Endocrine Abstracts

Introduction: Ovarian insufficiency in Turner Syndrome (TS) classically presents with absent puberty and primary amenorrhea. However, a proportion attain menarche spontaneously, with later reproductive phenotypes ranging from early-onset secondary amenorrhea, to ongoing menstrual cycles, to spontaneous pregnancies. TS karyotypes include monosomy X (45,X); X chromosome mosaicism (e.g., 45,X/46,XX); and X chromosome rearrangements (e.g., ring X). The additional X chromosome gene dosage conferred by the non-45,X cell lines has been proposed to account for the improved reproductive function associated with non-45,X TS. However, it is unknown why some women (~15%) with non-mosaic 45,X TS present with relatively conserved ovarian function rather than the expected primary amenorrhea. We hypothesised that low-level, previously undetected non-45,X cell lines may explain this phenomenon, and that single nucleotide polymorphism (SNP) genomic arrays may provide the resolution to detect this.

Methods: We performed SNP arrays (Illumina Global Screening Array v3.0; UCL Genomics) in women with TS attending University College London Hospital. Inclusion criteria included those with 1) 45,X karyotype on 30 cell line peripheral lymphocyte analysis; and 2) evidence of conserved ovarian function as suggested by spontaneous pubertal development and menarche with at least one spontaneous clinical menstrual cycle. Genomic data were analysed in GenomeStudio 2.0 (Illumina; CNVPartition).

Results: A total of 11 women with 45,X TS and evidence of conserved ovarian function were recruited. Of these, 9 had a 45,X sex chromosome complement matching their documented peripheral karyotypes. Two women had mosaicism not detected by peripheral karyotype analysis: one with an isochromosome X (45,X[75%]/46,X,i(X)[25%]) and another a ring X (45,X[87%]/46,X,i(X)(p22q23)[13%]).

Conclusions: The relatively preserved reproductive function seen in this cohort of women with 45,X TS is potentially explained by previously undetected low-level chromosomal mosaicism in a minority. However, we show that the spontaneous ovarian function seen occasionally in 45,X TS is mostly not associated with peripheral low-level chromosomal mosaicism. Explanations for this must lie beyond X chromosome haploinsufficiency or tissue-specific mosaicism within the ovaries of women with 45,X karyotypes. More broadly, we demonstrate the value of SNP array analysis in TS when faced with unexpected genotype-phenotype associations.