Cystic fibrosis (CF)

Cystic fibrosis (CF) affects epithelial tissues of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and sweat glands. Respiratory involvement is characterised by chronic productive cough, recurrent infections, and progressive bronchiectasis associated with persistent bacterial colonisation and neutrophilic inflammation. Pancreatic involvement results in exocrine pancreatic insufficiency, presenting with steatorrhoea, malabsorption, poor weight gain, and growth deficiency.

Additional manifestations include hepatobiliary disease, recurrent sinusitis, congenital bilateral absence of the vas deferens in nearly all affected males, and cystic fibrosis-related diabetes. Most affected individuals are identified through newborn screening, although clinical presentation can occur from infancy to adulthood. The clinical course is highly variable, ranging from mild disease to severe, progressive manifestations. Pulmonary involvement remains the major determinant of disease burden.

The prevalence of cystic fibrosis varies markedly between populations, with the highest frequencies observed in individuals of European descent, in whom the prevalence is approximately 1 per 2,500 live births. In other populations, cystic fibrosis is considerably less common.

Cystic fibrosis is caused by germline pathogenic variants in CFTR (7q31.2). CFTR encodes the cystic fibrosis transmembrane conductance regulator, an apical membrane chloride and bicarbonate channel that regulates epithelial ion and water transport.

Biallelic pathogenic variants result in impaired chloride and bicarbonate transport, leading to dehydrated airway secretions with impaired mucociliary clearance and bacterial colonisation, obstruction of pancreatic ducts with subsequent exocrine pancreatic insufficiency, and elevated sweat chloride concentrations.

Cystic fibrosis is inherited in an autosomal recessive manner.

The diagnosis of cystic fibrosis is established based on a combination of clinical features or a positive newborn screening result and evidence of CFTR dysfunction. Consensus diagnostic criteria are defined in guidelines published by the and are supported by standards. Quantitative pilocarpine iontophoresis sweat testing remains the primary diagnostic test, with chloride concentrations ≥60 mmol/L considered diagnostic and values of 30–59 mmol/L regarded as intermediate.

Identification of biallelic pathogenic variants in the CFTR gene is also consistent with the diagnosis. In cases with inconclusive findings, additional functional tests, such as nasal potential difference measurement or intestinal current measurement performed in specialised centres, may support the diagnosis.

Main differential diagnoses include:

• : recurrent sinopulmonary infection and bronchiectasis without pancreatic insufficiency.
• : pancreatic dysfunction with cytopenias and skeletal anomalies.
• Pseudohypoaldosteronism type I: elevated sweat chloride with normal pancreatic function.

• Establishing the diagnosis: molecular genetic testing confirms the diagnosis and provides the basis for accurate classification and genetic counselling.
• Clinical management: identification of the causative variant can inform clinical follow-up and support management, including monitoring for disease-related complications, with care guided by the treating physicians in consultation with the affected individual.
• Therapeutic implications: identification of CFTR variants enables access to genotype-specific CFTR modulator therapies, which can substantially modify disease course in eligible individuals.
• Family member testing: identification of the familial pathogenic variants enables testing of at-risk relatives and reproductive partners and supports informed reproductive and clinical decision-making.

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