Why the Confusion?

Mixed gonadal dysgenesis (MGD) is a difference of sex development (DSD) often confused with other conditions. The phenotypic heterogeneity and various interpretations of the MGD definition in the literature contribute to a poor understanding of the condition, even among urologists. In fact, this has even led some to recommend the term MGD be discontinued altogether in favor of language inclusive of descriptors of the anatomy and chromosomes such as “45,X/46,XY with atypical genitalia, dysgenetic testis, and streak gonad.” To help clarify these points of confusion and to provide urologists with diagnostic and management considerations for affected individuals, we recently performed a narrative review of the literature.¹ We included 50 articles in our review. Key points are summarized in the Table.

Table. Review Topics With Key Points for the Urologist Regarding Mixed Gonadal Dysgenesis

MGD is characterized by a mosaic karyotype (45,X/46,XY with rare exceptions), a unilateral streak gonad, and a unilateral dysgenetic testis at varying levels of descent. Unlike ovotesticular DSD (usually nonmosaic karyotype, differentiated testicular, and ovarian tissue), there are no differentiated ovarian elements. Unlike complete gonadal dysgenesis (bilateral streak gonads, nonmosaic karyotype, typical female external genitalia), there is at least some element of gonadal development (at minimum, unilateral). Unlike partial gonadal dysgenesis (nonmosaic karyotype, bilateral dysgenetic testes), there is unilateral testicular dysgenesis. In individuals with MGD, the degree of dysgenesis is asymmetric. Müllerian structures (eg, hemiuterus) are common and often ipsilateral to the streak gonad. The presence of atypical genitalia is requisite, but there is a wide phenotypic spectrum of both internal and external genitalia. The most common phenotypic finding is proximal hypospadias with perineal division of the corpus spongiosum and ventral curvature.

A second misconception is that the 45,X/46,XY karyotype is synonymous with an MGD diagnosis. This is not the case, and, in fact, this mosaic karyotype can be found with typical female or male external genitalia and outside the DSD setting. When a 45,X/46,XY mosaic karyotype is found with typical female external genitalia, individuals should be diagnosed with Turner syndrome with Y chromosome material. Interestingly, the most common phenotype associated with the 45,X/46,XY karyotype (as reported from amniocentesis data to be the case 89%-95% of the time) is typical male external genitalia. Even among “identical” twins, the phenotype can vary and sometimes result in different sexes of rearing.

A Hypothetical Case of Mixed Gonadal Dysgenesis From Birth to Puberty

Patient X was born to a family expecting male sex from prenatal testing. At birth, perineal hypospadias with severe chordee and bilateral nonpalpable gonads were noted. A multidisciplinary DSD team consisting of a pediatric urologist, pediatric endocrinologist, certified genetic counselor, and clinical psychologist was consulted. Peripheral blood chromosome analysis with expanded cell count (50 cells) was performed and revealed 45,X/46,XY mosaicism. Abdominopelvic ultrasound noted possible müllerian structures, an intra-abdominal right gonad, and no identifiable left gonad. Hormone studies performed at 4 weeks of life revealed antimüllerian hormone of 26 ng/mL and testosterone of 100 ng/dL. With the help of the multidisciplinary team, the parents designated the baby as male sex.

At 6 months of life, he was taken for an exam under anesthesia and diagnostic laparoscopy. This revealed a left streak gonad and right intra-abdominal testis with a spheroidal morphology and evidence of diminished structural integrity of the tunica albuginea (Figure).² A hypoplastic uterus and bilateral fallopian tubes were noted, with possible wolffian structures on the right. Examination under anesthesia noted proximal hypospadias with a perineal meatus and severe ventral curvature. The streak gonad was removed, and the right gonad was biopsied. Isolated spermatogenic germ cells were found in the right dysgenetic gonad, and experimental gonadal tissue cryopreservation was performed (hypothetically available at that time), as desired by the family. There was no evidence of premalignancy. Over a series of subsequent surgeries, the right gonad was brought into a low inguinal/high scrotal location where it could be palpated, and hypospadias repair was performed in 2 stages after preoperative testosterone stimulation. Müllerian structures were left in place.

Patient X continued to follow up annually with the multidisciplinary DSD team. Given the higher rate of Turner-associated multisystem comorbidities present in individuals with MGD compared to the general population (short stature, hearing loss, hypothyroidism, cardiac and renal anomalies, and abnormal neuropsychiatric evaluation), he was also referred to the Turner clinic for surveillance. His growth velocity slowed, and he was started on growth hormone injections at age 6. His right gonad remained palpable without masses and was followed with a physical exam alone. At age 12 he started showing signs of early puberty. Labs showed a low testosterone and elevated gonadotropins. Diagnosis disclosure occurred gradually with interdisciplinary support. He identified as male. It was discussed with patient X and his family that puberty may need to be augmented with testosterone. Sperm cryopreservation will be offered in the future if desired. The family has asked questions about his future fertility and is requesting the removal of his uterus. They were counseled that technology is not yet available for future use of his cryopreserved immature germ cells and that assisted reproductive technology through testicular sperm extraction is rare but reported. A shared decision-making approach with his input will be utilized to discuss the removal of his müllerian remnants. A formal health care transition will eventually be initiated with emphasis on his future fertility, sexual health, and psychosocial well-being.

Putting It All Together

MGD exists on a wide phenotypic spectrum, and management considerations reflect this heterogeneity. Care for individuals with MGD is lifelong and complex. Decisions should be made in a multidisciplinary setting with psychological support.

Acknowledgments

We thank co-authors Victoria Lee, Allison Goetsch Weisman, Ilina Rosoklija, Josephine Hirsch, Jax Whitehead, Abdullah Almaghraby, Jaclyn Papadakis, Briahna Yuodsnukis, and Diane Chen for their substantial contributions to the writing of the review.