right and left arms confirmed the diagnosis of CF. Consequentially, fecal elastase and pulmonary function testing were completed and found to be within normal limits. Her nutritional status was normal and lab testing was unremarkable with only a mild vitamin D deficiency. **Discussion:** The presence of nasal polyps in this case prompted a broader diagnostic workup, revealing two rare CFTR mutations. This case highlights the critical role of clinical vigilance beyond routine newborn screening in diagnosing CF, particularly when faced with atypical presentations such as nasal polyposis in the setting of an undetected genetic mutation on newborn screening. The awareness that a negative newborn screen may miss some CF diagnoses underscores the need for a high index of suspicion and thorough evaluation in the presence of persistent or unusual symptoms, enabling timely diagnosis and intervention for improved patient outcomes