Mixed Gonadal Dysgenesis

Gonad is the generic term used to indicate the organs that produce sperm and egg cells, i.e., the testicles and the ovaries, respectively. These organs also produce sex hormones (testosterone, oestrogen, progesterone). Mixed gonadal dysgenesis is characterized by the development of dysgenetic gonads, i.e., malformed, of varying shapes, and often different from each other in an individual. The internal and external reproductive organs can also vary greatly. For example, at birth a person can show typically male genitalia associated with hypospadias (opening of the urethra anywhere on the penis, the scrotum, or the perineum, i.e., area between the scrotum and anus) and/or cryptorchidism (testicles that do not fall into the scrotum), or typically female internal and external genitalia, together with a testicle in the abdomen and an unformed gonad. Finally, there may be atypical genitalia, that is, neither typically male nor female.

The frequence of this Variation of Sex Characteristics (VSC)/Difference of Sex Development (DSD) is estimated at 1/10,000-1/20,000, but it is difficult to establish it with certainty, precisely because of its extreme variability of forms.

Genetic traits
Mixed gonadal dysgenesis is a VSC/DSD characterized by chromosomal mosaicism, i.e., the presence of partly male and partly female sex chromosomes (for example, 45, X0/46, XY or 46, XX/46, XY) in the different cells of the body, due to a genetic alteration that develops right after conception.

Identification
Owing to the presence of atypical genitalia, this VSC/DSD is generally identified neonatally. This will bring up the issue of gender assignment, which is determined by multiple factors (such as the appearance of external genitalia, the degree of fetus exposure to male hormones during pregnancy, the expected functioning of the gonads after puberty). Of course, only the individual will be able to express their gender identity, which may or may not be congruent with the sex assigned at birth. It is important to identify any anatomical variations at birth – especially in the urinary tract – which could endanger the newborn, thus requiring immediate surgery.

The condition is identified as mixed gonadal dysgenesis by karyotyping, examining at least 50 cells from the person. Although there is no unanimous consensus on what criteria define mixed gonadal dysgenesis, through genetic testing, the classification currently includes individuals with a 45,X0/46,XY or 46,XX/46,XY karyotype. In persons with 45,X0 karyotype mosaicism, the differential diagnosis with Turner syndrome (characterized by 45,X0 karyotype) is significant. The correct classification of the condition is essential to predict the future oncological risk and the fertility potential of the individual.

Medical options
It is difficult to find universal treatment strategies because mixed gonadal dysgenesis occurs in quite different ways. 

Since this VSC/DSD is associated with an increased risk of developing tumours in the dysgenetic gonads, gonadectomy (removal of the gonads) was the universally adopted strategy in the past. However, the most recent international recommendations advise postponing partially reversible or irreversible medical-surgical interventions to a time when the intersex person may express their informed consent regarding their body. Therefore, professionals should assess individual cancer risk, and make decisions on a case-by-case basis, considering the history of the person with mixed gonadal dysgenesis. If the risk is low, gonadectomy should be postponed until the person will be able to express their consent more consciously, also based on their gender identity.

In any case, whether they are in the abdomen or in the scrotum, it is essential to have annual check-ups of these organs via magnetic resonance or ultrasound. If there are any lesions, an exploratory laparoscopy –a surgical inspection of the affected gonad– or a gonadectomy might be necessary.

In people with mixed gonadal dysgenesis the onset of puberty is sometimes spontaneous, especially if it develops along typically male lines. In any case, therapy with sex hormones (oestrogen or testosterone) may be necessary to induce puberty congruent with the person's gender identity. Replacement therapy must also be maintained in adulthood for the overall health of the individual, bones in particular.

The issue of fertility and its preservation should be addressed in counselling. In fact, germ cells (potentially usable for reproduction) can be found in dysgenetic gonads. However, the evolution of these cells over time, and their reproductive potential is difficult to determine, and many adults assigned to the male gender at birth show azoospermia, i.e., they do not seem able to produce sperm.

Bibliography 
Lee PA et al. Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care. Hormone research in paediatrics. 2016;85:158-180
Lindhardt Johansen M et al. 45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function--a retrospective longitudinal study. The Journal of clinical endocrinology and metabolism. 2012 Aug;97(8):E1540-9 
Weidler EM et al. Clinical management in mixed gonadal dysgenesis with chromosomal mosaicism: Considerations in newborns and adolescents. Seminars in pediatric surgery. 2019 Oct;28(5):150841 

Further Links 
Orphanet. 45,X/46,XY mixed gonadal dysgenesis