Cystic Fibrosis Diagnostic Confirmation
A 5 month old girl with weight faltering, greasy stools and recurrent chest infections has a sweat chloride of 78 mmol/L, repeated on a separate day at 82 mmol/L. Her parents are first cousins and her 4 year old brother is well. They want definitive confirmation of the diagnosis and counselling about the recurrence risk in a future pregnancy. Which is the most appropriate confirmatory test?
- A.CFTR mutation analysis in the infantCorrect
- B.Sweat chloride testing of both parents
- C.Sweat chloride testing of the well brother
- D.CFTR mutation analysis in the well brother
Explanation
The sweat chloride test is the standard screening and initial diagnostic test for cystic fibrosis, and 2 values of 60 mmol/L or more on separate occasions in a child with a compatible clinical picture strongly support the diagnosis. Definitive confirmation, however, comes from identifying 2 disease causing mutations in the CFTR gene on chromosome 7 in the affected child, which is also the only way to provide accurate genetic counselling, define the recurrence risk, permit carrier testing of relatives and offer prenatal or preimplantation diagnosis in future pregnancies. Genotyping additionally determines eligibility for CFTR modulator therapy, since drugs such as ivacaftor and elexacaftor combinations are approved for specific mutation classes, making the genetic result directly actionable. Cystic fibrosis is autosomal recessive, so with 2 carrier parents each subsequent pregnancy carries a 25 percent risk, and consanguinity raises the prior probability further. Testing the parents' sweat chloride is uninformative because obligate heterozygote carriers have normal sweat chloride values and are clinically well. Sweat testing the healthy brother screens him but does nothing to confirm the proband's diagnosis, although carrier testing of siblings by genotype is reasonable later for their own reproductive counselling. Genetic testing of the well brother likewise does not confirm the index case. Once confirmed, management includes airway clearance physiotherapy, mucolytics such as dornase alfa, pancreatic enzyme replacement, fat soluble vitamins A, D, E and K, a high calorie diet and aggressive treatment of infection, with Staphylococcus aureus predominating in younger children and mucoid Pseudomonas aeruginosa later.
Why each option
- A.
- Correct. Identifying 2 pathogenic CFTR mutations in the affected infant confirms the diagnosis, enables genetic counselling and determines eligibility for CFTR modulator therapy.
- B.
- Carrier parents have normal sweat chloride values, so testing them cannot confirm or refute the diagnosis in their child.
- C.
- Sweat testing a well sibling screens that child but contributes nothing to confirming the index patient's diagnosis.
- D.
- Genotyping the unaffected brother would only establish his carrier status and does not confirm the proband's diagnosis.
Reference: Nelson Textbook of Pediatrics, 22nd ed., 2024, Cystic Fibrosis
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