Vas Deferens, Congenital Bilateral Aplasia Of

A number sign (#) is used with this entry because at least one form of congenital bilateral aplasia of the vas deferens (CBAVD) is caused by homozygous or compound heterozygous mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR; 602421) on chromosome 7q31. Mutations in the same gene cause cystic fibrosis (219700).

Description

Congenital bilateral absence of the vas deferens is found in more than 25% of men with obstructive azoospermia, involving a complete or partial defect of the Wolffian duct derivatives. In 80% of men with CBAVD, mutations are identified in the CFTR gene (summary by Patat et al., 2016).

Genetic Heterogeneity of Congenital Bilateral Aplasia of Vas Deferens

Also see CBAVDX (300985), caused by mutation in the ADGRG2 gene (300572).

Clinical Features

Congenital bilateral aplasia of the vas deferens (CBAVD), which leads to male infertility, may occur in isolation or as a manifestation of cystic fibrosis. Kaplan et al. (1968) found that males with cystic fibrosis are infertile because of failure of normal development of the vas deferens. Oppenheimer and Esterly (1969) concluded that the changes in the transport ducts of the male genital system are responsible for infertility and are not a developmental anomaly but a degenerative change due to obstruction similar to that which occurs in the pancreas and salivary glands in cystic fibrosis.

Augarten et al. (1994) suggested that CBAVD patients with renal malformations are likely not to have cystic fibrosis. They investigated 47 CBAVD patients by ultrasonography and found that 10 (21%) had renal malformations and 37 (79%) did not. In the former group, no cystic fibrosis mutations were found and sweat chloride concentrations were normal. In the latter group, 18 patients (49%) carried at least 1 cystic fibrosis mutation and sweat chloride was high in 17 of 26 tested (65%).

Dumur et al. (1996) concluded with others that, unlike forms of CBAVD accompanied by renal maldevelopment, most cases of CBAVD without renal agenesis are related to CF. They found that the sweat test is useful for demonstrating the connection, especially when genetic analysis has not characterized mutations on both alleles of the CF gene.

Inheritance

Schellen and van Straaten (1980) described 4 brothers, aged 31 to 42 years, with aplasia of the vasa deferentia. No parental consanguinity could be demonstrated by a genealogic tracing 'as far back as 1750.' No associated abnormalities were found. There was no evidence of cystic fibrosis in this family.

In a study of families of males with azoospermia and extreme oligozoospermia, Budde et al. (1984) found 2 brothers with congenital aplasia of the vasa deferentia. Czeizel (1985) reported 2 unrelated male sib-pairs with bilateral congenital aplasia of the vasa deferentia. Kleczkowska et al. (1989) and Gilgenkrantz et al. (1990) reported affected families.

Silber et al. (1990) used sperm aspirated from the epididymis of patients with congenital absence of the vas deferens to fertilize human oocytes in vitro.

Rigot et al. (1991) pointed to the risk attendant on the possibility that these males are carriers of a mild form of cystic fibrosis. They had examined 19 azoospermic men with aplasia of the epididymis and vas deferens and found that 8 were heterozygous for the delF508 deletion (602421.0001), the most common mutation causing cystic fibrosis. All but 1 had chronic sinusitis and 2 had sweat chloride levels close to 100 mmol per liter. Anguiano et al. (1992) reported similar findings. They studied 25 unselected, unrelated azoospermic men with CBAVD, most of them of northern European ancestry, who had presented to a male infertility clinic of a teaching hospital. In 16 (64%), at least 1 detectable CF mutation was found. Three of these 16 men were shown to be compound heterozygotes, one of whom had a previously undescribed mutation. This, they suggested, represents a primarily genital phenotype of CF.

Martin et al. (1992) reported 2 brothers with congenital absence of the vas deferens discovered in childhood during inguinal hernia repair. The vas was absent unilaterally in one and bilaterally in the other. Martin et al. (1992) suggested that X-linked recessive or autosomal dominant male-limited inheritance is more likely. All fathers of affected males should be examined for the presence of unilateral CBAVD. Theoretically, females carrying an autosomal dominant CBAVD gene should lack the normal remnant of wolffian duct regression (Gartner duct), while these remnants should be present in females carrying an X-linked recessive gene. The Gartner duct is clinically undetectable, however.

