What is CAVD?
Congenital absence of vas deferens (CAVD), also known as CBAVD (when is bilateral), is a genetic condition due to the total or partial non-development of the vas deferens, whose task is to transport sperm. CAVD is one of the main causes of obstructive azoospermia, responsible for numerous cases of male infertility.
Obstructive azoospermia is the absence of spermatozoa in the ejaculate, due to a physical obstruction of the seminal ducts.
CAVD is present in approximately 1% -2% of infertile males and is clinically characterized by total azoospermia or severe oligospermia, hypoplasia/aplasia/atrophy or fibrosis of one or both vas deferens and reduced volume ejaculate. Testicular development and spermatogenesis are usually normal.
The diagnosis of CAVD is made in male subjects presenting azoospermia, absence of vas deferens on palpation and identification of pathogenic CFTR variants CAVD-related.
What are the causes of CAVD?
In most cases (80% -98%), CAVD is an autosomal recessive genetic condition due to mutations in the CFTR gene, the same one that causes cystic fibrosis. It has recently been discovered that hemizygous mutations in the ADGRG2 gene can also cause CAVD. However, in a small portion of patients, no mutations in these genes are identified and the cause remains unknown.
Genetics of CFTR and CAVD
In patients with CFTR mutations, CAVD can manifest associated with other mild symptoms (in this case we speak of CFTR-related disorders) or in an isolated form.
CFTR mutations are divided into 6 classes, depending on the effect of the mutation on the protein: (I) absence of protein synthesis; (II) defects in protein processing (such as p.ΔF508); (III) channel gating; (IV) channel conduction; (V) reduced quantity; (VI) reduced stability. Usually, class I, II and III mutations are considered severe because they lead to the almost complete loss of protein function, while those of class IV, V and VI are considered "mild" because they guarantee residual protein activity.
Often, patients with CAVD are compound heterozygous for a severe variant of CFTR and a mild pathogenic variant or two mild variants. In particular, the most frequent alleles in Caucasian patients with CAVD are p.ΔF508 (with a frequency of 13-21%), 5T polymorphism (with a frequency of 22-29%), and the missense mutation p.R117H ( with a frequency of 2-4%).
If I've got CAVD, can I be a father?
Until a few years ago, patients with CAVD could not have children. To date, thanks to the progression of medically assisted procreation technologies, it is possible that these individuals have children. In fact, patients with CAVD often have normal spermatogenic function. However, it must be taken into account that, from a physical point of view, they may have not only the absence of the vas deferens, but also the absence of epididymal segments or hardened epididymal tissue. Instead, the top of the epididymis, which derives from a different embryological origin, is almost always present.
Over time, numerous techniques have been developed that allow sperm to be extracted directly from the epididymis or testicles. These include microscopic epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA), testicular sperm extraction (TESE) and percutaneous testicular sperm aspiration (TESA). It is important to emphasize that sperm obtained from chronically obstructed ducts or before complete maturation in the epididymis, tend to have less motility and therefore it is recommended to use the ICSI technique compared to other in vitro fertilization systems.
Cystic fibrosis recurrence risk
Before proceeding with assisted reproduction techniques in couples in which the male partner has CAVD, it is always recommended to perform genetic counseling. This happens because, due to the possibility of transmission of CFTR mutations, the risk of recurrence of cystic fibrosis is greater and is closely linked to the genotype of the female partner. If the partner does not have CFTR mutations, then the risk of recurrence is estimated to be below 1%, but if the partner is a carrier, it is important to proceed with a preimplantation genetic diagnosis. To reduce the risk of recurrence of cystic fibrosis, it is not sufficient to screen for frequent mutations and it is also strongly recommended to test for large deletions/duplications in CFTR, which, although rare, may be present.
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Persily JB, Vijay V, Najari BB. How do we counsel men with obstructive azoospermia due to CF mutations?-a review of treatment options and outcomes. Transl Androl Urol. 2021 Mar;10(3):1467-1478. doi: 10.21037/tau-19-681. PMID: 33850781; PMCID: PMC8039579.
Cui X, Wu X, Li Q, Jing X. Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review). Mol Med Rep. 2020 Nov;22(5):3587-3596. doi: 10.3892/mmr.2020.11456. Epub 2020 Aug 24. PMID: 33000223; PMCID: PMC7533508.
OMIM Phenotypic Series - PS277180