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Reproductive outcomes in men with karyotype abnormalities: case report and review of the literature.

Case report

A 37-year-old man and his 39-year-old wife presented due to a complaint of primary infertility. They had been trying to conceive for 12 years. Two years previously, the patient had undergone bilateral testicular biopsies with successful sperm retrieval and conception. Unfortunately, the couple experienced recurrent pregnancy loss (both during first trimester) following two cycles of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) without genetic testing. On examination, the man had bilaterally descended testis with a right testicular size of 18 cc and a left testicle size of 16 cc. No varicocele was palpable; the vas deferens and epididymis were palpable bilaterally. Testosterone levels were 241 ng/dL, follicle stimulating hormone levels 7 mIU/mL, and luteinizing hormone levels were 5 mIU/mL. Semen analysis revealed no sperm. Based on the evaluation and previous operation at the outside institution, the patient was diagnosed with azoospermia likely secondary to epididymal obstruction.

The couple was sent for genetic evaluation due to recurrent pregnancy loss. Genetic evaluation showed that the husband had a reciprocal translocation involving chromosomes 4 and 8 [46,XY;t(4;8)(q31.1;q22.3)]. In addition, his wife had 45,X/46,XX mosaicism. The patient underwent a successful right testicular sperm extraction (TESE) with IVF/ICSI combined with pre-implantation genetic screening (PGS). The result was a successful live birth. Two years later, a repeat TESE was performed for another IVF/ICSI/PGS cycle, and the couple had a second healthy child.

Discussion

The prevalence of reciprocal translocations in the general population is about 1/625. (1) This prevalence is greater in infertile couples (1/166), in couples who have failed to achieve a pregnancy after >10 total embryos transferred for IVF (1/31), and in couples who have experienced [greater than or equal to] 3 consecutive first-trimester spontaneous abortions (1/11). (2) Studies have shown that for couples in whom the male has a reciprocal translocation, 75% of natural pregnancies will result in a spontaneous abortion, with a live birth rate of only 4.9%. (3,4) Increased frequency of male infertility in men with reciprocal translocations is due to abnormal meiosis during spermatogenesis. (5) Abnormal segregation during meiosis can result in sperm with unbalanced translocations (i.e., chromosomal duplications and deletions). (6) Embryos with unbalanced translocations are at a high risk of spontaneous abortion, stillbirth, or neonatal anomalies, and only 11.5% experience births of healthy infants. This explains why couples with a reciprocal translocation have significant problems conceiving and carrying to term. (7)

In recent years, preimplantation genetic screening (PGS) has significantly improved the frequency of healthy births in couples with genetic abnormalities. Screening the embryo prior to implantation assures that only those embryos with appropriate numbers of chromosomes are implanted. For couples in whom one or more partners have a reciprocal translocation, preimplantation genetic diagnosis (PGD) reduced the frequency of spontaneous abortions to 12.5% and increased the live birth rate to more than 80%. (3,4)

Due to the complexity of translocations and the high incidence of chromosomal aneuploidy with similar phenotypes, a review of the existing literature was critical (Table 1). Most patients with chromosomal abnormalities, with the notable exception of patients with 45,X/46,XY including those with complex chromosomal rearrangements, can still achieve pregnancies. This literature review reveals that sperm retrieval appears necessary in the presence of many sex chromosomal abnormalities, whereas patients with autosomal chromosomal abnormalities are often oligospermic and thus do not require testicular sperm extraction. Further, it appears that for patients with sex chromosomal abnormalities, including those with Kleinfelter syndrome, sperm retrieval combined with assisted fertility treatment offers a good prognosis for pregnancy.

While in this case report the IVF/ICSI attempts resulted with two healthy, live births, there is an ethical concern that an abnormal karyotype might be passed onto the prodigy. In countries where the law does not preclude assisted reproductive techniques for couples with a balanced chromosomal translocations, the couple ought to be referred to genetic counselling and be advised that an abnormal karyotype might be passed onto the prodigy before starting assisted reproductive techniques.

Conclusion

We report a successful pregnancy using TESE and IVF/ICSI in a couple in whom both individuals had abnormal karyotypes. The use of sperm extraction techniques and assisted fertility treatments, including pre-implantation genetic screening, dramatically helped these patients with chromosomal abnormalities achieve viable pregnancies. We expect genetic defects in men with infertility will be diagnosed with greater precision (beyond translocation) since molecular diagnostics, such as next-generation sequencing and microarray-based comparative genomic hybridization (array-CGH) analysis, have now been incorporated into clinical labs.

http://dx.doi.org/10.5489/cuaj.2902

Published online September 9, 2015.

Competing interests: The authors all declare no competing financial or personal interests.

