The portal for rare diseases and orphan drugs

Estimated prevalence is approximately 1/20,000 births. The disorder may account for less than 3-10% of all DSD.

About 20% of affected individuals are diagnosed before 5 years of age. Diagnosis is commonly made during the neonatal period due to atypical genitalia. Some present later with abnormal pubertal development. Signs include: lower abdominal pain, gynecomastia, inguinal hernia, an inguinoscrotal mass, cryptorchidism or amenorrhea/periodic hematuria depending on sex assignment. Most affected individuals have female internal genitalia (uterus, hemi-uterus or rudimentary uterus). Development of external genitalia ranges from apparent female to male genitalia with hypospadias or isolated bilaterally undescended ovotestes (gonads containing ovarian and testicular elements). Infertility is common in men whereas women have some potential for fertility. Malignant gonadal tumors are rare (less than 3% of cases).

The cause of 46,XX ovotesticular DSD is not elucidated for the majority of cases. A small proportion of individuals have a translocation of a Y chromosome fragment, including the SRY gene, to an X or another chromosome but most individuals (65%) are SRY negative. Copy number variations, resulting in duplication or deletion of regulatory genes, have been described for SOX9 (4 families), SOX3 (1 individual) and NR0B1 (1 individual). A recurrent NR5A1 variant has been reported in a number of unrelated individuals. Some individuals may have a chromosomal mosacism or a chimerism that results in the presence of Y chromosome containing cells in the gonad.

The assessment and diagnosis of DSD is complex. Consensus guidelines recommend referral to a specialist center for examination and treatment. Initial investigations include chromosome analysis and an ultrasound scan to check the internal reproductive organs. Patients who present later in life have higher differentiation of genitalia. Diagnosis requires careful anatomical assessment via imaging modalities and/or laparoscopy. Biochemical endocrine investigation, cytogenetic and molecular genetic tests are required. Definitive diagnosis is based on gonadal histology (testicular and ovarian tissue).

Differential diagnoses include other DSD, including mixed gonadal dysgenesis and 46,XX testicular DSD. NR2F2 gene variants have been described in individuals with a 46,XX testicular / ovotesticular DSD phenotype associated with cardiac defects, some with congenital diaphramatic hernia and blepharophimosis-ptosis-epicanthis inversus. Rarely, others include palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (caused by biallelic RSPO1 gene variants), SERKAL syndrome (recessive WNT4 variants).

Prenatal diagnosis may be possible following demonstration of atypical genitalia on ultrasound and amniocentesis revealing a 46,XX karyotype.

Genetic counseling should be offered to families of affected children. Recurrence risk depends on the type of genetic alteration found. The majority arise as de novo gene variants.

The patient and family must be provided with psychological support. Other treatments primarily involve hormone replacement. The need for and timing of surgical treatment is complex, depending on sex assignment and gonadal configuration. Management needs to balance the risks and benefits of gonadectomy and reconstructive surgery.

Patients usually have normal life expectancy.