Congenital bilateral absence of the vas deferens (CBAVD)

CBAVD is a congenital malformation of the mesonephric-duct-derived male genital tract in which the vas deferens is bilaterally absent, atrophic, or fibrotic. The anatomical defect is present from birth, but clinical recognition typically occurs post-pubertally during evaluation of primary infertility. Affected men present with obstructive azoospermia and reduced ejaculate volume, while testicular development and spermatogenesis are generally preserved; biological paternity is therefore achievable through surgical sperm retrieval and assisted reproductive technology (e.g., in vitro fertilisation). Reduced CFTR expression in the male genital tract has additionally been associated with reduced sperm count and concentration, decreased motility, and lower fertilisation rates in men with CBAVD undergoing sperm retrieval. Presentation shows considerable inter-individual variability: a small proportion of individuals with isolated CFTR-CBAVD subsequently develop adult-onset respiratory or pancreatic manifestations within the CFTR-related disorder (CFTR-RD) spectrum. CFTR-RD are associated with CFTR dysfunction that differs from classic (CF) and CBAVD is the most common; further CFTR-RD are acute recurrent or chronic pancreatitis and disseminated bronchiectasis.

CBAVD accounts for approximately 2-6% of male infertility and around 25% of cases of obstructive azoospermia

CBAVD is caused by germline pathogenic variants in CFTR (7q31.2) in the majority of cases and, in a smaller proportion of CFTR-negative individuals, by variants in the X-linked gene ADGRG2 (Xp22.13). CFTR encodes the cystic fibrosis transmembrane conductance regulator, an apical-membrane epithelial chloride and bicarbonate channel. Reduced channel function produces viscous luminal secretions that lead to obstruction and progressive involution of the developing vas deferens. Isolated CBAVD most commonly results from compound heterozygosity for a severe loss-of-function CFTR variant in trans with a non-CF-causing variant such as the intronic 5T allele (c.1210-12T[5]), which reduces splicing efficiency of CFTR exon 10. The adjacent TG-repeat tract further modulates residual CFTR function.

CFTR-related CBAVD is inherited in an autosomal recessive manner. For autosomal recessive CFTR-CBAVD, both parents are typically heterozygous carriers, and each future sibling of an affected individual has a 25% risk of being affected, a 50% risk of being a heterozygous carrier, and a 25% chance of inheriting neither variant. Carrier testing of the female partner of an affected man is an established component of reproductive counselling, given the elevated population-carrier frequency of CFTR variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis is established through a combined clinical, biochemical, and imaging work-up. Semen analysis demonstrates obstructive azoospermia with reduced semen volume (<1.5 mL), acidic pH (<7.2), and absence or reduction of fructose. Physical examination reveals non-palpable vas deferens bilaterally, confirmed by scrotal ultrasonography. Transrectal ultrasonography may show absent or hypoplastic seminal vesicles and ejaculatory ducts. Sweat chloride testing is performed to evaluate for classical cystic fibrosis (≥60 mmol/L diagnostic; 30-59 mmol/L intermediate). Molecular confirmation is obtained by CFTR sequencing including intron 8 poly-T/TG analysis for 5T allele.

Main differential diagnoses include:

• (classical, multisystem): multisystem sinopulmonary disease, pancreatic insufficiency, and elevated sweat chloride distinguishes classical CF from isolated CBAVD; biallelic CF-causing variants are typically present; CFTR
• ADGRG2-related X-linked CBAVD: bilateral absence of the vas deferens without identifiable biallelic CFTR variants, following an X-linked pattern (maternal transmission, no male-to-male transmission); ADGRG2
• Acquired obstructive azoospermia: obstructive azoospermia with palpable vas deferens and a history of vasectomy, epididymitis, or pelvic surgery; the vas deferens is anatomically present but obstructed

• Establishing the diagnosis: molecular genetic testing confirms the underlying genetic cause, distinguishes isolated from syndromic forms, and resolves diagnostic uncertainty where clinical and biochemical findings are equivocal.
• Guiding specific and individualised surveillance: identification of biallelic CFTR variants is a prerequisite for targeted medical care, including monitoring for adult-onset respiratory or pancreatic manifestations within the CFTR-RD spectrum, with decisions made by the treating physicians in consultation with the affected individual.
• Family member testing: clarification of the genetic cause in the index individual enables predictive and carrier testing in at-risk relatives, including the female reproductive partner, and informs reproductive planning.

• Savant A, Lyman B, Bojanowski C, Upadia J. Cystic fibrosis. 2001 Mar 26 [Updated 2024 Aug 8]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301428.
• Qu X, Li L, Cui C, Feng K, Xia Y, Wan F, et al. Correlation between CFTR variants and outcomes of ART in patients with CAVD in Central China. Sci Rep. 2023;13(1):64. doi:10.1038/s41598-022-26384-8. PMID:36604502; PMCID: .
• Markulić J, Fuller M. Diagnostic yield of cystic fibrosis from a South Australian monocentric cohort: a retrospective study. BMJ Open. 2025;15(1). doi:10.1136/bmjopen-2024-092209. PMID:39855646; PMCID: .
• Bombieri C, Claustres M, De Boeck K, Derichs N, Dodge J, Girodon E, et al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros. 2011;10 Suppl 2. doi:10.1016/S1569-1993(11)60014-3. PMID:.