Human Reproduction, Vol. 15, No. 2, 449-451,
February 2000
© 2000 European Society of Human Reproduction and Embryology
Compound genetic factors as a cause of male infertility: Case Report
1 Department of Urology, 2 Department of Pathology, University of California San Francisco, 2330 Post Street, 6th Floor, San Francisco, CA 94115–1695 and 3 Department of Clinical Cytogenetics, Stanford University Medical Center, Stanford, California, USA
 |
Abstract |
|---|
 Top Abstract IntroductionCase reportDiscussionReferences |
|---|
A 40 year old healthy Chinese male with primary infertility was seen in a university male infertility and genetic counselling clinic. He presented with congenital bilateral absence of the vas deferens (CBAVD) and the finding of testis atrophy. Fine needle aspiration mapping of the testis identified and localized sperm production within the testicles for in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Careful evaluation of testicular cytology revealed late maturation arrest of spermatogenesis. Cystic fibrosis gene mutation analysis revealed heterozygosity for the 5T variant within the polypyrimidine tract of intron 8. Cytogenetic analysis revealed a pericentric inversion of chromosome 6 with break points at p12 and q21 [46,XY,inv(6)(p12q21)]. This case illustrates that spermatogenesis is not necessarily normal with congenital bilateral absence of the vas deferens. Compound genetic defects may coexist and underlie male infertility.
Key words: azoospermia/CBAVD/cytogenetic inversion/infertility
|
Introduction |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
The fact that chromosomal abnormalities are increased in infertile men relative to fertile men is well established. In cases of non-obstructive azoospermia, there is a 15% risk of an associated chromosome abnormality, including both aneuploidies and structural rearrangements (Hook, 1992
). More recently, it has also become clear that these men harbour a 13% risk of Y chromosome microdeletions in a region of the Y chromosome that contains genes associated with spermatogenesis (azoospermia factor, or AZF region) (Reijo et al., 1995).
Men who have obstructive azoospermia due to congenital bilateral absence of the vas deferens (CBAVD) have a 64% chance for carrying at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) genes (Anguiano et al., 1992). In addition, men with CAVD have an increased chance of possessing a variant thymidine repeat sequence, the 5T allele, in intron 8 of this gene (Chillón et al., 1995). This brings the likelihood of an identifiable genetic cause for CBAVD up to 80% (Jarvi et al., 1995; Zielenski and Tsui, 1995). However, it is generally assumed that CAVD is associated with normal spermatogenesis, and therefore men with CAVD are not at increased risk for the genetic factors that predispose to non-obstructive azoospermia.
|
Case report |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
A 40 year old Chinese male presented with a 3 year history of primary infertility. His past medical and exposure history revealed mild cholesterolaemia and a prior right inguinal herniorraphy at age 16 years, but no other infertility risk factors, such as radiation or chemical exposure, childhood history of cryptorchidism or testis trauma. There was no history of gonadotoxic medication, tobacco or alcohol use. There was no established history of infertility in either his brother or sister. His partner was 41 years old and had evidence of compromised ovarian reserve on formal evaluation. The couple was considering the use of assisted reproductive technology with donor oocytes.
On physical examination, he had normal secondary sexual characteristics without evidence of gynaecomastia. Scrotal examination revealed descended testes with a bilateral testicular volume of 15 ml bilaterally by Prader orchidometer (ASSI, Westbury, NY, USA) and an abnormally soft testicular consistency. A grade II left varicocele was present. No scrotal vas deferens was palpated on either side. A small remnant of the caput epididymis was observed bilaterally. A rectal examination was unremarkable.
Laboratory investigation revealed a microscopically negative urinalysis and an ejaculate volume of 0.8 ml with no spermatozoa detected. Seminal fructose was absent. A serum follicle stimulating hormone concentration was 8.8 mIU/ml (normal range 1–14 mIU/ml). A renal ultrasound revealed normal kidneys bilaterally.