This paper has been peer-reviewed.

References

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Correspondence: Dr. Larry Lipshultz, 6624 Fannin St., Suite 1700, Houston, TX 77030; larryl@bcm.edu

Taylor P. Kohn, MPhil; * Raul Clavijo, MD ([dagger]) Ranjith Ramasamy, MD; * Tariq Hakky, MD; * Aravind Candrashekar, MD, MBA; * Dolores J. Lamb, PhD, HCLD; * Larry I. Lipshultz, MD *

* Department of Urology, Baylor College of Medicine, Houston, TX; ([dagger]) Department of Urology, University of California, Los Angeles, CA
Table 1. Summary of literature pertaining to sperm retrieval in
patients with autosomal and sex chromosome abnormalities

Study                 Age      Year        Karyotype abnormality

                        Autosomal chromosome abnormality

Current case           42      2015      46,XY,t(4;8)(q31.1;q22.3)
Ananthapur             34      2013     46, XY, t (2;11) (p14;q21)
  et al. (8)
Almeida                31      2012       46,XY,t(2;2)(p25.1;q23)
  et al. (9)
Motoyama               28      2011   46,XY, t(10; 21)(q11.2; p11.2)
  et al. (10)
Joly-Helas             35      2007      46,XY,t(4;11)(q34;q13.5)
  et al. (11)
Drouineaud             34      2003     45,XY, der(13;14),(q10;q10)
  et al. (12)                         46,XY,t(7;9)(q22;p24),ins(8;7)
Cai et al. (13)        35      2000      (q21.2;q22q32).ish der(9)
                                             (wcp7+);ins(8;7)
                                               (wcp8+,wcp7+)
Belin                  NA      1999    46,XY,t(20;22)(q12.0;q11.21)
  et al. (14)
Meschede               NA      1997       46,XY,t(1;9)(q44;p11.2)
  et al. (15)                              45,XY,der(13;13)(q10;
                                       q10)/46,XY,t(13;13)(p10;p10),
Veld et al. (16)     41, NA    1997            der(13p;13p)
                                                    AND
                                         45,XY,der(13;14)(q10;q10)

                         Sex chromosome abnormality

Flannigan RK           27      2014             45,X/46,XY
  et al. (17)
Abdel-Razic          23-40     2011               47,XYY
  et al. (18)
Kilic et al. (19)    25-32     2010             45,X/46,XY
Spinner                NA      2008              46,Xr(Y)
  et al. (20)
Sugawara               27      2005            46, XX/46, XY
  et al. (21)
                             Kleinfelter syndrome

Sabbaghian             32      2014               47,XXY
  et al. (22)        (mean)
Greco et al. (23)      35      2013               47,XXY
                     (mean)
Vicdan                 35      2011               47,XXY
  et al. (24)
Ramasamy               33      2009               47,XXY
  et al. (25)        (mean)
Yarali                 32      2009               47,XXY
  et al. (26)        (mean)
                       30
Kyono et al. (27)   (mean 2)   2007               47,XXY
                       38
                    (mean 1)
Koga et al. (28)       36      2007               47,XXY
                     (mean)
Schiff               24-52     2005         47,XXY (39) AND 46,
  et al. (29)                                  XX/47,XXY(3)
Okada et al. (30)    25-43     2005               47,XXY
Seo et al. (31)                2004         47,XXY (25) AND 46,
                     26-42                     XY/47,XXY(11)
Vernaeve              29.5     2004               47,XXY
  et al. (32)        (mean)
Westlander             33      2003               47,XXY
  et al. (33)        (mean)
Yamamoto               NA      2002               47,XXY
  et al. (34)
Friedler              28.7     2001               47,XXY
  et al. (35)        (mean)
Cruger                 28      2001               47,XXY
  et al. (36)
Poulakis             33,35     2001               47,XXY
  et al. (37)
Levron                 NA      2000               47,XXY
  et al. (38)
Ron-El                 31      2000               47,XXY
  et al. (39)
Nodar                  39      1999               47,XXY
  et al. (40)
Tourmaye               NA      1997               47,XXY
  et al. (41)

Study                No.        Semen analysis         Sperm
                    cases                            retrieval

                        Autosomal chromosome abnormality

Current case          1          Azoospermia            Yes
Ananthapur            1          Oligospermia           No
  et al. (8)
Almeida               1     Oligoasthenozoospermia      No
  et al. (9)
Motoyama              1     Oligoasthenozoospermia      Yes
  et al. (10)
Joly-Helas            1          Oligospermia           No
  et al. (11)
Drouineaud            1          Azoospermia            Yes
  et al. (12)
Cai et al. (13)       1          Oligospermia           No
Belin                 1          Oligospermia           NA
  et al. (14)
Meschede              1          Oligospermia           NA
  et al. (15)
Veld et al. (16)      2          Oligospermia           No

