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46,XX Testicular Disorder of Sex Development

Synonyms: 46,XX Testicular DSD; XX Male Syndrome. Includes: SRY-Negative 46,XX Testicular Disorder of Sex Development; SRY-Positive 46,XX Testicular Disorder of Sex Development
, MD, PhD, FACMG
Departments of Human Genetics, Pediatrics, and Urology
University of California School of Medicine
Los Angeles, California

Initial Posting: ; Last Update: May 26, 2009.

Summary

Disease characteristics. 46,XX testicular disorder of sex development (46,XX testicular DSD) is 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 80% of individuals with 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 20% of individuals with 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 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 only gene known to be associated with 46,XX testicular DSD; at least one more as-yet-unknown gene at another locus is implicated. Approximately 80% of individuals with the 46,XX testicular DSD are SRY positive as shown by use of FISH or PCR amplification of SRY; approximately 20% of individuals with 46,XX testicular DSD are SRY negative.

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.

Surveillance: Monitor for testosterone effects during testosterone replacement therapy, including prostate size and prostate-specific antigen (PSA) in adults; 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 the gene 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. The mode of inheritance of SRY-negative 46,XX testicular DSD is not known, but autosomal recessive inheritance has been postulated. Prenatal diagnosis for pregnancies at risk for SRY-positive 46,XX testicular DSD is possible.

Diagnosis

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.

Molecular Genetic Testing

Gene. SRY, the gene that encodes the sex-determining region Y protein, is the gene most commonly known to be associated with 46,XX testicular disorder of sex development (46,XX testicular DSD).

Approximately 85% of individuals with XX testicular DSD are phenotypic males with unambiguous male genitalia at birth who are SRY positive and are not diagnosed until puberty fails to proceed normally [Queipo et al 2002, Zenteno-Ruiz et al 2001].

The remaining 15% of individuals with XX testicular DSD have genital ambiguity and are SRY positive in only a minority of cases [Zenteno-Ruiz et al 2001, Kusz et al 1999].

Clinical testing

  • FISH (fluorescence in situ hybridization). A commercially available FISH probe specific for SRY detects the presence of SRY in approximately 80% of individuals with 46,XX testicular DSD. The SRY-positive region is almost always on an X chromosome.
  • PCR amplification of SRY may be used if FISH fails to detect the SRY region; PCR is more likely to detect a small amount of Y chromosome translocated on to the X chromosome and to detect the Y-chromosome material in an individual who is an XX-SRY positive/XX-SRY negative mosaic.

Table 1. Summary of Molecular Genetic Testing Used in 46,XX Testicular Disorder of Sex Development

Gene SymbolTest Method to Detect Presence of SRYSRY Detection Frequency by Test Method
Male Genitalia
NormalAmbiguous
SRYFISH or PCR amplification80%Rare

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.

Clinical Description

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.

Differential Diagnosis

Syndromic XX testicular DSD

  • Syndromic cases of XX testicular DSD – characterized by palmoplantar keratosis and predisposition to squamous cell carcinoma of the skin – have been shown to be associated with mutations in R-Spondin 1 (RSPO1) [Parma et al 2006, Tomaselli et al 2008].
  • 46,XX testicular DSD may be associated with microphthalmia and linear skin defects when the X/Y abnormal interchange involves microdeletion of Xp [Kobayashi et al 1998, Kono et al 1999, Anguiano et al 2003].

Isolated XX testicular DSD

The most common disorders in the differential diagnosis of 46,XX testicular DSD can be distinguished by karyotype and by FISH testing.

Sex chromosome abnormalities

  • Klinefelter syndrome. Klinefelter syndrome (47,XXY) and its variants (48,XXXY, 49,XXXXY, and 46XY/47,XXY mosaicism) are suspected in males with hypogonadism, small testes, and gynecomastia, all of which are also present in individuals with 46,XX testicular DSD. In contrast to 46,XX testicular DSD, Klinefelter syndrome is often characterized by normal or tall stature, speech delay, learning disorders, and behavioral problems.
  • 46,XX/46,XY. Individuals with 46,XX/46,XY chimerism may present as true hermaphrodites depending on the relative ratio of XX and XY cells; phenotypes may vary from normal male to normal female. In addition, evidence suggests that some XX individuals (whether males or true hermaphrodites) who are masculinized show some low-level hidden mosaicism for Y-chromosome derived sequences [Queipo et al 2002].
  • 45,X/46,XY. Affected individuals often present as male and may have short stature depending on the percentage of 45,X cells. Clinically, this presentation is indistinguishable from 46,XX testicular DSD; however, the chromosome findings are diagnostic. If the percentage of 45,X cells is very high, the phenotype is likely to be female with classic Turner syndrome.

A mosaic duplication of 17q23.1-q24.3, including SOX9, was reported in one individual with 46,XX testicular DSD who was SRY negative [Huang et al 1999]. Duplication of SOX9 is thought to be responsible for the 46,XX testicular DSD in this individual.

46,XX ovotesticular DSD. Individuals with ovotesticular DSD are true hermaphrodites (i.e., they have both testicular and ovarian tissue either as an ovotestis or as an ovary and a testis), whereas individuals with 46,XX testicular DSD have only testicular tissue. The type of gonadal tissue in a true hermaphrodite can be established by gonadal biopsy. Possible bias of sampling of a gonadal biopsy that may miss the ovarian portion of the gonads needs to be considered. True hermaphrodites may have a uterus, or a hemi-uterus; individuals with 46,XX testicular DSD have no Müllerian structures. Endocrine investigations may reveal estrogen production in true hermaphrodites.

21-hydroxylase deficiency causing congenital adrenal hyperplasia. This is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-hydroxylase deficiency (21-OHD), excessive adrenal androgen biosynthesis results in virilization of all 46,XX females and salt wasting in some. Virilized females have ambiguous external genitalia and a normal uterus and ovaries. The diagnosis of 21-OHD is established by comparison of baseline and stimulated serum concentrations of the steroid precursor 17-hydroxy progesterone (17-OHP) by molecular genetic testing of the causative gene, CYP21A2. Inheritance is autosomal recessive.

Prenatal exposure of a pregnancy with an XX karyotype to externally administered androgens such as danazol or endogenously produced androgens by the mother can cause virilization resulting in an infant with ambiguous genitalia that may look similar to those of a male with 46,XX testicular DSD and genital ambiguity.

Management

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 probandSRY 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.
  • 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 probandSRY 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 probandSRY 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 probandSRY 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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • InterNational Council on Infertility Information Dissemination, Inc. (INCIID)
    PO Box 6836
    Arlington VA 22206
    Phone: 703-379-9178
    Fax: 703-379-1593
    Email: inciidinfo@inciid.org
  • Intersex Society of North America (ISNA)
    Rohnert Park CA 94928

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. 46,XX Testicular Disorder of Sex Development: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SRYYp11​.31Sex-determining region Y proteinSRY homepage - Mendelian genesSRY

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for 46,XX Testicular Disorder of Sex Development (View All in OMIM)

40004546,XX SEX REVERSAL 1; SRXX1
480000SEX-DETERMINING REGION Y; SRY

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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Chapter Notes

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
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