Cystic fibrosis: diagnosis and screening — formative SAQs

SAQ 1 (10 marks)

A 4-week-old girl is referred after a positive newborn bloodspot screen for cystic fibrosis: her immunoreactive trypsinogen was raised and the panel found one copy of ΔF508 (Phe508del). She is feeding well, gaining weight and looks entirely well on examination. Her parents are frightened and ask whether she "has cystic fibrosis". [1] [2]

1. What confirmatory test will you arrange, and how will you interpret the possible results? (4) [1] [3]
2. What does a single ΔF508 mutation on the screen mean for the diagnosis? (3) [2]
3. How will you explain the situation and plan to the parents today? (3) [2]

Model answer — SAQ 1

(1) Confirmatory test and interpretation (4). I would refer her to an accredited paediatric CF centre for a confirmatory sweat chloride test by pilocarpine iontophoresis, ensuring an adequate sweat sample. I interpret the result against reference thresholds: a chloride at or above sixty millimoles per litre is diagnostic of CF when confirmed on repeat testing, a value of thirty to fifty-nine is intermediate and needs extended CFTR genetics and repeat testing, and below thirty makes CF unlikely. Technique and sample adequacy matter, so testing is done in an accredited laboratory. [1] [3]

(2) Meaning of a single ΔF508 (3). A single CF-causing mutation on the screen makes her a confirmed carrier but does not, by itself, establish a diagnosis, because CF requires evidence of CFTR dysfunction — a raised sweat chloride, two CF-causing mutations, or an abnormal nasal potential difference. Her diagnosis therefore hinges on the sweat test and, if needed, extended gene analysis. If the sweat chloride is intermediate with fewer than two CF-causing mutations, she would be labelled CRMS or CFSPID rather than CF. [2] [1]

(3) Explanation and plan (3). I would acknowledge their fear and explain, in plain terms, that a positive screen is a flag for further testing, not a diagnosis, and that many screened babies turn out not to have CF. I would explain that we confirm with a sweat test at a specialist centre and use genetics, and that we will give clear results and a plan quickly. I would avoid both false reassurance and premature alarm, arrange the sweat test promptly, and offer written information and support. [2] [1]

SAQ 2 (10 marks)

A 3-year-old boy presents in summer with lethargy and dehydration. He has not been vomiting. His bloods show a hypochloraemic, hypokalaemic metabolic alkalosis. On review, his parents mention he has always had a moist cough, bulky greasy stools, and that he "tastes salty". His newborn screen, done overseas, was reported as normal. [1] [5]

1. What underlying diagnosis do you suspect and what is the biochemical syndrome called? (3) [1]
2. Why does a "normal" newborn screen not exclude this diagnosis? (3) [2]
3. Outline your immediate management and definitive diagnostic steps. (4) [1] [3]

Model answer — SAQ 2

(1) Diagnosis and syndrome (3). I suspect cystic fibrosis. The combination of a chronic wet cough, bulky greasy (steatorrhoeic) stools, salty-tasting skin and now salt-loss dehydration is highly suggestive. The biochemical picture of a hypochloraemic, hypokalaemic metabolic alkalosis with dehydration and no vomiting to explain it is pseudo-Bartter syndrome, a classic CF presentation, particularly in hot weather when salt loss through sweat is greatest. [1] [5]

(2) Why a normal screen does not exclude CF (3). Newborn screening is not perfect and misses some affected infants, particularly those with rarer mutations not covered by the local panel or with an initially normal trypsinogen, and screening protocols and panels differ between countries. A screen reported as normal overseas therefore cannot exclude CF in a child whose clinical picture fits, so the correct response to this presentation is to perform a sweat test regardless of the screen result. [2] [1]

(3) Immediate and definitive management (4). Immediately, I would resuscitate his dehydration with isotonic saline to correct the sodium and chloride deficit, add potassium once he is passing urine, and reassess his electrolytes and clinical state. Once he is stable, I would arrange a confirmatory sweat chloride test at an accredited CF centre and CFTR genetic analysis, interpreting the sweat chloride against the standard thresholds. If CF is confirmed, I would refer him to the multidisciplinary CF team, start salt supplementation, and offer genetic counselling to the family. [1] [3]