                         Sex chromosome abnormality

Flannigan RK          1          Azoospermia            Yes
  et al. (17)
Abdel-Razic           9        Oligospermia (7)         No
  et al. (18)                  Azoospermia (2)
Kilic et al. (19)     3        Azoospermia (2)        Yes (2)
                               Oligospermia (1)
Spinner               1          Oligospermia           Yes
  et al. (20)
Sugawara              1          Azoospermia            Yes
  et al. (21)

                             Kleinfelter syndrome

Sabbaghian           134         Azoospermia         Yes (38)
  et al. (22)
Greco et al. (23)    38          Azoospermia         Yes (15)
Vicdan                1          Azoospermia            Yes
  et al. (24)
Ramasamy             68          Azoospermia         Yes (45)
  et al. (25)
Yarali               33          Azoospermia         Yes (22)
  et al. (26)
Kyono et al. (27)    17          Azoospermia          Yes (6)
Koga et al. (28)     26          Azoospermia         Yes (13)
Schiff               42          Azoospermia         Yes (29)
  et al. (29)
Okada et al. (30)    51          Azoospermia         Yes (26)
Seo et al. (31)      36          Azoospermia         Yes (10)
Vernaeve             50          Azoospermia         Yes (24)
  et al. (32)
Westlander           18          Azoospermia          Yes (5)
  et al. (33)
Yamamoto             24          Azoospermia         Yes (12)
  et al. (34)
Friedler             12          Azoospermia          Yes (5)
  et al. (35)
Cruger                1          Oligospermia           No
  et al. (36)
Poulakis              2          Azoospermia            Yes
  et al. (37)
Levron               20          Azoospermia          Yes (8)
  et al. (38)
Ron-El                1          Azoospermia            Yes
  et al. (39)
Nodar                 1          Azoospermia            Yes
  et al. (40)
Tourmaye             15          Azoospermia          Yes (8)
  et al. (41)

Study               Assisted    Pregnancy
                    Fertility

                    Autosomal chromosome abnormality

Current case           Yes         Yes
Ananthapur             No        Yes (3)
  et al. (8)
Almeida                No          Yes
  et al. (9)
Motoyama               Yes         Yes
  et al. (10)
Joly-Helas             Yes         Yes
  et al. (11)
Drouineaud             Yes         Yes
  et al. (12)
Cai et al. (13)        No          Yes

Belin                  Yes         Yes
  et al. (14)
Meschede               Yes         Yes
  et al. (15)

Veld et al. (16)       Yes         Yes

                      Sex chromosome abnormality

Flannigan RK           Yes         No
  et al. (17)
Abdel-Razic          Yes (2)     Yes (1)
  et al. (18)
Kilic et al. (19)    Yes (1)       No

Spinner                Yes         Yes
  et al. (20)
Sugawara               Yes         Yes
  et al. (21)

                     Kleinfelter syndrome

Sabbaghian          Yes (18)     Yes (4)
  et al. (22)
Greco et al. (23)   Yes (11)    Yes (11)
Vicdan                 Yes         Yes
  et al. (24)
Ramasamy            Yes (45)    Yes (33)
  et al. (25)
Yarali              Yes (22)     Yes (7)
  et al. (26)
Kyono et al. (27)    Yes (6)     Yes (5)
Koga et al. (28)    Yes (13)     Yes (3)
Schiff              Yes (29)    Yes (18)
  et al. (29)
Okada et al. (30)   Yes (26)    Yes (12)
Seo et al. (31)     Yes (10)     Yes (4)
Vernaeve               NA          NA
  et al. (32)
Westlander           Yes (5)     Yes (2)
  et al. (33)
Yamamoto            Yes (12)     Yes (4)
  et al. (34)
Friedler             Yes (5)     Yes (5)
  et al. (35)
Cruger                 Yes         Yes
  et al. (36)
Poulakis               Yes         Yes
  et al. (37)
Levron               Yes (8)     Yes (4)
  et al. (38)
Ron-El                 Yes         Yes
  et al. (39)
Nodar                  Yes         Yes
  et al. (40)
Tourmaye             Yes (7)     Yes (2)
  et al. (41)
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Title Annotation:CASE REPORT
Author:Kohn, Taylor P.; Clavijo, Raul; Ramasamy, Ranjith; Hakky, Tariq; Candrashekar, Aravind; Lamb, Dolore
Publication:Canadian Urological Association Journal (CUAJ)
Article Type:Case study
Geographic Code:1USA
Date:Sep 1, 2015
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