Clinical Diagnosis

46,XX testicular disorder of sex development (46,XX testicular DSD) is diagnosed in individuals with:

• A 46,XX karyotype using conventional staining methods
• Male external genitalia that range from normal to ambiguous (penoscrotal hypospadias with or without chordee)
• Two testicles
• Azoospermia
• No evidence of Müllerian structures

Testing

Endocrine testing

• Endocrine studies usually show hypergonadotropic hypogonadism secondary to testicular failure [Pérez-Palacios et al 1981].
  • Basal serum concentration of LH and FSH are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL).
  • Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1030 ng/dL in adult males).
  • Human chorionic gonadotrophin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after IM injection of hCG.
• The hypothalamic-pituitary axis is preserved.
  • GnRH stimulation testing shows a normal LH and FSH response.
    Note: Such testing is not warranted for diagnosis.

Cytogenetic studies. Routine cytogenetic studies demonstrate a 46,XX karyotype.

Note: If Y chromosome material including SRY is located on the short arm of one X chromosome, it is usually too small to visualize without FISH (see Molecular Genetic Testing, Clinical testing).

Histology. Testicular biopsy shows a decrease in size and number of seminiferous tubules, peritubular fibrosis, absence of germ cells, and hyperplasia of Leydig cells [de la Chapelle 1981].

Note: Such testing is not warranted for diagnosis.

Testing Strategy

To confirm the diagnosis in a proband, the following algorithm is suggested:

1.

First, a conventional G-banded cytogenetic analysis should be performed to rule out other chromosome aberrations as well as to make the diagnosis of a normal female karyotype (46,XX).

2.

Next, FISH of an SRY probe to metaphase chromosomes should be performed to determine the nature of the rearrangement (SRY located on an X chromosome versus SRY located on an autosome). The inheritance patterns and genetic counseling issues are different for each one of these rearrangements.

3.

If SRY by FISH is not positive, PCR for SRY is the next step because PCR has greater sensitivity than FISH. Note, however, that cytogenetic analysis showing a 46,XX karyotype and a positive result by PCR for SRY sequence is not sufficient to determine the etiology and thus understand the inheritance pattern of this disorder.

Prenatal diagnosis for pregnancies at risk for SRY-positive 46,XX testicular DSD requires conventional cytogenetic analysis and FISH of an SRY probe. If SRY by FISH is not positive, PCR for SRY may be performed.

Genetically Related (Allelic) Disorders

46,XX ovotesticular disorder of sex development (formerly known as “true hermaphrodism” and defined as presence of both testicular and ovarian tissue in an individual) is SRY positive in 10% of the cases, most commonly as a result of abnormal interchange between an X and Y chromosome resulting in translocation of SRY on to the X chromosome. Intrafamilial variability has been described, with SRY-negative 46,XX ovotesticular DSD and 46,XX testicular DSD within the same family [Ramos et al 1996].

Natural History

Approximately 80% of individuals with 46,XX testicular disorder of sex development (46,XX testicular DSD) present after puberty with normal pubic hair and normal penile size, but small testes, gynecomastia, and sterility resulting from azoospermia. The small testes are usually soft but may become firmer with age. Among these individuals, a minority have cryptorchidism (undescended testes) and/or anterior hypospadias (atypical urethral opening) [Boucekkine et al 1994]. Gender role and gender identity are reported as male for the common, unambiguous presentation, but systematic psychosexual assessment has not been performed on a significant number of individuals with 46,XX testicular DSD.

Approximately 20% of individuals with 46,XX testicular DSD present at birth with ambiguous genitalia, typically penoscrotal hypospadias with or without chordee.

46,XX testicular DSD is not associated with learning disorders or behavioral issues.

The natural history of the 46,XX testicular DSD, if untreated, is similar to the typical consequences of testosterone deficiency:

• Low libido and possible erectile dysfunction
• Decrease in secondary sexual characteristics, such as sparse body hair, infrequent need to shave, and reduced muscle mass
• Increase in fat mass with lower muscle strength
• Increased risk of osteopenia
• Increased risk of depression

SRY-positive 46,XX testicular DSD. Individuals with SRY-positive 46,XX testicular DSD typically present after puberty with the following:

• Shorter-than-average stature (mean height: 168.2 cm, compared to normal mean height: 173.5 cm) [de la Chapelle 1972]
• Gynecomastia
• Small testes
• Azoospermia

Individuals with SRY-positive 46,XX testicular DSD rarely present with atypical genitalia and are less likely than individuals with SRY-negative 46,XX testicular DSD to have gynecomastia [Ferguson-Smith et al 1990, Boucekkine et al 1994, Ergun-Longmire et al 2005].

SRY-negative 46,XX testicular DSD. Individuals with SRY-negative 46,XX testicular DSD tend to present with ambiguous genitalia at birth, such as penoscrotal hypospadias and cryptorchidism, and, if untreated, almost always develop gynecomastia around the time of puberty.

