Cystic fibrosis: diagnosis and screening — branching viva

Opening

Examiner: A well-looking 5-week-old is referred with a positive newborn screen for cystic fibrosis — raised trypsinogen and one ΔF508 mutation. How do you approach this? [1]

Candidate: I would treat a positive screen as a flag for confirmatory testing, not a diagnosis. My first step is prompt referral to an accredited paediatric CF centre for a confirmatory sweat chloride test, supported by CFTR genetic analysis. I would take a history for any early features and a family history, examine her, and, crucially, explain to the anxious parents that many screened babies do not turn out to have CF while we confirm the result quickly. [1] [2]

Branch 1 — confirming the diagnosis

Examiner: How is the sweat test done, and how do you interpret it? [3]

Candidate: Sweat is stimulated by pilocarpine iontophoresis, collected, and its chloride concentration measured in an accredited laboratory with an adequate sample. I interpret the result against thresholds: a chloride below thirty millimoles per litre makes CF unlikely, thirty to fifty-nine is intermediate and needs genetics and repeat testing, and sixty or above is diagnostic when confirmed. An inadequate sample gives an unreliable result, so technique matters. [3] [1]

Examiner (probe): What are the full diagnostic criteria for cystic fibrosis? [1]

Candidate: Diagnosis needs a trigger plus objective evidence of CFTR dysfunction. The trigger is a clinical feature, a positive newborn screen, or a sibling with CF. The evidence of CFTR dysfunction is a sweat chloride at or above sixty millimoles per litre, two CF-causing mutations, or an abnormal nasal potential difference. A single mutation makes a carrier, not a diagnosis. [1] [2]

Branch 2 — the equivocal result

Examiner: Her sweat chloride comes back at 42 mmol/L and genetics show only the one ΔF508. What is her diagnosis? [2]

Candidate: She does not meet criteria for CF. An intermediate sweat chloride with fewer than two CF-causing mutations is an equivocal result, labelled CFTR-related metabolic syndrome in North America or CF screen-positive inconclusive diagnosis, CFSPID, in Europe. She needs structured monitoring at a CF centre, because a minority evolve into CF, and honest communication that avoids both a firm CF label and false reassurance. [2] [1]

Examiner (probe): How would you counsel the family about this uncertainty? [1]

Candidate: I would explain that her tests do not confirm CF but are not entirely normal, so we will watch her carefully with regular reviews for any features and may repeat testing. I would confirm the parents' carrier status and explain the recurrence risk, offer genetic counselling, and give clear advice on what symptoms should prompt earlier review, so they feel informed and supported rather than either alarmed or dismissed. [1] [2]

Branch 3 — the clinically presenting child

Examiner: A different child, aged 2, has a chronic wet cough, poor growth and greasy stools, but his newborn screen was negative. Does that exclude CF? [2]

Candidate: No. Newborn screening misses some affected children, especially with rarer mutations or a normal initial trypsinogen, so a negative screen never excludes CF when the clinical picture fits. This child's failure to thrive with a chronic wet cough and steatorrhoea is a classic picture, so I would arrange a sweat test and CFTR genetics regardless of the screen result. [2] [4]

Examiner (probe): Name two acute presentations that should always prompt a sweat test. [1]

Candidate: Meconium ileus in a newborn, which is CF until proven otherwise, and pseudo-Bartter syndrome — a dehydrated child with a hypochloraemic, hypokalaemic metabolic alkalosis and no vomiting, typically after salt loss in hot weather. Both should prompt a sweat test even if a newborn screen was negative. [1] [4]

Close

Examiner: Why does it matter that we diagnose cystic fibrosis early? [5]

Candidate: Because early diagnosis changes the child's trajectory. The Wisconsin randomised trial showed that children diagnosed early through newborn screening had significantly better nutritional status than those diagnosed clinically, and early entry into specialist care protects growth and lung function. So the diagnostic goal is to identify affected children promptly, confirm accurately, and refer without delay. [5] [1]