SOX9 – 46,XX Ovotesticular Disorder of Sex Development

A 2019 report describes two 46,XX siblings, both SRY-negative, presenting with histologically confirmed testicular and ovarian tissue and varying degrees of masculinization due to a ~150 kb duplication upstream of SOX9. This duplication spans the minimal critical 46,XX sex reversal region and segregates in the father (46,XY, unaffected) and possibly in a maternal aunt, indicating autosomal dominant transmission with variable expressivity (PMID:31661700). The phenotype ranges from overt female appearance to varying masculinization, highlighting incomplete penetrance.

Genetic evidence is limited to a single kindred with two affected probands carrying the same enhancer duplication. Functional evidence demonstrates that increased copy number of the upstream regulatory element is sufficient to drive overexpression of SOX9 and trigger testicular differentiation in the absence of Y-chromosomal determinants. No conflicting reports have been published.

Key Take-home: SOX9 enhancer duplications constitute a limited but actionable molecular diagnosis in SRY-negative 46,XX ovotesticular DSD cases, guiding genetic testing and family counselling.

References

• Hormone research in paediatrics • 2019 • Similar Cause, Different Phenotype: SOX9 Enhancer Duplication in a Family. PMID:31661700

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