Genotype-Phenotype Correlations

In 46,XX testicular DSD, the presence of SRY is often associated with the presence of normal male external genitalia, whereas the absence of SRY is more often associated with ambiguous genitalia [Grigorescu-Sido et al 2005]. However, genotype-phenotype correlation is not entirely reliable, because a small number of individuals with SRY-negative 46,XX testicular DSD have normal external genitalia [Vilain et al 1994, Zenteno et al 1997, Kolon et al 1998, Vernole et al 2000, Abusheikha et al 2001].

Penetrance

Penetrance is believed to be 100%, but no data are available.

Nomenclature

At an international consensus conference on the management of Intersexuality held in October 2005 under the auspices of the Lawson Wilkins Pediatric Endocrine Society (USA) and the European Society for Pediatric Endocrinology, a multidisciplinary panel of experts proposed that the name in current use, "XX male syndrome," be replaced by the name "46,XX testicular disorder of sex development" [Hughes et al 2006, Lee et al 2006].

Prevalence

The prevalence of 46,XX testicular DSD is estimated at one in 20,000 males.

No populations are known to be at greater or lesser risk for this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed 46,XX testicular disorder of sex development (46,XX testicular DSD), the following evaluations are recommended:

• Assessment of mood, libido, energy, erectile function, acne, and breast tenderness and size by history and/or physical examination
• Dexascan to evaluate for osteopenia

Treatment of Manifestations

Testosterone replacement therapy. Management of individuals with 46,XX testicular DSD with testosterone deficiency is similar to that for other causes of testosterone deficiency. Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy.

After age 14 years, low-dose testosterone therapy can be initiated. Note: If an individual has short stature and is eligible for growth hormone therapy, testosterone therapy should be either delayed or given at lower doses initially in order to maximize the growth potential.

Testosterone enanthate is given IM every three to four weeks, starting at 100 mg and increasing by 50 mg every six months to 200-400 mg. Initial high doses of testosterone should be avoided to prevent priapism. The treatment should plateau, in adulthood, at the best possible dosage, typically between 50 and 400 mg every two to four weeks.

Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage; however, side effects include pain associated with injection and large variations of serum testosterone concentration between injections, resulting in a higher risk of mood swings.

Alternative delivery systems that result in a more stable dosing include transdermal patches (scrotal and non-scrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of new hydroalcoholic gels [Kuhnert et al 2005].

Gynecomastia. Regression of gynecomastia may occur with testosterone replacement therapy. If it does not, and if it causes psychological distress to the individual, reduction mammoplasty can be offered.

Osteopenia. Depending on the degree of osteopenia, treatment may include: calcium, exercise, vitamin D, biphosphonates, or calcitonin. Referral to an internist, pediatrician, or endocrinologist is recommended.

Psychological support. Sensitivity is necessary when conveying information to individuals with 46,XX testicular DSD about the genetic cause and associated sterility of the disorder. This information must be presented in a manner that helps minimize psychological distress and to anticipate the need for further psychological assistance.

Surveillance

Monitoring during testosterone replacement therapy should include:

• Evaluation of mood, libido, energy, erectile function, acne, and breast tenderness and size
• Measurement of serum testosterone concentration at three-month intervals (prior to the next injection) to evaluate nadir testosterone concentrations. Concentrations lower than 200 ng/dL or higher than 500 ng/dL may require adjustment of total dose or frequency.
• In adults, digital rectal examination and measurement of prostate-specific antigen (PSA) prior to treatment and three, six, and 12 months after initiation of therapy to evaluate for the presence of an overt prostate cancer, which would be a contraindication to the treatment. Such testing should then be performed annually.
• For individuals on testosterone replacement therapy, evaluation of hematocrit at three, six, and 12 months, then annually because of risk of increased hematocrit with subsequent risk of hypoxia and sleep apnea
• Lipid profile and liver function tests, as testosterone may alter lipid profile and liver function
• Bone mineral determination by bone densitometry (DEXA) once a year, 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 (especially for long-term therapy) because of liver toxicity.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

SRY-positive 46,XX testicular disorder of sex development (46,XX testicular DSD) is generally not inherited as 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, as in the case reported by Abbas et al [1993], fertility is preserved, sex-limited autosomal dominant inheritance is observed.

The mode of inheritance of SRY-negative 46,XX testicular DSD is not known. Although recurrence in sibs has suggested autosomal recessive inheritance [McElreavey et al 1993, Zenteno et al 1997, Kolon et al 1998], it is not known if that mode of inheritance is the correct explanation for the recurrence pattern observed.

Risk to Family Members — SRY-Positive 46,XX Testicular DSD

Parents of a proband – SRY translocation to an X chromosome

• Almost all males with SRY-positive 46,XX testicular DSD have a de novo translocation of SRY to the X chromosome.
  • Fathers are unaffected and are not carriers.
  • Mothers are unaffected and are not carriers.
• Rarely, an individual has an inherited translocation of SRY to the X chromosome.
  
