1. Etiology
Congenital absence of the vas deferens has always been suspected to be related to genetic factors as a congenital malformation of the male reproductive system. It has been found that the disease has an aggregation phenomenon in some families, and the close clinical correlation between cystic fibrosis and congenital absence of the vas deferens provides strong evidence for the important role of genetic factors. Since the late 1980s, significant progress has been made in the clinical and molecular genetic research of cystic fibrosis, and the study of the molecular level relationship between the disease and congenital absence of the vas deferens has initially elucidated the genetic basis of congenital absence of the vas deferens.
Cystic fibrosis is a common lethal autosomal recessive genetic disease, with an incidence of 1 in 2000 live births in whites, and the frequency of carriers of the causative gene is as high as 1 in 22. The clinical manifestations are mainly chronic lung diseases, insufficient exocrine pancreatic function, increased electrolyte concentration in sweat, and male infertility. The causative gene of this disease has been localized to chromosome 7 long arm 3 region 1 band (7q31) and has been cloned and sequenced. The gene is 250kb in length, with 27 exons, an eDNA length of 6129bp, and encodes a protein called the cystic fibrosis transmembrane conductance regulator, which functions as a chloride ion channel. To date, more than 600 mutations and variations have been found in this gene, covering the entire CFTR gene region, among which 70% of the mutations in whites are △F508, that is, a codon encoding a phenylalanine at position 508 of the polypeptide chain is missing at nucleotides 1653 to 1655 of the 10th exon.
In the study of cystic fibrosis, it was found that the vast majority of male patients are infertile due to congenital absence of the vas deferens, indicating that the mutation of this gene is closely related to the abnormal development of the vas deferens. Studies have confirmed that the first type of congenital absence of the vas deferens is caused by CFTR gene mutation. However, whether the congenital absence of the vas deferens in males without typical cystic fibrosis symptoms or who appear healthy is related to CFTR gene abnormalities is still unclear. In 1983, Petit et al. first reported a case of congenital absence of the vas deferens in a patient without typical cystic fibrosis symptoms, accompanied by chromosomal abnormality on chromosome 7, namely inv(7)(p15, q32), inv(9)(p11, q13). At that time, since the CF gene had not been localized, it was not considered to be related to cystic fibrosis. Now it is known that the CFTR gene is precisely located at 7q31. The interchromosomal inversion in this case may have destroyed the structure of the CFTR gene adjacent to chromosome 7, thereby causing congenital absence of the vas deferens. This case suggests that the occurrence of the second type of congenital absence of the vas deferens may be related to CFTR gene abnormalities. Secondly, with the in-depth study of clinical and molecular genetics of cystic fibrosis, it is increasingly evident that the clinical manifestations of cystic fibrosis are diverse, and there is a close correlation between the mutation gene type and the phenotype, that is, different mutation gene types can lead to different clinical manifestations, and the same mutation gene type may also have different clinical manifestations in different individuals. Many researchers have conducted extensive mutation screening of the CFTR gene exons and the splice sites between exons and introns in such CBAVD patients. The results show that such CBAVD is indeed closely related to CFTR gene mutations. Among these patients, at least 50% to 70%, and sometimes up to 86%, carry a CFTR mutation gene, among which 10% are complex heterozygotes for CFTR gene mutations, that is, each of the two 7th chromosomes has a CFTR gene mutation. This is significantly different from the frequency of 4% of CFTR gene mutation carriers in the normal population and the incidence rate of 0.2%. In addition, it was also found that many new or relatively rare mutations were present in the CFTR gene of such CBAVD patients, which were different from the types and frequencies of mutations carried by typical cystic fibrosis patients. This further confirms the relationship between the mutation gene type and the phenotype of cystic fibrosis, that is, more common mutations cause typical cystic fibrosis symptoms, while some relatively rare mutations may only cause CBAVD.
In summary, the current consensus is that a considerable number of CBAVD males without typical symptoms of cystic fibrosis are a unique genetic group of cystic fibrosis. CBAVD, along with lung diseases and insufficient pancreatic function, are important phenotypes of cystic fibrosis gene mutations. The mutation in the coding region of the CFTR gene is one of the most important genetic causes of the second type of CBAVD.
In addition, in the study of CUAVD, researchers found that when the patient has unilateral absence of the vas deferens and the contralateral vas deferens is blocked at the inguinal or pelvic level, the mutation rate of the CFTR gene is often as high as 89%, similar to CBAVD, and significantly different from the normal population. This confirms that the mutation in the coding region of the CFTR gene is also one of the most important genetic causes of this type of CUAVD.