Molecular Genetics

See 602421 (e.g., 602421.0060) for mutations of the CFTR gene responsible for isolated bilateral absence of the vas deferens.

Goshen et al. (1992) described the case of a 2.5-year-old boy who was found to have fibrous replacement of the vas deferens when surgery was done for undescended testis and repair of an indirect inguinal hernia. One year later the patient developed diarrhea with steatorrhea, and sweat tests revealed elevated chloride. DNA studies demonstrated compound heterozygosity for the delF508 mutation and the trp1282-to-ter mutation (602421.0022).

To test the hypothesis of commonality of CBAVD and CF, Rave-Harel et al. (1995) reasoned that 2 brothers with CBAVD could be expected to carry the same 2 CFTR alleles, while their fertile brothers would be expected to carry at least one different allele. Eleven families were studied, of which 2 families, with unidentified CFTR mutations, did not support this hypothesis. In these families, 2 brothers with CBAVD inherited different CFTR alleles. Their fertile brothers inherited the same CFTR alleles as their brothers with CBAVD. The results suggested that although in some families CBAVD is associated with 2 CFTR mutations, in other families it is caused by other mechanisms, such as mutations at other loci or homozygosity or heterozygosity for partially penetrant CFTR mutations.

Mercier et al. (1995) analyzed the entire coding sequence of the CFTR gene in a cohort of 67 men with congenital bilateral aplasia of the vas deferens who were otherwise healthy. They identified 4 novel missense mutations: A800G, G149R, R258G, and E193K. They showed that 42% of these subjects were carriers of 1 CFTR allele and that 24% were compound heterozygotes for CFTR alleles. Thus, they were unable to identify the presence of 2 CFTR mutations in 76% of these patients. Furthermore, they described the segregation of CFTR haplotypes in the family of 1 CBAVD male; in this family, 2 male sibs with identical CFTR loci displayed different phenotypes, one of them being fertile and the other sterile. This suggested that one or more additional genes are involved in the etiology of CBAVD.

Chillon et al. (1995) characterized the mutations in the CFTR gene in 102 patients with CBAVD. They also analyzed a DNA variant (the 5T allele) in a noncoding region of CFTR that causes reduced levels of the normal CFTR protein. (Studies of CFTR mRNA in tissues from normal persons have identified various mRNA molecules that lack exon 4, 9, or 12. Whether or not CFTR mRNA contains exon 9 depends on the variable length of a stretch of thymine residues in intron 8 of CFTR. This sequence, known as a polyT sequence, contains 5, 7, or 9 thymines (the 5T, 7T, and 9T alleles, respectively). Since the 5T allele causes reduced levels of normal CFTR mRNA, this variant would appear likely to be involved in the pathogenesis of CBAVD.) In 19 of the 102 patients, mutations in both copies of the CFTR gene were found, and none of these had the 5T allele. A mutation was found in 1 copy of CFTR in 54 patients, and 34 of them (63%) had the 5T allele in the other CFTR gene. No CFTR mutations were found in 29 patients, but 7 of them (24%) had the 5T allele. The frequency of this allele in the general population is about 5%.

Chillon et al. (1995) concluded that the combination of the 5T allele in 1 copy of the CFTR gene with a cystic fibrosis mutation in the other copy is the most common cause of CBAVD. The 5T allele mutation has a wide range of clinical presentations, occurring in patients with CBAVD or moderate forms of cystic fibrosis and in fertile men.

Grangeia et al. (2007) screened DNA samples from 45 patients with congenital absence of the vas deferens by different molecular approaches, including screening for the 31 most frequent CF mutations. This approach identified 8 common mutations were identified in 40 patients. Denaturing gradient gel electrophoresis, denaturing high performance liquid chromatography, and DNA sequencing identified 17 additional mutations, 3 of which were novel. Semiquantitative fluorescent mutiplex PCR detected a 21-kb deletion (602421.0123) in 1 individual and confirmed the true homozygosity of 2 individuals. Overall, 42 patients (93.3%) had 2 mutations and 3 patients (6.7%) had 1 mutation detected.

Sun et al. (2006) analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10 to determine the haplotype of the 5T variant in trans. The authors evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant and found that 10 of 12 had the 12TG-5T-470V haplotype.