  Abbas et al [1993] reported a fertile 46,XY male, with a copy of SRY translocated to his X chromosome and one copy of SRY on his normal Y chromosome. He had two affected children: a son who had SRY-positive 46,XX testicular DSD and a daughter who was an SRY-positive XX true hermaphrodite. Karyotype of the father of a male with SRY-positive 46,XX testicular DSD is warranted if the parents request genetic counseling, in order to evaluate for the rare possibility that the father has an extra X-linked copy of SRY. In this case, the risk of recurrence is 50% (all children who have a 46,XX karyotype will have 46,XX testicular DSD).

Parents of a proband – SRY translocation to an autosome

• Some males with SRY-positive 46,XX testicular DSD have a de novo or inherited translocation of SRY to an autosome.
• Unaffected fathers may carry this translocation.
  
  Kasdan et al [1973] reported a father whose karyotype was 47,XY +mar. The marker presumably included a copy of SRY, which was transmitted to two XX male offspring.
• Mothers are unaffected and are not carriers.

Sibs of a proband – SRY translocation to an X chromosome

• Most occurrences of 46,XX testicular DSD caused by SRY translocation to an X chromosome are de novo, and the risk to the XX sibs of a proband is low (<1%). XY sibs will not be affected.
• If the XY father has two copies of SRY (one translocated to his X chromosome and one on his Y chromosome), the XX sibs of a proband will have the 46,XX testicular DSD or XX true hermaphroditism. XY sibs will not be affected.
• No instances of germline mosaicism have been reported, but it remains a possibility.

Sibs of a proband – SRY translocation to an autosome

• If the proband has a de novo translocation of SRY to an autosome, the risk to the sibs is not increased.
• If the father carries an SRY gene translocated onto an autosome, the XX sibs of a proband each have a 50% chance of inheriting the translocated SRY and having 46,XX testicular DSD or XX true hermaphroditism.

Offspring of a proband. Men with SRY-positive 46,XX testicular DSD are infertile.

Risk to Family Members — SRY-Negative 46,XX Testicular DSD

Parents of a proband

• When SRY-negative 46,XX testicular DSD is inherited in an autosomal recessive manner, the parents of a proband are obligate heterozygotes.
• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Men with SRY-negative 46,XX testicular DSD are infertile.

Related Genetic Counseling Issues

Management of infertility. A management option for infertility in individuals with 46,XX testicular DSD who wish to have a family is artificial insemination with donor sperm [Lissens et al 2002].

Family planning. The optimal time for determination of genetic risk and discussion of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at risk for SRY-positive 46,XX testicular DSD is possible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation can be analyzed using FISH.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

In most cases, the suspicion of 46,XX testicular DSD arises during pregnancy when the karyotype (done for an unrelated reason) is discordant with the phenotypic sex observed by ultrasound examination.

An SRY-positive result decreases (but does not exclude) the likelihood of ambiguous genitalia. The main issues with prenatal diagnosis of 46,XX testicular DSD are the unknown reliability of the determination of the anatomic sex by ultrasound examination and the difficulty in prenatally diagnosing or ruling out all the conditions that could be associated with discordant phenotypic and chromosomal sex.

Molecular Genetic Pathogenesis

46,XX testicular disorder of sex development (46,XX testicular DSD) can be explained in approximately 80% of individuals by the presence of a small Y-chromosome fragment, including SRY, in the genome. This is the result of an abnormal terminal X-Y exchange during paternal meiosis [Evans et al 1979, Andersson et al 1986]. This abnormal recombination involves highly homologous loci (recombination hotspots) on the sex-specific part of the X and Y chromosomes [Weil et al 1994]. One particular hotspot of recombination is located between PRKY, a protein kinase gene, and its X-linked homologue PRKX, and accounts for one third of all SRY-positive individuals with 46,XX testicular DSD [Schiebel et al 1997]. PRKY and PRKX are localized far from the pseudo-autosomal region where XY exchange normally occurs. The high homology between PRKY and PRKX explains the high frequency of abnormal recombination responsible for individuals with 46,XX testicular DSD.

Normal allelic variants. SRY is an intronless gene encoding a 204-amino acid protein [Sinclair et al 1990]. The SRY promoter contains two GC-rich regions with several Sp1 sites.

Pathologic allelic variants. 46,XX testicular DSD is caused by the translocation of a normal SRY allele onto an X chromosome. Note: Many abnormal allelic variants of SRY are observed in individuals with 46,XY disorder of sexual development (46,XY DSD) and 46,XY complete gonadal dysgenesis (46,XY CGD) but not in individuals with 46,XX testicular DSD.

Normal gene product. SRY encodes a transcription factor that is a member of the HMG (high mobility group) box family. The HMG box confers the ability to bind and bend DNA. Two nuclear localization sequences, located on each side of the HMG box, are required for the nuclear translocation of SRY.

Abnormal gene product. No abnormal product is observed in this disorder.

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Revision History

• 26 May 2009 (me) Comprehensive update posted live
• 5 April 2006 (me) Comprehensive update posted to live Web site
• 30 October 2003 (me) Review posted to live Web site
• 29 May 2003 (ejv) Original submission