Clinical aspects of 49 infertile males with 45,X/46, XY mosaicism karyotype: A case series

Abstract

Disorders of sex development (DSD) are congenital abnormalities as an atypical development process in either gonadal or chromosomal structure. It is the cause of the abnormality in phenotype and characteristics. Chromosomal analysis plays an important role in the DSD determination. 45,X/46,XY mosaicism is a rare karyotype, and its prevalence is about 1.5 in 10,000 newborns. It affects the growth, hormonal balance, gonad development and histology. All data such as height, male general appearance, testis size and volume, external genitalia, spermogram and hormonal levels, testis pathology, Y chromosome microdeletion and karyotype, and assisted reproductive technology (ART) outcome were recorded based on patients profile and history. We investigated 64 infertile males with 45,X/46,XY mosaicism. Fifteen cases who had structural abnormalities in Y chromosome were excluded. From 49 available spermogram, 21 cases reported as azoospermic men, while 28 of them classified as nonazoospermic patients in which four of them displayed normal spermogram. According to hormonal evaluation, there were no significant differences between azoospermic and nonazoospermic groups. In azoospermia, only three couples underwent an ART cycle in which all of them failed. From 14 nonazoospermic cases who entered into the ART cycle, three cases experienced a successful pregnancy that one of the prosperous outcomes was twins. In 45,X/46,XY cases, both 45,X and 46,XY cell lines are seen. Various distributions of both cell lines can reflect a wide range of phenotypes that may be the most comprehensive evaluation in infertile males with 45,X/46,XY karyotype. It assumes that karyotyping as a main diagnostic test can enable us to find these rare cases.

45,X/46,XY Mosaicism and Normozoospermia in a Patient with Male Phenotype

“…Reviewing the literature, 45,X/46,XY mosaicism in males usually results either in azoospermia or severe reduced sperm production, elevated gonadotropins, and short stature [3, 4, 6, 9, 12]. Layman et al [3] presented three adult cases with 45,X/46,XY mosaicism in which one adult showed growth retardation as well as elevated gonadotropins and azoospermia.…”

“…In peripheral blood lymphocytes, the third case demonstrated 26% 45,X cells compared to the 6% 45,X cells in the present case. Interestingly, Mohammed Lashkari et al [6] reported 49 infertile males with 45,X/46,XY mosaicism in peripheral lymphocytes of whom, four cases were normozoospermic. Nonetheless, two of them presented with varicocele and the third had a high DFI.…”

“…The incidence of sex chromosomal mosaicism, including 45,X/46,XY, is estimated to be 1.5 of 10,000 [6] to 1.7 of 10,000 [7], thus indicating that it is a rare condition. Female phenotypes are overrepresented [8] as they may be diagnosed due to a host of causes whereas males are only diagnosed when encountering infertility complications during adulthood, or growth retardation or genital abnormalities during childhood [1, 2].…”

“…In addition, increased risk of developing cardiovascular diseases and cancer among 45,X/46,YX mosaic karyotypes have been reported [9, 10]. To date, case reports or series [1–4, 6, 9, 11, 12] and larger studies [8, 13, 14] regarding 45,X/46,XY mosaic males have described growth retardation, elevated gonadotropins, azoospermia or severe oligozoospermia, and high sperm DNA fragmentation index (DFI). We herein present a case with 45,X/46,XY mosaicism and infertility despite normal semen parameters and normal DFI.…”

Pedigree analysis of two brothers with severe oligozoospermia caused by maternal inv(X) (p22.3, q22) chromosome abnormality

“…At present, four major X chromosome aberrations have been identified: (a) X chromosome numerical abnormality: for example, Klinefelter syndrome, 45, X/ 46, XY (Ropke & Tuttelmann, 2017). (b) X chromosome structural abnormality, involving X chromosome translocation, such as t (x; 18) (Q11; p11.1) and t (x; 14) (p11.4; P12) (Hwang et al, 2007; Mohammadpour Lashkari et al, 2018; Perrin et al, 2008); (c) CNV (Copy number variations) affecting X chromosome (Yatsenko et al, 2015); and (d) gene point mutation interfering with X chromosome, such as Rhox, tex11 and miRNA (Borgmann et al, 2016; Sha et al, 2018; Sosa, Flores, Yan, & McCarrey, 2015). X chromosome inversion is rare, and studies have shown that the phenotypic effect of X inversion is very heterogeneous (Madan, 1983).…”