1 Departments of Urology and 2 Pediatrics, and 3 Center for Human Genetics, Boston University School of Medicine, Boston, MA, 4 Reproductive Science Center of Boston, Waltham, MA and 5 University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
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Abstract |
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Key words: congenital bilateral absence of the vas deferens/cystic fibrosis/renal agenesis
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Introduction |
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However, 1040% of CBAVD men form a subset with no recognizable CFTR gene abnormalities when routine CFTR analysis is applied. In addition, a second subset of CBAVD men have unilateral renal agenesis (URA) along with their vasal aplasia, and will be termed URA/CBAVD in this report (Augarten et al., 1994; Schlegel et al., 1996
; Vohra and Morgentaler, 1997
; de la Taille et al., 1998
). Since CF gene anomalies are not generally present in this second subset, the pathophysiology of men with these combined abnormalities may not be part of the CF mutation spectrum but may represent a different, discrete clinical and genetic entity. Each mesonephric duct proper has two derivatives: the ipsilateral ureteral/renal system; and the ipsilateral vas deferens, seminal vesicle and distal two-thirds of the epididymis. The physical separation of the two limbs occurs at week 7 of gestation (Gibbons et al., 1978
; Oates et al., 1995
). If an insult, whether genetic or toxic in nature, occurs prior to week 7, the entire mesonephric duct and its derivatives will be adversely affected. If the insult occurs after this time period, only one of the two by-products will be altered. Since males afflicted with clinical CF and those in our CF/CBAVD group have normal renal anatomy, CFTR protein abnormalities probably do not affect the primitive mesonephric duct, and may exert their effect only on the developing reproductive ductal derivatives including the vas, seminal vesicle and distal epididymis, perhaps even as late as postnatally (Gaillard et al., 1997
).
In this regard, we postulate that males with URA/CBAVD have a different genetic basis for their renal and vasal agenesis than those men with CF/CBAVD and normal renal anatomy. This presumed genetic anomaly would disrupt precise morphogenesis of the early mesonephric ducts. The most severe phenotypic manifestation would be bilateral renal and vasal agenesis, whereas men with URA/CBAVD would necessarily possess a slightly less severe phenotype (a solitary renal unit develops), allowing them to live normally and to express their consequent infertility in adulthood.
The transmission pattern for URA/CBAVD is unknown, as this combination leads to an absolute inability of a man naturally to pass along his genetic aberration to offspring. This fact limits assessment by analysing family trees. However, with the advent of surgical sperm aspiration combined with advanced reproductive technologies, the inheritance pattern may be more easily deduced by analysing the urinary and reproductive anatomy of an affected male's progeny. If URA/CBAVD is distinct from CF/CBAVD, are there significant differences in the anatomical, laboratory and radiographic manifestations between these two groups? Are there any differences in fertilization and pregnancy rates when microsurgical epididymal sperm aspiration (MESA) and intracytoplasmic sperm injection (ICSI) are applied to these couples? Lastly, is there a genetic basis we can elucidate, what is the transmission pattern, and what pathological phenotypic spectrum will befall the renal and reproductive system of the children?
The objectives of this study were to evaluate the incidence of URA in our CBAVD population, document the physical and radiographic findings, determine the presence or absence of CFTR gene mutations, examine the success rate for conception using surgical sperm harvesting and ICSI, and ascertain the frequency of renal agenesis/dysplasia in family members/offspring of men with URA/CBAVD.
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Materials and methods |
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Ultrasound examination was performed following documentation of CBAVD on the majority of patients to evaluate the upper urological and lower genital tract. The presence, absence and location of each renal unit was documented. Transrectal ultrasonography (TRUS) was used to image the ejaculatory ducts, seminal vesicles, vasal ampullae and prostate. Ninety-seven men had CBAVD, normal renal anatomy and CFTR gene mutations/polymorphisms detected (CF/CBAVD), and were presumed to have CBAVD based upon these CF gene anomalies. Seventy-eight men in this group had TRUS.
Seventeen men had concomitant URA and CBAVD, and these men constituted the prime study group (URA/CBAVD). Abdominal ultrasound examination was offered to all family members and offspring of these patients to assess their renal position and number.
