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46,XX ovotesticular disorder of sex development

Orpha number ORPHA2138
Synonym(s) 46,XX ovotesticular DSD
True hermaphroditism
Prevalence 1-9 / 100 000
Inheritance
  • Autosomal recessive
Age of onset Childhood
ICD-10
  • Q56.0
OMIM
UMLS
  • C2748895
MeSH
  • D050090
MedDRA -
SNOMED CT
  • 18978002

Summary

46,XX ovotesticular disorder of sex development (46,XX ovotesticular DSD) is characterized by histologically confirmed testicular and ovarian tissue in an individual with a 46,XX karyotype.

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 herniae, 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 chordee and hypospadias. Rarely, patients have normal or near-normal male penis and bilaterally descended ovotestes (gonads containing ovarian and testicular elements). Gonadal configurations vary. Infertility is common in men whereas women have some potential for fertility. Malignant gonadal tumors are rare (less than 3% of cases).

The exact cause of 46,XX ovotesticular DSD has not been elucidated for the majority of cases but may be related to mosaicism or genetic mutations. Most cases (65%) are SRY (sex determining region of the Y chromosome)-negative. Rarely, patients possess a copy of the SRY gene, have SOX9 gene duplication or mutations in the RSPO1 or WNT4 genes as part of palmoplantar keratoderma - XX sex reversal - predisposition to squamous cell carcinoma and Serkal syndrome respectively (see these terms).

Many patients have obvious genital ambiguity and are diagnosed at birth. 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 (see these terms).

This may be possible following demonstration of atypical genitalia on ultrasound and amniocentesis revealing a 46,XX karyotype or to exclude the presence of a known familial genetic mutation.

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

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.

Expert reviewer(s)

  • Pr Faisal AHMED
  • Dr Angela LUCAS-HERALD
  • Dr Ruth MCGOWAN
  • Pr Edward TOBIAS

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