Letter to the Editor: “Clinical but Not Histological Outcomes in Males With 45,X/46,XY Mosaicism Vary Depending on Reason for Diagnosis”

We read with great interest the article recently published by Ljubicic et al. (1) concerning the outcomes of males with 45,X/46,XY mosaicism based on the reason for diagnosis. The originality of this article relies on a number of histological assessments in adulthood and direct comparison between patients diagnosed because of genital anomalies and patients diagnosed for other reasons. This multicenter retrospective study corroborates previous studies that underlined the possibility of growth failure, testicular impairment, risk of tumor development, and infertility in these patients even in the absence of variations in genital development (2–4).

However, we consider that the conclusions of this paper are not completely supported by the data presented. Indeed, the authors state that 45,X/46,XY males diagnosed for reasons other than genital anomalies had better health outcomes than ones diagnosed on the basis of genital differences, whereas results on growth, associated comorbidities, and gonadal dysgenesis were found at similar frequencies.

Indeed, when final height corrected for target height is considered, the groups have similar reduced heights (−2.49 and −2.21 SD scores) with no statistical difference. This is particularly important regarding data previously published by our group that showed stunted growth in patients diagnosed both prenatally and postnatally, with neither diagnosis due to a genital anomaly and with growth curves (in SD scores) similar to those shown in the article by Ljubicic et al. (1). Growth was altered starting from the antenatal period and worsened at puberty in relation to a poor pubertal growth spurt (2). This growth pattern was also shown in cohorts of 45,X/46,XY patients with genital anomalies (3, 4). In addition, patients appear to have a similar GH response with or without genital anomalies (1–3).

Comorbidities (i.e., cardiac or renal malformations) were found in both groups, with no statistical difference and at similar occurrences to those reported in our previous study (2).

Regarding gonadal function, it would have been relevant to have inhibin B levels that might have shown a correlation with histological findings. In addition, we regret the absence of any comparison with cytogenetic findings, particularly in gonadal tissues, providing evidence of a correlation between gonadal histology and an AZF microdeletion or Y chromosome structural anomaly (isodicentricism, Yq deletion), both of which are frequently associated with 45,X/46,XY mosaicism (2, 3), as previously suggested (5). Of note, the results seem to corroborate the hypothesis of a progressive alteration of gonadal phenotype toward dysgenesis over time, with the possibility of accelerated loss of the Y chromosome and emergence of the 45,X cell line in germ cells going through mitotic divisions. Thus, it is likely that the seminiferous tubules with focal spermatogenesis maintained 46,XY spermatocytes, as in Klinefelter syndrome (6). These results open possibilities for fertility preservation for all of these patients, but they also induce an ethical dilemma of risk of recurrence of the loss of an aberrant Y chromosome in offspring.

In conclusion, we believe that all patients with a 45,X/46,XY karyotype should be screened for comorbidities and followed up medically with a similar protocol, regardless of the reason for diagnosis.

Additional Information

Disclosure Summary: The authors have nothing to disclose.

References and Notes