46,XX ovotesticular disorder of sex development (DSD):-Duplication of the XX Sr region upstream of the critical testicular gene SOX9

Abstract

Objectives: A term baby had a 2cm phallus (mild chordee), perineal urogenital opening, bifid fusion of labioscrotal folds containing palpable gonads and no other dysmorphic features. Karyotype was 46,XX (no Y chromosome). FISH was negative for SRY and Y centromere probes. Sinugram indicated a large prostatic utricle. Surgical assessment on day 11: no fallopian tubes/uterus; vas deferens, vessels entered the inguinal rings; gonads macroscopically were bipolar ovotestes, histologically ovarian/testicular tissue in upper/lower poles. A male gender of rearing was decided. A 2-stage penile reconstruction and urethroplasty was performed. Gender confusion, rather than dysphoria, was apparent from 4 years, amidst complex psychosocial circumstances. Breast tissue developed prior to 8 years with Tanner stage 1 pubic hair/genitalia. Leuprorelin testing was pubertal. Ultrasound indicated symmetrical, prepubertal sized gonads. α-FP and β-HCG were low. At 9 years (height 8th percentile, bone age advanced for a male), puberty is suppressed with depo leuprorelin. Gender identity will continue to be assessed. Objective:-Genetic analysis of this patient with SRY-negative 46,XX ovotesticular DSD. Methods: Genomic DNA analysed (i) Targeted Massively Parallel Sequencing (MPS) DSD panel (64 diagnostic genes including SOX9) (ii) Single-nucleotide polymorphism (SNP) array analysis (iii) Multiplex Ligation-dependent Probe Amplification (MLPA) - known DSD genes, including SOX9 and upstream regulatory regions. Results: No causative variations were identified by the MPS DSD panel. SNP array detected a heterozygous interstitial duplication at 17q24.3, 519-623Kb upstream of SOX9. MLPA confirmed (i) SRY-negative 46,XX DSD (ii) a duplication upstream of SOX9. This covers the XX SR/RevSex (XX sex reversal) region, but does not extend to XY SR at the 5' end, nor the TESCO (testis-specific enhancer of SOX9 core), or the SOX9 gene at the 3' end. Conclusions: The SOX9 enhancer duplication likely led to high levels of SOX9 in the developing ovary, causing ovotestes. An increased risk of germ cell cancer is not expected. The testicular/ovarian components may be hormonally active. Ongoing assessment of gender identity will be crucial to guide management.L6279782332019-06-11 <br />