Because of the finding of testicular atrophy, diagnostic fine needle aspiration (FNA) mapping of both testicles was performed under local anaesthesia to confirm and localize spermatogenesis (Turek et al., 1997; Turek et al., 1999). Testis FNA from 18 different sites revealed mature spermatozoa with tails at all sites, but in disproportionately low numbers relative to the abundant numbers of earlier germ cell forms (Figure 1). This was consistent with a cytological diagnosis of late, incomplete maturation arrest of spermatogenesis.
|
The couple underwent formal genetic counselling and testing in the Program in the Genetics of Infertility (PROGENITM) at the University of California San Francisco. This revealed a maternal first cousin, consanguineous marriage with no prior fertility in either spouse. His parents had trouble conceiving their first pregnancy. There was no family history of recurrent spontaneous abortions, stillborns, infants that died, birth defects or mental retardation. Genetic testing, including CFTR gene mutation analysis, Y chromosome microdeletions and cytogenetic analysis was discussed and consented to by the patient. An assessment of 30 CFTR gene mutations revealed no alterations. Analysis of the polypyrimidine tract within the splicer acceptor site in intron 8 of the CFTR gene revealed that the patient was heterozygous for the 5T variant. In addition, the karyotype analysis revealed a pericentric inversion of chromosome 6, with breakpoints at p12 and q21 [46, XY, inv(6)(p12q21)]. There were no deletions of the AZF a, b or c regions of the Y chromosome.
|
Discussion |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
This represents the first reported case in which two completely distinct genetic defects contribute to primary male infertility. Congenital bilateral absence of the vas deferens, with a well recognized obstructive phenotype, has obvious implications for male infertility (Oates et al., 1992
; Schlegel et al., 1996). In cases of CBAVD, pregnancies are routinely achieved with aspirated epididymal or testis spermatozoa in conjunction with in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) (Schlegel et al., 1994; Oates et al., 1996; Nudell et al., 1998). It has generally been assumed that testicular sperm production is normal in patients with CBAVD. However, it was recently suggested (Larriba et al., 1998) that the combination of CBAVD and the related 5T thymidine variant within the CFTR gene may predispose such patients to decreased spermatogenesis. In this study, we observe that CBAVD patients may also harbour two separate and unrelated genetic lesions as causes of obstructive and non-obstructive azoospermia. Patients with CBAVD should be counselled appropriately and, in the presence of a clinical suspicion of testis failure, should undergo an assessment of spermatogenesis by biopsy or FNA.
Careful evaluation of this apparently `obstructed' patient led to a complete genetic evaluation for non-obstructive azoospermia, including analyses for cytogenetic abnormalities and Y chromosome microdeletions. The karyotypic finding of a structural rearrangement in a large chromosome has a recognized association with infertility (De Braekeleer and Dao, 1991). It has been postulated that pairing anomalies during prophase I of meiosis may lead to spermatogenic arrest and subsequent infertility (Gabriel-Robez and Rumpler, 1994). The presence of the 5T thymidine variant within the CFTR gene may be a second contributing factor to abnormal spermatogenesis, as this allelic variant has been related to decreased spermatogenetic efficiency in CBAVD patients (Laribba et al., 1998). Both or either of these distinct genetic defects could produce the maturation arrest pattern observed on testicular cytology in this patient.
The implications of the genetic findings in this case of obstructive and non-obstructive azoospermia are significant. This patient was advised that this karyotypic finding may be familial and that testing of other family members is indicated, especially if a sibling is being considered as a sperm donor. Concerning future pregnancy, the patient and his wife were advised that there is an increased risk for spontaneous abortions of karyotypically unbalanced embryos or fetuses (Kaiser, 1988). Additionally, there is an increased risk for liveborns with birth defects and mental retardation. Unfortunately, in this situation, potential fetal phenotypes are unknown, because structural rearrangements tend to be unique to families and therefore empirical data are quite limited. Lastly, the patient was informed that epididymal sperm aspiration would probably fail, and that testis sperm extraction would be needed to procure mature spermatozoa for IVF and ICSI, given that sperm production is lower than normal. In summary, compound genetic factors are possible in male infertility and have profound genetic implications for biological fatherhood, given the advances in assisted reproductive technology.
|
|
Notes |
|---|
4 To whom correspondence should be addressed
|
References |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
Anguiano, A., Oates, R.D., Amos, J.A. et al. (1992) Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. J. Am. Med. Assoc., 267, 1794–1797.