The remaining 54 men were in an indeterminate group, whose genetic aetiology was hard to know at that point. All had normal renal anatomy. If included in either the CF/CBAVD or the URA/CBAVD population, the data would have been significantly diluted or contaminated. They may have had the same genetic basis as CF/CBAVD with undetected mutations in CFTR, they may have had less of a severe manifestation of the possible genetic abnormality that underlies URA/CBAVD, and they may have been a combination of the above, or they may have possessed a third, completely unknown genetic basis. Therefore, these men were not included in this study so as to keep the CF-mediated (CF/CBAVD) and URA (URA/CBAVD) populations pure.
Twelve men with URA/CBAVD opted for MESA or testicular sperm extraction (TESE) to access spermatozoa for use with ICSI. The technique of MESA and the details of oocyte stimulation, harvesting, ICSI and embryo transfer have been described previously (Oates et al., 1996). Most couples were able to use a frozenthawed approach for their cycles. The number of ICSI cycles completed, fertilization rates, pregnancy rates and number of live births were calculated for each couple. The results of fetal ultrasounds were obtained to determine the incidence of renal agenesis in the conceived offspring. Scrotal examination of all male children was scheduled to evaluate the status of their vasa. Data were given as mean ± SD. Z test for means, analysis of variance (ANOVA) and
2 statistical tests were applied, as appropriate, to the two populations using Microsoft Excel software.
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Results |
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Demographics
The mean age of patients at time of assessment was 34.2 ± 4.5 years, and that of their partners was 31.2 ± 3.8 years. All were referred for assessment of infertility. No other major physical abnormalities or health issues were identified. There was no history of maternal diabetes, obvious teratogen exposure or evidence of known congenital syndromes in themselves, or their families, that the men in either group could recall. There were no significant correlations with ethnic origin.
Physical examination
Testicular size and consistency was normal for both groups (Table I). Among men in the URA/CBAVD group, 13 had only the caput epididymis present bilaterally, two had a caput remnant on one side and a corpus-length remnant on the other, while the final two had full-length epididymides bilaterally. Within the CF/CBAVD group, the majority of men had just the caput remnant. No significant differences could be found with regard to remnant length within the groups, and all patients had at least the caput present. The remainder of the physical examination was normal.
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CFTR mutation analysis
CF genotyping was recommended to all patients and partners. For the purposes of this study, all CF/CBAVD patients, by definition, had at least one CFTR mutation, excluding a 5T variant of the IVS8-T tract alone. Two URA/CBAVD patients had a F508 deletion on one allele, and one patient had a 5T polymorphism detected on one allele. One spouse of a URA/CBAVD man was found to be a carrier for
F508 mutation, while the husband had no detectable mutations.
Transrectal ultrasonographic assessment
Transrectal ultrasound (TRUS) results of both groups are detailed in Table I. No statistical differences could be determined between the two groups when comparing the presence or absence of the ampullae of the vas, or the absence, atrophy or presence of the seminal vesicles.
Renal sonographic assessment
Left renal agenesis was present in nine men, and right agenesis in eight. One patient with CF/CBAVD (1%) was diagnosed with pelvic kidney compared to two men (12%) with URA/CBAVD (P < 0.01).
MESA and ICSI
Twelve out of 17 couples pursued MESA with ICSI (Table II). Twenty-six cycles have been completed, and seven couples have achieved pregnancies: four with the first cycle, two with the second cycle, and one couple became pregnant four times in five cycles accomplished. The fertilization rate (number of viable embryos/number of oocytes injected) was 58.2 ± 26.3%, with an embryo implantation rate of 18%. A pregnancy rate per cycle of 38% (10 conceptions/26 cycles ICSI) was achieved, with seven live births (three girls, four boys), there was one early spontaneous abortion, one therapeutic termination, and one ongoing twin pregnancy was documented. This compares favourably with data from our centre for MESA/ICSI for CF/CBAVD (Oates et al., 1996
).
