Clinical characteristics: Nonsyndromic 46,XX testicular disorders of sex development (46,XX testicular DSD) are characterized by the presence of a 46,XX karyotype; male external genitalia ranging from normal to ambiguous; two testicles; azoospermia; and absence of müllerian structures. Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia. Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia. Gender role and gender identity are reported as male. If untreated, males with 46,XX testicular DSD experience the consequences of testosterone deficiency.
Diagnosis/testing: Diagnosis of nonsyndromic 46,XX testicular DSD is based on the combination of clinical findings, endocrine testing, and cytogenetic testing. Endocrine studies usually show hypergonadotropic hypogonadism secondary to testicular failure. Cytogenetic studies at the 550-band level demonstrate a 46,XX karyotype. SRY, the gene that encodes the sex-determining region Y protein, is the principal gene known to be associated with 46,XX testicular DSD. Approximately 80% of individuals with nonsyndromic 46,XX testicular DSD are SRY positive as shown by use of FISH or chromosomal microarray (CMA). Rearrangements in or around SOX9 and SOX3 detected by CMA, or rarely karyotype, have recently been reported in a few cases; at least one more as-yet-unknown gene at another locus is implicated.
Management: Treatment of manifestations: Similar to that for other causes of testosterone deficiency. After age 14 years, low-dose testosterone therapy is initiated and gradually increased to reach adult levels. In affected individuals with short stature who are eligible for growth hormone therapy, testosterone therapy is either delayed or given at lower doses initially in order to maximize the growth potential. Reduction mammoplasty may need to be considered if gynecomastia remains an issue following testosterone replacement therapy. Treatment for osteopenia is by standard protocols. Providers are encouraged to anticipate the need for further psychological support.
Surveillance: Monitor for testosterone effects during testosterone replacement therapy, including prostate size and prostate-specific antigen (PSA) in adults; routine monitoring of hematocrit, lipid profile, and liver function tests; bone mineral density determination by bone densitometry (DEXA) annually, if osteopenia has been diagnosed.
Agents/circumstances to avoid: Contraindications to testosterone replacement therapy include prostate cancer (known or suspected) and breast cancer; oral androgens such as methyltestosterone and fluoxymesterone should not be given because of liver toxicity.
Genetic counseling: SRY-positive 46,XX testicular DSD is generally not inherited because it results from de novo abnormal interchange between the Y chromosome and the X chromosome, resulting in the presence of SRY on the X chromosome and infertility. When SRY is translocated to another chromosome or when fertility is preserved, sex-limited autosomal dominant inheritance is observed.
Autosomal dominant inheritance has been documented for familial cases thought to be caused by CNV in or around SOX9.
The mode of inheritance of other SRY-negative 46,XX testicular DSD is not known, but autosomal recessive inheritance has been postulated. Prenatal testing for pregnancies at risk for SRY-positive 46,XX testicular DSD is possible.
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