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CFTR-RD ↔ CF

❓What❓

  • A spectrum of disease characterized by variable dysfunction of the CFTR protein, an ion channel that, in health, allows efflux of airway epithelial chloride with resultant attraction of H2O & production of normal mucus &, in disease, results in ↑ viscosity of secretions (lung, GI/HPB system, epididymis/vas deferens)
  • In medical school, dysfunction of the CFTR protein is usually taught in the context of cystic fibrosis, which represents the most severe phenotype of this spectrum of disease, with biallelic, highly-pathogenic mutations resulting in early onset, multi-system disease (e.g. F508del/F508del)
  • However, the combination of a CF-causing & non-CF-causing mutation (”compound heterozygote”), or the combination of 2 non-CF-causing mildly-pathogenic mutations often allows the CFTR protein to retain some level of functionality, with myriad milder phenotypes not meeting full criteria for CF — these protean presentations are known as “CFTR-related disorders” (CFTR-RD)
Additionally, the so called “CFTR-associated disorders” describes an even milder phenotype defined by mutations thought to result in >50% wild-type CFTR function, where the clinical consequences are felt to arise not just from the mild mutations, but from environmental modifiers as well
Additionally, the so called “CFTR-associated disorders” describes an even milder phenotype defined by mutations thought to result in >50% wild-type CFTR function, where the clinical consequences are felt to arise not just from the mild mutations, but from environmental modifiers as well

❓Presentation❓

Respiratory 🫁

  • “Typical” CF: pediatric, severe OLD → upper-lobe bronchiectasis through adulthood, accompanied by multi-organ involvement; recurrent sinusitis & nasal polyposis
  • CFTR-RD (”Atypical”): late-onset, progressive OLD (”asthma mimicker”) → upper-lobe bronchiectasis in adulthood, often organ-limited; recurrent sinusitis & nasal polyposis
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Gastrointestinal ⊕ HPB 🟢

  • Pancreas: exocrine pancreatic insufficiency (with vs. without pancreatitis, with vs. without cystosis) → fat malabsorption (weight loss, ↓ ADEK), insulin-dependent DM
  • Hepatobiliary: mild transaminosis → sclerosing cholangitis → biliary cirrhosis; microgallbladder; cholelithiasis & cholecystitis
  • GI: distal intestinal obstruction syndrome (”meconium ileus equivalent”), constipation (inspissated stool), intussusception (lead point = inspissated stool)
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Epididymis → Vas Deferens ⚪

  • “Typical” CF: nearly ~100% have congenital bilateral absence of VD (CBAVD), & ~80% of infertile males worked-up for CBAVD have at least 1 CFTR mutation
  • CFTR-RD (”Atypical”): spectrum of oligospermia → epididymal obstruction, which can lead to isolated infertility (i.e. no other organ-specific damage)
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❓Diagnosis❓

  • For final diagnostic labeling, the clinician needs to interpret the clinical picture within the context of functional assays & CFTR genetics when the diagnosis remains unclear
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Sweat Test = CFTR Dysfunction Surrogate 🥵

  • The “sweat chloride concentration” (SCC) reflects abnormal transepithelial [Na+] transport resulting in ↑ [chloride] on the skin; therefore, levels ≥60 mmol/L are suggestive of CF, levels below 30 mmol/L make CF “unlikely,” & levels between 30-59 mmol/L are “intermediate”
  • Unfortunately, in patients with CFTR-RD, which is already an elusive diagnosis, measurements ranging from the “normal” to “CF” range have been reported when testing is repeated, meaning a “normal” result does not rule-out CFTR dysfunction. (Variability in measurements is even seen in F508del homozygotes, with differences of 20 mmol/L seen when testing is repeated for those in the “intermediate” range.)
  • Ultimately, it is now well-described that while CFTR-RD patients generally have higher measurements than non-diseased controls & lower measurements than CF patients, there is considerable overlap, especially between CFTR-RD & heterozygotes, & the correlation between “intermediate” measurements & phenotype is weak/inconsistent
  • For this reason, in cases with 0-1 CFTR mutations & a measurement less than 60 mmol/L, the diagnosis remains uncertain & additional biomarkers should be performed (nasal potential difference, intestinal current measurement)

Genetic Testing 🧬

  • Unless full sequencing of CFTR gene performed, diagnosis can be missed given the wide spectrum of phenotypes/mutations

📚 References 📚