Deletion upstream of SOX9 in a 46 XY female without campomelic dysplasia and in her mother with premature ovarian failure

MIRTA GRYNGARTEN; MARCELA VENARA; BÁRBARA CASALI; MARÍA EUGENIA ESCOBAR; DEL REY GRACIELA; MARÍA ANGELES MORI ALVAREZ; ANDREA ARCARI; RODOLFO DE BELLIS; JULIAN NEVADO; PILAR BARRUZ; SOL RODRIGUEZ AZRAK; ADRIANA BOYWITT; PABLO LAPUNZINA

Washington

Congreso; 10th International Meeting of Pediatric Endocrinology; 2017

Sociedad Latinoamericana de Endocrinología Pediátrica

SOX9 acts as a testis-inducing transcription factor downstream of SRY essential for the differentiation of bipotential gonads into testes and chondrocytes. SOX9 haploinsufficiency due to mutations or genomic deletions in 17q24.3 cause campomelic dysplasia in combination with sex-reversal in 75% of 46,XY individuals. SOX9 expression is regulated by several long-distance enhancers/cis regulatory elements whose disruption causes phenotypic variability in bone disease and disorders of sex development.We report a deletion of SOX9 encompassing the known 32.5kb sex-reversal region presents in a 46,XY female with delayed puberty. The same deletion was found in her 46,XX mother with premature ovarian failure.Case Report: A 14.5 yr-old girl was referred for incomplete pubertal development. Familial background: mother 36 yr-old with polycystic ovaries and amenorrhea since 33 yrs of age, maternal cousin with menopause at 36 yrs, and grandmother with delayed puberty. At clinical examination: her height and weight were at 3rd-10thcentiles, pubertal development B I/III, PH II, and normal female external genitalia. No skeletal malformations were observed. Laboratory results: LH 44 IU/L; FSH 128 IU/L; E2 10pg/mL;T 41ng/dL. Pelvic ultrasound detected a small uterus (29x7x14 mm) and two images corresponding to small gonads (18 and 16 mm). High levels of gonadotrophins (repeated one month apart), and low AMH (< 1.2 pmol/L) confirmed complete gonadal dysgenesis. Karyotype was: 46,XY. Parental karyotypes were normal. Prophylactic gonadectomy was performed, histological analysis showed bilateral streak without germ cells. Lumbar Spine densitometry detected decreased bone mineral density.SRY, NR5A1 and AR did not reveal mutations. Copy-number variation using CYTOSNP 850K (Illumina) and Karyoarray® (8x60K Agilent based CGH) showed a 260kb deletion at 420kb upstream-SOX9 in the patient and her mother; According to the Databases: arr[hg19]17q24.3(69436041-69696519)x1.Conclusion: Our results detected a new case of 46,XY complete gonadal dysgenesis without campomelic dysplasia, and suggest for the first time an association between a deletion in the SOX9 regulatory sequences and premature ovarian failure in a 46,XX female.