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Discussion |
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In this ongoing study, statistical analysis could find no significant differences in the clinical findings of CF/CBAVD and URA/CBAVD men when comparing physical, laboratory or TRUS findings, which describe the anatomy and/or function of the reproductive ductal derivatives of the two mesonephric ducts. Therefore, the only phenotypic differences in these two groups are found in the renal derivatives of the mesonephric ducts. Renal agenesis cannot be predicted by any of these parameters and the need for abdominal ultrasonography of all newly diagnosed CBAVD patients cannot be over-emphasized. The percentage of men with a pelvic kidney was 10-fold higher in the URA/CBAVD cohort than the CF/CBAVD group. This is a statistically significant finding between the two groups (P < 0.01), and strengthens the hypothesis that URA/CBAVD may be due to a genetic defect affecting the mesonephric duct early in embryogenesis prior to week 7, and not due to CF gene mutations. The pregnancy rate in both CF/CBAVD and URA/CBAVD couples is excellent.
Speculations on the genetic basis of URA/CBAVD
Cystic fibrosis is an autosomal recessive disease that results from mutations in the CF gene located on 7q31. This gene encodes the cystic fibrosis transmembrane regulator (CFTR) protein, which is involved in the regulation of chloride ion membrane transport in respiratory and pancreatic epithelia. There must also be a role for CFTR in vasal development, because nearly all adult males with CF have bilateral vasal aplasia (Oates, 1999). There is evidence that the vasa are normal in fetal life and become atretic postnatally in CF males (Gaillard et al., 1997
). Mutations in the CFTR gene are found in 6090% of patients with CBAVD (Dork et al., 1997
; Oates, 1999
). Among the 97 men in the CF/CBAVD group, 15% had CFTR gene mutations on both chromosomes, this rate being in keeping with the 1136% compound heterozygote incidence stated in the literature (Donat et al., 1997
; Lissens et al., 1999
; Phillipson et al., 2000
).
The rate of CF mutations for the URA/CBAVD group is higher than the 4% expected carrier frequency in the normal population (Mak et al., 1999). Interestingly, each of these two men has one
F508 allele, the most common mutation detected world-wide. Perhaps it is because the URA population size is so small that the mutation rate is only apparently elevated. Perhaps one or both of these men do have CF-mediated CBAVD and have URA coincidentally as a second anomaly, though this would be extremely unlikely. Perhaps the reduction in the total CFTR pool in these men predisposes them to the vasal developmental effects of a `mesonephric duct gene' anomaly, but this is also an extremely unlikely scenario. That one patient (6%) has a 5T variant present on one allele is consistent with the carrier frequency (5.3%) of this allele in the unaffected general population (Chillon et al., 1995
).
Unilateral renal agenesis is a relatively common congenital condition that may be caused by a problem with formation of the entire Wolffian duct, ureteral bud maldevelopment, or degeneration of the ureteral bud at an early stage (Mesrobian et al., 1993). It is found in ~0.1% of autopsies and has been associated with other non-urological malformations and contralateral collecting system anomalies (Robson et al., 1995
; Cascio et al., 1999
). In up to 70% of men with URA there may be an absence of the ipsilateral epididymis, vas deferens and/or seminal vesicle (Robson et al., 1995
). The absence of a kidney itself is usually asymptomatic, and the diagnosis was made in our select population specifically because we were looking for renal agenesis in association with CBAVD.
Men with URA/CBAVD may have a different genetic basis than those with CF/CBAVD. Could URA/CBAVD be a variant in expression of an abnormality in a gene, or genes, required for nephrogenesis? This possible genetic aberration may hinder proper morphogenesis of the early mesonephric duct prior to separation of the renal and reproductive portions at week 7 of gestation. As our data show, anatomical expression of the reproductive ductal derivatives in adult men with URA/CBAVD and CF/CBAVD is similar. By definition, the phenotypic outcome of the renal portion of the mesonephric duct is quite different.
Extensive research with animal and organ culture models has established that faulty nephrogenesis may be a result of a mutation in master genes encoding diverse molecules, prenatal obstruction of the urinary tract, or by teratogens (Dressler, 1996; Winyard and Feather, 1996
; Woolf and Winyard, 1998
). Several murine genes have been identified which are critical in the pathway of renal development: homozygous null-mutations of wt-1, deletion of pax-2 in Krd mice, lack of c-ret and homozygous null mutations of forming ld (Dressler, 1996
; Woolf and Winyard, 1998
). Human dysplastic renal epithelia have been found to express PAX2, BCL2 and galectin-3 (Woolf and Winyard, 2000
). The correlation of animal models to human disease is, obviously, not always precise, and further elucidation of the full systemic ramifications of these mutations is required before they can be associated with specific human disorders/ syndromes (Cunliffe et al., 1998
).
