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A newborn with meconium ileus is found to have an elevated immunoreactive trypsinogen on newborn screening. Sweat chloride is 85 mEq/L. Genetic testing reveals F508del homozygosity.
AR; CFTR (cystic fibrosis transmembrane conductance regulator)
- F508del (p.Phe508del): ~70% of alleles in Caucasians
- Variant classes affect treatment eligibility
Variant Classes:
| Class | Defect | Example | CFTR Modulators |
|---|---|---|---|
| I | No protein (nonsense/frameshift) | G542X | Limited |
| II | Trafficking defect | F508del | Lumacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor |
| III | Gating defect | G551D | Ivacaftor |
| IV | Conductance defect | R117H | Ivacaftor |
| V | Reduced quantity | 3849+10kbC>T | Variable |
- Pulmonary: Chronic infections (Pseudomonas, Staph), bronchiectasis, respiratory failure
- GI: Pancreatic insufficiency, meconium ileus, distal intestinal obstruction, hepatobiliary disease
- Reproductive: Male infertility (CBAVD, 97% of CF males), reduced female fertility
- Other: Nasal polyps, CF-related diabetes, osteoporosis
CBAVD is the obstructive cause of azoospermia found in 97-98% of males with classic CF and is also a frequent sole presentation of CFTR disease in otherwise asymptomatic men evaluated for infertility: a CFTR-related disorder at the mild end of the phenotypic spectrum, not classic CF.
Genetics of isolated CBAVD:
- Most isolated CBAVD males carry one severe CFTR variant in trans with one mild variant, most commonly the 5T allele of the intron 9 (now intron 8) polypyrimidine tract (a splicing-efficiency variant that reduces normal CFTR transcript)
- The 5T allele's penetrance is modulated by the adjacent TG-repeat tract length (TG12 or TG13 in cis with 5T markedly increases the chance of CBAVD)
- A minority of CBAVD males have two mild variants or one severe + 5T
Counseling implications:
- Any male with CBAVD should have full CFTR analysis (sequencing + 5T/TG genotyping), not just the standard panel
- The female partner must be tested with comparable sensitivity before IVF/ICSI; if she carries any CFTR variant, offspring are at risk for classic CF or a CFTR-related disorder
- Sweat chloride may be normal or borderline in isolated CBAVD; diagnosis is genetic
- Renal ultrasound is recommended (unilateral renal agenesis can co-occur with unilateral, not bilateral, vas deferens absence, a developmental clue that the etiology is not CFTR)
- Newborn screening (IRT + DNA or IRT/IRT)
- Sweat chloride ≥60 mEq/L (diagnostic)
- CFTR genetic testing
Carrier Screening: Recommended for all reproductive-age individuals
- CFTR modulators are the disease-modifying mainstay: elexacaftor/tezacaftor/ivacaftor for eligible variants, ivacaftor for gating variants
- Airway clearance plus inhaled therapies (dornase alfa, hypertonic saline, inhaled antibiotics) and aggressive treatment of pulmonary exacerbations
- Pancreatic enzyme replacement with fat-soluble vitamin (A, D, E, K) supplementation and high-calorie nutrition
- Surveillance for CF-related diabetes, hepatobiliary disease, and bone disease; lung transplantation for end-stage disease