The current research on the gene expression of cystic fibrosis not only involves the coding region of the gene, but also includes a few non-coding regions, such as the poly(T) of intron8. In the study of the CFTR gene expression in the respiratory epithelium, it has been confirmed that the allele 5T can affect the normal splicing of the 9th exon of the gene, causing a decrease in transcription levels, leading to incomplete expression of the CFTR gene, resulting in a decrease in the level of CFTR protein, and can trigger a series of clinical symptoms. Therefore, it is currently believed that the 5T mutation in intron8 is one of the reasons for the diversity of clinical manifestations of cystic fibrosis. To explore the relationship between CBAVD and 5T mutation, some authors divided the results of the CBAVD study into three groups according to the mutation of the cystic fibrosis gene: the first group accounts for about 15%, and all are complex heterozygotes with CFTR gene mutations, without 5T mutation; the second group accounts for about 60%, with one CFTR gene mutation, among which more than 60% are accompanied by another 5T mutation on another CFTR gene; the third group accounts for about 25%, no other CFTR gene mutations were found, and the frequency of 5T mutation carriers was about 25%, even with 5T homozygotes. It can be seen that when both CFTR genes are mutated, the occurrence of CBAVD may be related only to the former, and not related to 5T mutation; while the frequency of 5T mutation carriers in the latter two groups is significantly higher than that in the normal population of 5% carriers, showing a significant difference, indicating that the presence of 5T mutation on the intron8 of the CFTR gene may be another genetic cause of congenital absence of the vas deferens. Moreover, a mutation in one CFTR gene coding region plus a 5T mutation in another CFTR gene non-coding region may be the most common cause of congenital absence of the vas deferens.
The study of the transcription level of the CFTR gene in CBAVD males also indicates that when a CFTR gene mutation and a 5T mutation form a heterozygote, the transcription product is only 6% to 16% of normal, and the transcription product of a 5T mutation homozygote is only 24% of normal. This further provides a theoretical basis for the important role of 5T mutation in the occurrence of congenital absence of the vas deferens, and to some extent, reveals that even when there is only one gene coding region mutation, as a recessive autosomal genetic disease, cystic fibrosis can also be a cause of congenital absence of the vas deferens. In addition, the transcription of this gene has a certain tissue specificity, such as the respiratory epithelium has a higher transcription level than the epididymal epithelium, which may be one of the reasons why patients with congenital absence of the vas deferens carrying CFTR gene mutations have no other clinical manifestations.
A considerable number of simple congenital absence of the vas deferens are the result of CFTR gene mutations, which are a special phenotype of cystic fibrosis. However, in another part of CBAVD and CUAVD patients, no CFTR gene mutation has been found. The possible reasons are: ① The CFTR gene is large, and the current polymerase chain reaction-single strand conformation polymorphism and other technologies are still difficult to detect all mutations; ② To date, only mutations in the exons, splice sites, and a few introns of the CFTR gene have been analyzed, and the existence of mutations in the promoter region or other regulatory sites cannot be excluded, and the latter is possible; ③ In some pedigrees, when父子 or siblings carry the same mutation, only one of them develops CBAVD, which indicates that in the process of occurrence of congenital absence of the vas deferens, in addition to CFTR gene abnormalities, other genetic factors and environmental factors may also play a role; ④ In patients with congenital absence of the vas deferens complicated with other urinary system malformations (such as renal malformations) and almost normal unilateral vas deferens in CUAVD, no CFTR gene mutation has been found, suggesting that such congenital absence of the vas deferens is unrelated to the CFTR gene, and also supports the existence of other etiologies.
Considering that the molecular genetic research on congenital absence of the vas deferens is still limited to gene coding and a few non-coding regions, it is necessary to continue to detect more mutations in the CFTR gene coding region, and gradually expand the screening area to the gene promoter region and other regulatory regions. It is also necessary to study other genes that may be related to the occurrence of congenital absence of the vas deferens outside of the CFTR gene, so as to more fully reveal the molecular genetic basis of congenital absence of the vas deferens.
Secondly, pathogenesis
Congenital absence of the vas deferens can be divided into:
1. Absence of bilateral vas deferens (CBAVD):Due to the underdevelopment or incomplete development of both middle renal tubes, absence of epididymis and seminal vesicle may occur, and rarely associated with renal malformation or agenesis.
2. Unilateral absence of the vas deferens (CUAVD):Caused by the underdevelopment or incomplete development of the unilateral mesonephric duct, often accompanied by the underdevelopment or absence of the ipsilateral ureteric bud, leading to renal underdevelopment, and the absence of the ipsilateral kidney, ureter, vas deferens, and epididymis.
3. Partial absence of the vas deferens:It can also be divided into absent vas deferens in the scrotal segment and absent vas deferens in the pelvic segment, which may be caused by the sudden cessation of the mesonephric duct during the differentiation into the vas deferens. Other malformations of the vas deferens include a fibrous cord-like segment of the vas deferens, and the lumen is blocked and not patent. The mesonephric duct branches develop into duplicated vas deferens, and in most reported cases of duplicated vas deferens, there are two testes on the duplicated side, and each vas deferens is connected to one testis. In addition, the vas deferens can deviate from the spermatic cord and open abnormally at other sites. In 1978, Kaplan reported 8 cases of patients with ectopic vas deferens malformation, 6 of whom had other urogenital organ malformations, and 3 had congenital anal atresia. Since the testis develops from the genital ridge, the testis is generally normal when there is a malformation of the vas deferens.
According to clinical manifestations and the relationship with cystic fibrosis, congenital absence of the vas deferens can be divided into two types: the first type is clearly related to cystic fibrosis, and patients are mostly diagnosed with chronic lung diseases, pancreatic insufficiency, and other chronic diseases. During examination, typical symptoms of cystic fibrosis, such as increased electrolyte concentration in sweat, can be found; the second type has an unknown etiology, and is mainly diagnosed with infertility, while no other abnormalities are found during physical examination.