De Braekeleer, M. and Dao, T.N. (1991) Cytogenetic studies in male infertility: a review. Hum. Reprod., 6, 245–250.
Chillón, M., Casals, T., Mercier, B. et al. (1995) Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N. Engl. J. Med., 332, 1475–1480.
Gabriel-Robez, O. and Rumpler, Y. (1994) The meiotic pairing behaviour in human spermatocytes carrier of chromosome anomalies and their repercussion on reproductive fitness, I: inversion and insertions. A European collaborative study. Ann. Genet., 37, 3–10.[Web of Science][Medline]
Hook, E.B. (1992) Chromosome abnormalities: prevalence, risks and recurrence. In Prenatal diagnosis and screening. Churchill Livingstone, Edinburgh, pp. 351–392.
Jarvi, K., Zielenski, J., Wilschanski, M. et al. (1995) Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia. Lancet., 345, 1578.[Web of Science][Medline]
Kasier, P. (1988) Pericentric inversions: their problems and clinical significance. In: The cytogenetics of mammalian autosomal rearrangements. A.R. Liss, New York, pp. 163–247.
Laribba, S., Bassas, L., Gimenez, J. et al. (1998) Testicular CFTR splice variants in patients with congenital absence of the vas deferens. Hum. Mol. Genet., 7, 1739–1744.
Nudell, D.M., Conaghan, J., Pedersen, R.A. et al. (1998) The mini-MESA for sperm retrieval: a study of urological outcomes. Hum. Reprod., 13, 1260–1265.
Oates, R.D., Honig, S., Berger. M.J. et al. (1992) Microscopic epididymal sperm aspiration (MESA): a new option for treatment of the obstructive azoospermia associated with cystic fibrosis. J. Assist. Reprod. Genet., 9, 36–40.[Web of Science][Medline]
Oates, R.D., Lobel, S.M., Harris, D.H. et al. (1996) Efficacy of intracytoplasmic sperm injection using intentionally cryopreserved epididymal spermatozoa. Hum. Reprod., 11, 133–138.
Reijo, R., Lee, T.Y., Salo, P. et al. (1995) Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat. Genet., 10, 383–393.[Web of Science][Medline]
Schlegel, P., Berkeley, A.S., Goldstein, M. et al. (1994) Epididymal micropuncture with in vitro fertilization and oocyte micromanipulation for the treatment of unreconstructable obstructive azoospermia. Fertil. Steril., 61, 895–901.[Web of Science][Medline]
Schlegel, P.N., Shin, D. and Goldstein, M. (1996) Urogenital anomalies in men with congenital absence of the vas deferens. J. Urol., 155, 1644–1648.[Web of Science][Medline]
Turek, P.J., Cha, I. and Ljung, B.M. (1997) Systematic fine needle aspiration of the testis: correlation to biopsy and the results of organ `mapping' for mature sperm in azoospermic men. Urology, 49, 743–748.[Web of Science][Medline]
Turek, P.J., Givens C.A., Schriock E.D. et al. (1999) Testis sperm extraction and intracytoplasmic sperm injection guided by prior fine needle aspiration mapping in nonobstructive azoospermia. Fertil. Steril., 71, 552–558.[Web of Science][Medline]
Zielenski, J. and Tsui, L.C. (1995) Cystic fibrosis: genotypic and phenotypic variations. Ann. Rev. Genet., 29, 777–807.[Web of Science][Medline]
Submitted on June 28, 1999; accepted on November 11, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||