Commentary on “PGT or ICSI? The impression of NGS-based PGT outcomes in nonmosaic Klinefelter syndrome”

Klinefelter syndrome (KS), described for the first time in 1942, is the most common chromosome aneuploidy in men, affecting from 1/500 to 1/1000 newborn males, and it frequently causes azoospermia. In the majority of cases, KS patients present a nonmosaic karyotype 47,XXY or a mosaic 47,XXY/46,XY karyotipe.1 KS is characterized usually by gynecomastia, small testes, and alteration of germinal epithelium and Sertoli cell.

The retrospective study by Tong et al.2 evaluated the clinical outcomes of patients with nonmosaic KS and nonobstructive azoospermia (NOA) undergoing preimplantation genetic test (PGT) with frozen-thawed testicular sperm. The study population included 18 couples, of these 13 presented euploid embryos and completed 14 frozen embryo transfer cycles. Ten couples had clinical pregnancies, and 6 of them had already delivered 5 healthy babies and 1 monozygotic twin. There were also 4 ongoing pregnancies and 2 biochemical pregnancies. The authors concluded that paternal genetic risk of sex chromosome abnormalities in nonmosaic KS offspring is extremely low in men with KS.

In this article, microsurgical testicular sperm extraction (micro-TESE) was performed and spermatozoa were retrieved successfully from all male cases. Indeed, in nonmosaic KS the main method to retrieve spermatozoa is micro-TESE. Several studies have reported that successful sperm retrieval in KS patients by conventional TESE and by micro-TESE is defined between 42% and 57%.3 In the present study, the sample included males with a median age of 29 and it is widely accepted that younger KS patients have a great sperm retrieval rate (SRR) by micro-TESE. In young males (16–30 years) SRR is 40%–70% and may be attributed to fewer lesions in the testicular tissue.4 Obviously, the spermatozoa obtained from KS men were cryopreserved.

We agree with Tong et al.2 that cryopreservation allows a better planning of ICSI cycles so as to make the cycle timing most favorable for patients. A disadvantage of conventional spermatozoa freezing/thawing methods could be sperm loss during the process of repeated centrifugation and washing. Future directions to avoid sperm loss in case of rare spermatozoa retrieved are single sperm cryopreservation systems (cryotop, cryostrip, and cryoleaf).

The authors obtained an euploidy blastocysts rate of 67% and none of the aneuploids and mosaics embryos had chromosomal sex aneuploidies. Some studies showed that nonmosaic KS patients had a 47,XXY karyotype (analyzes of peripheral lymphocytes, buccal tissue, and peripheral blood) while the testis presented a mosaicism karyotype.

Indeed, KS men have focal spermatogenesis from euploid spermatocytes and only 46,XY spermatocytes can achieve meiosis. Therefore, since testicular injury status varies in individual KS patients, it could be a good marker. These genetic findings have been further clarified in a study by Sciurano et al.,5 who detected spermatogenesis foci in testicular biopsies of 6/11 men with nonmosaic KS. Whereas the majority of seminiferous tubules were devoid of germ cells, 8%–24% contain germ cells. Same authors confirmed by FISH the euploidy of spermatocytes and the ability to form haploid gametes.

As Tong et al.2 discussed, the possibility of KS men of transmitting chromosomal abnormalities to offspring makes doubtful the safety of ICSI treatment. In fact, the analysis of sperm karyotype from KS showed that the frequency of sex chromosomal disomy in male gametes is 3% in contrast to 1% in infertile male.

However, an increased risk of sex chromosome trisomy seems unlikely, as the embryos have the capacity to correct itself. In 1998, Reubinoffet et al. reported a birth after testicular fine needle aspiration combined with ICSI and PGT in a case of nonmosaic KS.

Greco et al.6 already in 2001 published the birth of 21 children born from nonmosaic KS, with only one child with a 47,XXY karyotype. The same author in 2013 describes the birth of 16 children from nonmosaic KS suggesting that PGT could be avoid.7 Probably in the testis, nonmosaic Klinefelter can be converted locally to mosaic during premeiotic germ cell multiplication, however subsequent germline can be corrected, concluding that ART in nonmosaic KS patients is relatively safe.

Interestingly, the successful fathering of 60 children has been achieved by TESE and ICSI in men with KS. Karyotype studies that were performed in approximately 50 children revealed no chromosomal abnormalities. However, the risk of KS transmission remains: a case report showed a 47,XXY fetus conceived after ICSI of spermatozoa from a patient with KS nonmosaic gametes.8

The analysis of the origin of sex chromosome trisomies is not straightforward, a variety of nondisjunctional mechanisms involving sex chromosomes have already been identified, some of which appear to be associated with aberrant recombinations dependent by maternal age.

How it was highlighted in a multicenter study by Mazzilli et al.9 that analyzed data from 7549 biopsed blastocysts, a significant correlation was only found between 47,XXY karyotype and maternal age.8

Tong et al.2 concluded that in young nonmosaic KS, the ICSI procedure is comparably effective to PGT but more economical. Furthermore, it is well known that biopsy during the process of PGT could increase the risk of abortion due to injury of the embryo. In the future, KS couples will benefit from a noninvasive PGT technique.10 Regardless of ICSI or PGT treatment undertaken by KS couples, the prenatal genetic diagnosis is always recommended.

COMPETING INTERESTS

All authors should declare no competing interests.