Clinical characteristics: Nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are characterized by: the presence of a 46,XX karyotype; external genitalia ranging from typical male to ambiguous; two testicles; azoospermia; absence of müllerian structures; and absence of other syndromic features, such as congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues. 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. Other causes in SRY-negative individuals include small copy number variants (CNVs) in or around SOX3 or SOX9 and specific heterozygous pathogenic variants in NR5A1 or WT1.
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 growth potential. Reduction mammoplasty may be considered if gynecomastia remains an issue following testosterone replacement therapy. Standard treatment for osteopenia, hypospadias, and cryptorchidism. Providers are encouraged to anticipate the need for further psychological support.
Surveillance: Measurement of length/height at each visit. Assessment of mood, libido, energy, erectile function, acne, breast tenderness, and presence or progression of gynecomastia at each visit in adolescence and adulthood. For those on testosterone replacement therapy: measurement of serum testosterone levels every three months (just prior to the next injection) until testosterone dose is optimized; then annual measurement of serum testosterone levels, lipid profile, and liver function tests. Measurement of hematocrit at three, six, and 12 months after initiation of testosterone therapy, then annually thereafter. Digital rectal examination and measurement of serum prostate-specific antigen at three, six, and 12 months after initiation of testosterone therapy in adults, then annually thereafter. Dual-energy x-ray absorptiometry scan every three to five years after puberty or annually, if osteopenia has been identified.
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: The mode of inheritance and recurrence risk to sibs of a proband with a nonsyndromic 46,XX testicular DSD depend on the molecular diagnosis in the proband and the genetic status of the parents.
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. In the rare cases when SRY is translocated to another chromosome or when fertility is preserved, sex-limited autosomal dominant inheritance is observed.
Pathogenic variants in NR5A1 are inherited in an autosomal dominant fashion, with incomplete penetrance and variable expressivity. If a fertile parent is heterozygous, they will pass the variant to 50% of their offspring; offspring who are XX are at risk for testicular or ovotesticular DSD.
To date, all known individuals with CNVs in or around SOX3 whose parents have undergone molecular genetic testing have the disorder as a result of a de novo pathogenic variant. In this scenario, the risk to sibs is low.
Autosomal dominant inheritance has been documented for familial cases thought to be caused by CNVs in or around SOX9. However, only those with a 46,XX karyotype will be affected.
To date, all known individuals with a pathogenic WT1 variant that causes nonsyndromic 46,XX testicular DSD whose parents have undergone molecular genetic testing have the disorder as a result of a de novo pathogenic variant. In this scenario, the risk to sibs is low.
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