Endocrine Abstracts (2011) 26 OC2.4

Genetic and molecular cytogenetic investigations in Turner syndrome patients with spontaneous pubertal development

R Rossetti1,2, C Castronovo2, C Cacciatore1,2, D Rusconi2, V Calcaterra3, P Finelli1,2, D Larizza3 & L Persani1,2

1Dipartimenti di Scienze Mediche e di Biologia e Genetica, Università degli Studi di Milano, Milan, Italy; 2IRCCS Istituto Auxologico Italiano, Milan, Italy; 3Dipartimento di Pediatria, Università di Pavia, Pavia, Italy.

Spontaneous puberty occurs in a subset of Turner syndrome (TS) patients with significant 45,X/46,XX mosaicism. This observation leads to the belief that haploinsufficiency of still unidentified genes on the X chromosome is the cause of the accelerated follicle atresia in TS. Examination of particular X chromosome rearrangements/deletions led to the identification of 2 Xq and 1 Xp loci associated to the ovarian defect in TS. The availability of new generation genetic and cytogenetic investigations leads us to reexamine this issue on 39 TS patients aged 12–46 years. Spontaneous menarche (SM) was registered in 6 of them and 33 had primary amenorrhea (PA). Conventional techniques assigned the 45,X karyotype to 2/6 with SM and 28/33 with PA. Array CGH analysis was performed on blood DNA of 6 SM cases and 6 PA, used as negative controls, and revealed the unique case of a 45,X TS woman with SM harboring a duplication containing entirely the only BMP15 gene. The BMP15 duplication was confirmed by FISH analysis and Taqman RT-PCR excluded significant 45,X/46,XX mosaicism in vaginal and buccal epithelia. Interestingly, this 45,X TS patient with a double dose of the only BMP15 gene had regular menses for >4 years. Array CGH and FISH analyses revealed the presence of mosaicism at variable levels in the other 5 TS cases with SM and at very low levels (1–10%) in those with PA, including those previously karyotyped as 45,X. Therefore, our data indicate that likely all TS patients are indeed mosaics but only those with a 46,XX cell line above 10% in circulating leukocytes are likely to have spontaneous puberty. A double dose of the only BMP15 gene at Xp11.2 appears sufficient to support spontaneous menarche in a TS patient, but double dose of other X-linked genes is indeed required to sustain prolonged ovarian function.

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