Ovotesticular Difference of Sex Development: Genetic Background, Histological Features, and Clinical Management

Abstract

<b><i>Background:</i></b> Ovotesticular disorder/difference of sex development (DSD) refers to the co-presence of testicular and ovarian tissue in one individual. Childhood management is challenging as there are many uncertainties regarding etiology, gonadal function, and gender outcome. <b><i>Summary:</i></b> Ovotesticular DSD should mainly be considered in 46,XX children with atypical genitalia and normal adrenal steroid profiles. Various underlying genetic mechanisms have been described. Histological assessment of ovotestes requires expert revision and has many pitfalls. Neonatal sex assignment is essential, but as gender outcome is unpredictable, this should be regarded as provisional until a stable gender identity has developed. Therefore, it is crucial not to perform any irreversible medical or surgical procedure in affected individuals until adolescents can give their full informed consent. Gonadal function mostly allows for spontaneous pubertal development; however, fertility is compromised, especially in boys. Specific long-term outcome data for ovotesticular DSD are lacking but can be extrapolated from studies in other DSD populations. <b><i>Key Messages:</i></b> Management of ovotesticular DSD has changed in recent years, prioritizing the child’s future right for autonomy and self-determination. The benefits and pitfalls of this new approach have not been documented yet and require intensive monitoring on an international scale.

Dermatologic care of patients with differences of sex development

“…Ovotesticular DSD is a form of gonadal dysgenesis wherein ovarian and testicular tissue coexist, potentially within the same gonad. 125 Ovotesticular DSD should be suspected in a newborn with atypical genitalia, normal adrenal steroid levels with anti-Mullerian hormone levels above female reference range. 126,127 Diagnosis requires gonadal biopsy, and gonadectomy may be performed around puberty to avoid cross-gender hormone production and potential malignant transformation.…”

“…126,127 Diagnosis requires gonadal biopsy, and gonadectomy may be performed around puberty to avoid cross-gender hormone production and potential malignant transformation. 125 Testosterone levels may decline as tubules become atrophic, so male-identifying patients may need testosterone replacement. 128…”

“…126,127 Diagnosis requires gonadal biopsy, and gonadectomy may be performed around puberty to avoid cross-gender hormone production and potential malignant transformation. 125 Testosterone levels may decline as tubules become atrophic, so male-identifying patients may need testosterone replacement. 128 A female patient with ovotesticular DSD and atypical genitalia had significant pubic hair and menarche starting at 15, and was noted to have no acne or hirsutism despite elevated testosterone.…”

SOX3 duplication in a boy with 46,XX ovotesticular disorder of sex development and his 46,XX sister with atypical genitalia: Probable germline mosaicism

“…Though molecular etiology for most cases remains unknown, gain‐of‐function changes of pro‐testicular genes or their regulatory regions or insufficient expression of pro‐ovarian genes have been implicated in syndromic and nonsyndromic OT‐DSD. Copy number variations (CNV) including SOX genes ( SRY ‐related HMG‐box genes) or its regulatory regions, such as SOX3 ( SRY ‐box transcription factor 3, MIM# 313430), SOX9 ( SRY ‐related HMG box gene 9, MIM# 608160) and SOX10 ( SRY ‐box transcription factor 10, MIM# 602229) have also been described (Syryn et al, 2021; Vetro et al, 2015).…”

“…Ovotesticular disorder of sex development (OT-DSD) is characterized by functional ovarian and testicular tissues in the same individual, either in opposite gonads or in the same gonad (ovotestis), and a wide range of ambiguous genitalia. Karyotype is mostly 46,XX, followed by mosaics or chimeras with a Y-chromosome bearing cell line, and rarely 46,XY (Syryn et al, 2021).…”