Renal aplasia can occur in many human syndromes with a known genetic basis (Table III) (Rudd et al., 1990
; Dressler, 1996
; Winyard and Feather, 1996
; Woolf and Winyard, 1998
). All of the men involved in our study were healthy and did not have any of the anomalies associated with murine models or the above syndromes, especially of the branchial arch or the auditory system. Of interest, although renal adysplasia is commonly found in conjunction with maldevelopment of organs in other systems, none of the animal models or human disorders lists URA in association with CBAVD. Our men with URA/CBAVD are essentially healthy, aside from their infertility. There was no known history of maternal diabetes or exposure to harmful agents during the first trimester when the critical events of kidney organogenesis were taking place. Their family history did not reveal any unusual medical issues that could alert a physician to a potential genetic condition. At their urological evaluations they did not have any obvious facial, skeletal or neurological abnormalities associated with any of the multitude of syndromes that include URA as a component. Numerous syndromes with an unknown genetic basis also have absence of one (or rarely both) kidney(s) as an element of a collection of congenital anomalies (Murugasu et al., 1991
; Robson et al., 1995
; Cascio et al., 1999
).
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One fetus out of 10 evaluable conceptions in this study had BRA along with bilateral vasal agenesis at 20 weeks gestation. This would be consistent with an early devastating disruption of the entire primitive mesonephric duct, a different pathogenesis from that suspected for CF/CBAVD patients. This is twice the frequency found by others (Roodhooft et al., 1984) in their review. Perhaps URA/CBAVD is within the spectrum of BRA.
Postulating that their phenotypic expression of an inherited genetic aberration was even milder than their fathers, only involving the reproductive derivatives but not the renal derivatives, an attempt was made to document the presence or absence of vasa in male offspring. The oldest child was the first to be examined (at age 4 years). One could not say unequivocally that the vasa were palpable bilaterally, as the vasa are quite fine and not easily discerned from other cord structures at this age. An ultrasound of the scrotum is not appropriate as the scrotal vasa are difficult to visualize in a fully developed male, let alone a preschool, prepubescent male. It has been reported (Phillipson et al., 2000) that eight boys born to CBAVD fathers were all found to have palpable vasa. This physical finding could be anticipated in the sons of CF/CBAVD males, as evidence has been shown that this is an autosomal recessive disorder with incomplete penetrance of the phenotype, giving a risk of <1% of having a son with the same condition if the wife were negative for any tested CFTR mutation or polymorphism (Shin et al., 1997
). If our theory that URA/CBAVD stems from a different genetic aetiology is correct, then what will be the chances of finding vasa in male offspring? The possibility exists that these sons with normal renal anatomy may have competent vasa, or vasal agenesis alone, reflecting further variation in the manifestation of the putative anomaly. Further clinical examination and evaluation of these children as they age is necessary to define the variation of phenotypic expression.
In conclusion, URA/CBAVD occurred in ~10% of presenting CBAVD males at this institution. Clinical history, physical findings, semen analyses, CF genotype analysis and TRUS findings cannot dependably predict the presence or absence of renal units, and so abdominal ultrasonography is recommended for all men with CBAVD to document kidney number and location. Analysis of each partners' medical and family history and CF genotype, in addition to genetic counselling are required before initiating treatment, thus permitting couples to make informed decisions in their pursuit of parenthood. Our data show that couples opting for sperm harvesting and ICSI have an excellent live birth rate, and a low potential for passing on renal agenesis to their children. One pregnancy did result in a male fetus with BRA, and the potential for this fatal anomaly being transmitted from men with URA/CBAVD cannot be ignored and must be communicated to patients. A prenatal ultrasound to screen for renal agenesis is essential. Follow-up physical evaluation of sons is required to reliably determine their vasal anatomy. Research is still at an early stage in trying to define the roles of genetic factors in CBAVD and nephrogenesis. URA/CBAVD appears to be a genetic entity separate from CF/CBAVD as well as any of the reported syndromes that include renal agenesis as a component. Further family studies are required in both the CBAVD population and in males with unilateral renal agenesis to determine the proportion of cases with genetic causes, the penetrance of the respective mutations, and the frequency of abnormal renal and vasal phenotypes.
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Notes |
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References |
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Submitted on July 3, 2000; accepted on October 19, 2000.