Chalmers, S.

Abstract Introduction: Cystic Fibrosis (CF) is traditionally diagnosed through elevated sweat chloride levels followed by genetic testing. However, depending on types of specific CFTR gene mutations, sweat chloride test may not always be conclusive. This case study presents a unique instance of CF in a 50-year-old patient with negative sweat chloride levels who was later found to have CFTR dysfunction during the evaluation for worsening bronchiectasis, highlighting the diagnostic challenges posed by atypical presentations. Description: A 50-year-old female with a long-standing history of bronchiectasis and recurrent exacerbations was evaluated at our clinic. Initial sweat chloride testing yielded negative results (21 and 28 on two separate occasions), which made a CF diagnosis very unlikely. She was subsequently treated with standard airway hygiene measures while alternative diagnoses were explored. However, despite thorough work-up and management, her bronchiectasis continued to worsen, leading to genetic testing to complete the comprehensive evaluation of her condition. The CFTR mutation panel revealed the presence of G551D and D1152H (variants known to be associated with normal sweat chloride test). Despite the negative sweat chloride test, the patient's clinical presentation, including bronchiectasis, recurrent exacerbations, and the identified CFTR mutations, supported a diagnosis of CF. The patient has since responded positively to combination therapy with Elexacaftor, Tezacaftor and Ivacaftor, which is indicated for her genotype. Discussion: This case underscores the limitations of relying solely on sweat chloride testing for diagnosing CF, particularly in patients with atypical CFTR mutations. Variants like D1152H have been reported with normal sweat chloride levels, challenging traditional diagnostic paradigms. Genetic testing plays a crucial role in these cases by identifying mutations that may still lead to significant CFTR dysfunction. The patient's improvement on CFTR modulator therapy further supports the role of genotype-driven treatment strategies in CF care. This case highlights the need for a broader diagnostic approach, including comprehensive genetic testing and clinical correlation, especially for patients presenting with non-classical CF features. It contributes to the growing understanding that CF is a spectrum disorder with varied clinical and biochemical presentations, emphasizing the importance of individualized diagnosis and treatment strategies to optimize patient outcomes.