Genetics of the congenital absence of the vas deferens

Abstract

Congenital absence of the vas deferens (CAVD) may have various clinical presentations depending on whether it is bilateral (CBAVD) or unilateral (CUAVD), complete or partial, and associated or not with other abnormalities of the male urogenital tract. CBAVD is usually discovered in adult men either during the systematic assessment of cystic fibrosis or other CFTR-related conditions, or during the exploration of isolated infertility with obstructive azoospermia. The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed. The diagnosis of CAVDs is based on clinical, ultrasound, and sperm examinations. The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing and in case of a positive result, genetic counseling prior to conception. Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility. However, despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis. An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth. How the dysfunction of CFTR, ADGRG2, or other genes such as SLC29A3 leads to this involution is the subject of various pathophysiological hypotheses that are discussed in this review.

Fig. 1

Anatomy of the adult vas deferens. The proximal part of the vas deferens (VD, in red) that follows the epididymis (E) is located in the scrotum, easily accessible for palpation. The VD then travels through the inguinal canal and then into the pelvis in a retroperitoneal position. The dilated terminal part of the VD is called the ampulla of the vas deferens. The ejaculatory duct follows the ampulla of the vas deferens with the end of the seminal vesicle and opens in the posterior surface of the prostatic urethra (U). B bladder, P prostate, SV seminal vesicle

Fig. 2

Brief history of the development of the Wolffian duct in males. a Apparition and elongation of the WD (cord of cells indicated in red) during the 5th week of gestation (WG). b WD derivatives (indicated in red) at 14 WG. The efferent ductules (EfD, in purple), derived from the mesonephric tubules, occupy the head of the epididymis, the body and tail of which contain the epididymal duct (EpD) which is followed by the vas deferens (VD). The ascent of the mature kidney leads outside the image which only shows the right ureter (U). c Testis and genital male tract in adulthood

Fig. 3

Main functions of the efferent ductules, the epididymal duct, and the vas deferens. The Sertoli cells secrete a fluid in the lumen of seminal tubules which converge towards the rete testis (R); about 90% of it is reabsorbed by the non-ciliated epithelial cells of the efferent ductules (in purple), leading to a concentration of spermatozoa. These are then transported into the epididymal duct where some of the epithelial cells contribute to the creation of a new intraluminal fluid that bathes the spermatozoa (Sp.). These cells are also at the origin of the sperm maturation process. Sperm are continuously produced in the epithelium of the seminal tubules and are stored in the tail of the epididymal duct. Part of this stock is mobilized during ejaculation (emission phase) and propelled into the vas deferens, where the layers of smooth muscle cells enable these spermatozoa to be rapidly transported into the posterior urethra via the ejaculatory duct. Gray dotted highlighting indicates structures that, in addition to the vas deferens, may be absent in CAVD. SV seminal vesicle

Fig. 4

Presentations of the morphological anomalies of CBAVD and CUAVD. Three presentations of CBAVD and two presentations of CUAVD are morphologically identifiable based on the absences reported by imaging of the vas deferens alone (indicated in red). Possible absences of a kidney and/or one or both seminal vesicles are represented by the organs with dotted lines. Other potentially associated anomalies such as absences from the body and/or tail of the epididymis, the ampulla of the vas deferens and the ejaculatory ducts are not taken into account. E epididymis, K kidney, T testis, U urethra

Fig. 5

Representation of an enlarged non-ciliated cell microvilli with a schematic overview summarizing different molecular models* of four pathophysiological processes induced by deleterious mutations of CFTR, ADGRG2, or SLC9A3: impairment of the intraluminal fluid water–ion–pH homeostasis (1) by at least one of the following three mechanisms, (i) deregulation of the water channel c-AMP dependent aquaporin-9, AQP9 (1a); (ii) deregulation of the apical electrolytes transport and the intraluminal pH by impairment of the complex interaction networks linking the co-localized Cl⁻ channel CFTR, Cl⁻/HCO3⁻ exchangers (SLC26A3/A6) and Na⁺/H⁺ exchangers (NHE3, SLC9A3) (1b). (iii) deregulation of the luminal fluid reabsorption by ADGRG2-activated Gq protein deficiency (1c); deregulation of CFTR and/or ADGRG2 intracellular trafficking (2); impairment of the epithelial integrity and tubulogenesis by tight-junctions’ (TJs) disorganization (3); impairment of the epithelial cell proliferation/differentiation regulation (4). *Almost of these models has been constructed from experimental data of in vitro or in vivo studies with knockout animals (mouse or less often rat)

Fig. 6

Flowchart for managing men referred to the andrologist for suspected CAVD. Uroandrologic assessment should include clinical examination (anamnesis and scrotal palpation), semen analysis (sperm count, pH, volume, and biochemical markers), and a scrotal ultrasonography (US) plus a transrectal ultrasonography (TRUS). This assessment is mandatory to confirm and characterize any suspicious CAVD (Mieusset et al. 2020). URA unilateral renal absence

Fig. 7

Flowchart of the CFTR testing process for genetic counseling purposes in couples where the male partner has a CAVD. 1: first choice strategy, that consists in carrying out a CFTR targeted CF-causing mutation test (commercial kit) in the two partners. Because for men with isolated CAVDs, particularly CUAVDs, the commercial CFTR test is often negative, it may be appropriate, as an alternative strategy (2), to directly apply a CFTR scanning method