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46,XX testicular disorder of sex development

ORPHA393
Synonym(s) 46,XX testicular DSD
De la Chapelle syndrome
XX, male syndrome
Prevalence 1-9 / 100 000
Inheritance -
Age of onset Infancy
Neonatal
ICD-10
  • Q99.1
OMIM
UMLS
  • C0432475
  • C2936419
MeSH
  • D058531
MedDRA -

Summary

46,XX testicular disorder of sex development (46,XX testicular DSD) is characterized by male external genitalia, ranging from normal to ambiguous with associated testosterone deficiency.

The estimated prevalence is 1/20,000 males.

The clinical phenotype is variable, with features that include: normal male external to atypical genitalia, undescended testes with absent Müllerian structures and infertility. Presentation depends on the presence of the SRY-gene (sex determining region of the Y chromosome). SRY positive cases (80-90%) are usually otherwise normal men who present after puberty with short stature, normal pubic hair and penile size but small testes, gynecomastia and azoospermia-related sterility. Cryptorchidism and hypospadias are also reported. There are usually no concerns about gender role and identity. SRY-negative individuals (10-20%) usually present at birth with features such as penoscrotal hypospadias and cryptorchidism. Long-term complications due to male hypogonadism include: low libido, erectile dysfunction, decreased secondary sexual characteristics, osteopenia and depression.

In most patients, the disease is caused by the presence of a small Y-chromosome fragment including SRYin a karyotypic XX genome. Translocation of a normal SRY allele onto an X chromosome is a common cause but in SRY-negative cases, other genes are implicated e.g. SOX9, SOX3, RSPO1 and WNT4.

Diagnosis is based on clinical signs and endocrine testing showing hypergonadotrophic hypogonadism and cytogenetic testing. Fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) techniques may detect the SRY gene.

The main differential diagnoses are 45,X/46,XY mixed gonadal dysgenesis, 47,XXY Klinefelter syndrome, 46,XX ovotesticular DSD and sex chromosome mosaicisms. Rarely, others include palmoplantar keratoderma with squamous cell carcinoma of the skin and XX sex reversal (caused by RSPO1 gene mutations) and microphthalmia with linear skin defects (MIDAS) syndrome (see these terms).

Prenatal testing in pregnancies at risk for SRY-positive 46,XX testicular DSD is possible.

SRY-positive cases are generally not inherited because when the SRY gene is present on the X chromosome, it almost always causes infertility. Penetrance may be as high as 100%. In the majority of SRY-negative cases, the pattern of inheritance is unknown except when mutations are detected in other genes e.g. RSPO1 or WNT4 (both recessively inherited).

The mainstay of treatment is testosterone replacement therapy to correct hormonal imbalance, prevent gynecomastia and to induce development of male secondary sex characteristics. Hypergonadotrophic hypogonadism is uncommon prior to adulthood. Reduction mammoplasty may be considered in some cases. Psychological support and timely referral to an assisted conception service should be offered.

Management of male hypogonadism reduces complications. Affected patients are typically infertile. Tumorigenic risk is low.

Expert reviewer(s)

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

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Detailed information

Clinical genetics review
  • EN (2009)
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