Extra X chromosomes show ‘dose–response’ impact on the endocrine system

medwireNews: Research has demonstrated a dose–response relationship between the number of supernumerary X chromosomes in young people with high-grade aneuploidies (HGAs) and the level of endocrine system impairment experienced.

“The increase in the number of extra-Xs was associated with a progressive adverse effect on height, pubertal development, testicular volume and function, adrenal steroidogenesis, and thyroid function”, report Daniele Gianfrilli, from the Sapienza University of Rome in Italy, and co-authors in the Journal of Clinical Endocrinology & Metabolism.

The team examined the impact of HGA in 23 affected patients and compared their development with that of 46 age-matched individuals with 47,XXY Klinefelter syndrome (KS).

Specifically, the researchers classified the patients according to their number of supernumerary X chromosomes into three groups: 46 patients with KS and one extra X chromosome and 10 HGA patients with the 48,XXYY karyotype; five HGA patients with two extra X chromosomes, manifesting as either the 48,XXXY (n=4) or 49,XXXYY (n=1) karyotype; and eight HGA patients with the 49,XXXXY karyotype.

The average age of the HGA group was 18.5 years and there was a significant delay in pubertal stage in patients with HGA versus their age-matched KS counterparts.

Compared with the KS group, the HGA group had a significantly greater weight standard deviation score (SDS, 1.20 vs –0.15) and BMI SDS (1.03 vs –0.55) and there was a trend towards shorter height SDS, but there was no significant correlation between these measures and the number of X chromosomes.

There was a significant linear correlation, however, between the number of supernumerary X chromosomes and mean ultrasonographic bitesticular volume (US-BTV), which was significantly lower in patients with HGA than KS (3.00 vs 5.90 mL). The mean volume was 5.93 mL for HGA and KS patients with one additional X chromosome versus 1.26 mL for HGA patients with four additional X chromosomes. Penile length was not significantly related to the number of X chromosomes.

Gianfrilli et al also identified a relationship between basal levels of some hormones and supernumerary X chromosomes. These included a reduction in free thyroxine levels and an increase in the ratio of free triiodothyronine to free thyroxine with increasing numbers of X chromosomes, but this did not result in a “compensatory rise” in thyroid-stimulating hormone, they write.

In addition, an increasing number of X chromosomes was associated with a linear decrease in serum testosterone but a linear increase in adrenocorticotropic hormone (ACTH), the latter being accompanied by a reduction in dehydroepiandrosterone sulphate and androstenedione levels.

“Consistently, the cortisol/ACTH ratio, a marker of adrenal responsiveness, was affected by the number of extra-Xs and, as such, was lower in the HGA group than in the KS group, although serum cortisol levels were not different between the groups”, the researchers observe.

The team did not find a linear relationship between X chromosome numbers and metabolic parameters, and although the HGA group had higher basal and 2-hour post-oral glucose tolerance test levels of glucose and insulin than the KS group, there was no difference in glycated haemoglobin between the two groups.

Echocardiography also demonstrated a linear relationship between increasing numbers of X chromosomes and impact on both cardiac structure (greater reductions in left and right ventricular end-diastolic diameter) and cardiac function (greater reduction in ejection fraction), thus “linking cardiac structure alterations with functional changes”, write Gianfrilli and co-authors.

Finally, the researchers compared the HGA patient group with a second cohort of 46 patients with KS who were matched by pubertal stage. This confirmed that there were significant correlations between the number of X chromosomes and gonadal development, thyroid function, adrenal function and echocardiographic markers. But there was no significant association with testicular endocrine function by Tanner stage.

“To date, no guidelines are available for the management of these complex syndromes”, Gianfrilli et al conclude.

“As such, a better understanding of their intrinsic characteristics could guide medical practitioners toward earlier identification of complications and thus allow for more tailored management and appropriate treatment of each patient”, they suggest.

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Endocrinol Metabol 2023; doi:10.1210/clinem/dgad730/7513226
Martin Savage
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