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46,XX testicular disorder of sex development
A rare disorder of sex development (DSD) associated with a 46, XX karyotype and characterized by male external genitalia, ranging from normal to atypical with associated testosterone deficiency.
ORPHA:393Classification level: Disorder
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. Undescended testes 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 undescended testes. Long-term complications due to male hypogonadism include: low libido, erectile dysfunction, decreased secondary sexual characteristics, osteopenia and depression.
In most patients, the condition is caused by translocation of a small Y chromosome fragment, including SRY onto an X or other chromosome. In SRY negative cases, copy number variations, involving regulatory genes, (SOX3, SOX9) and a common recurrent NR5A1 variant are reported.
Diagnosis is based on clinical signs and endocrine testing showing hypergonadotrophic hypogonadism and cytogenetic or molecular testing (SNP array) confirming an XX genome. Fluorescence 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. 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) and microphthalmia with linear skin defects (MIDAS) syndrome.
Prenatal testing in pregnancies may be possible if the underlying genetic cause has been identified.
Genetic counseling should be offered to affected individuals and their families. Recurrence risk depends on the type of genetic alteration found. SRY positive cases are generally not inherited because this is usually associated with infertility. In SRY negative cases, the pattern of inheritance depends on the genetic cause, if known.
Management and treatment
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 individuals are typically infertile. Tumorigenic risk is low.