What is the most appropriate next investigation for a young boy with rectal prolapse, constipation, bulky and foul-smelling stools, failure to thrive, and recurrent pneumonia, with a positive sweat chloride test?

Most Appropriate Investigation for Confirmed Cystic Fibrosis

The most appropriate next investigation is DNA analysis of the affected boy (patient) for CFTR gene mutations (Option C or D, depending on which refers to the patient), not testing of asymptomatic family members. Once CF is confirmed by positive sweat chloride testing in a symptomatic patient, CFTR genetic testing should be performed on the affected individual to identify the specific disease-causing mutations for prognostic information, genetic counseling, and potential mutation-specific therapies 1, 2.

Rationale for Patient CFTR Genetic Testing

The diagnosis of CF is already established in this boy based on classic clinical features (rectal prolapse, pancreatic insufficiency with steatorrhea, failure to thrive, recurrent pneumonia) plus a positive sweat chloride test. The next critical step is identifying his specific CFTR mutations 1, 3.

Why Genetic Testing of the Patient is Essential

• Mutation identification enables mutation-specific therapies that have revolutionized CF treatment, making genotyping essential for optimal management 2
• Prognostic information varies significantly by mutation class, with classes I-III associated with pancreatic insufficiency and more severe disease, while classes IV-V allow residual CFTR function 3
• Genetic counseling for the family requires knowing both mutations in the affected child to provide accurate recurrence risk information 4
• The Cystic Fibrosis Foundation recommends CFTR genetic testing for all individuals who meet sweat chloride criteria for CF diagnosis 3

Why Testing Asymptomatic Family Members is NOT the Priority

Parents (Options A and B)

• Sweat chloride testing of asymptomatic parents has no clinical utility - they are obligate carriers but do not have CF 1
• Carrier testing via DNA analysis may be offered for family planning, but this is secondary to establishing the patient's complete genotype 3
• Parents being "healthy with no clinical symptoms" confirms they are carriers, not affected individuals 3

Sibling (Options referring to the sibling)

• The asymptomatic sibling has a 25% chance of having CF (if both parents are carriers) but is currently without symptoms 3
• Sweat chloride testing could be considered for the sibling, but only after the proband's diagnosis is fully characterized 1
• Testing asymptomatic siblings is not the immediate priority when the affected child's genotype remains unknown 3

Clinical Context Supporting This Approach

This boy presents with the classic CF triad that strongly predicted his diagnosis even before sweat testing 3:

• Rectal prolapse occurs in 18.5% of CF patients and should always prompt sweat testing 5
• Pancreatic insufficiency with bulky, foul-smelling stools (steatorrhea) indicates severe CFTR dysfunction 3
• Failure to thrive below 5th percentile is characteristic, with mean Z-scores of -1.0 at age 1 year in undiagnosed CF 3
• Recurrent pneumonia reflects progressive lung disease that begins early in CF 3

Critical Pitfall to Avoid

Do not delay CFTR genotyping of the affected patient to test family members first. The patient's specific mutations determine:

• Eligibility for CFTR modulator therapies (ivacaftor, lumacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor) 2
• Expected disease severity and pancreatic function 3
• Accurate genetic counseling with specific recurrence risks 4

In the era of mutation-specific therapies, knowing the patient's genotype is not just academic - it directly impacts treatment options and outcomes 2.