U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

Synonym: 46,XX Testicular DSD

, PhD and , MD, PhD, FACMG.

Author Information and Affiliations

Initial Posting: ; Last Update: May 26, 2022.

Estimated reading time: 31 minutes

Summary

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.

GeneReview Scope

Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Included Disorders
  • SRY-positive 46,XX testicular disorders/differences of sex development
  • SRY-negative 46,XX testicular disorders/differences of sex development

For synonyms and outdated names see Nomenclature.

Diagnosis

No consensus clinical diagnostic criteria for nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have been published. However, algorithms have been developed for the evaluation and diagnosis of DSD, including nonsyndromic 46,XX testicular DSD [Délot & Vilain 2021].

Suggestive Findings

Nonsyndromic 46,XX testicular DSD should be considered in individuals with the following clinical, supportive laboratory, and imaging findings.

Clinical findings

  • Male external genitalia that ranges from typical to ambiguous (penoscrotal hypospadias with or without chordee)
  • Two testicles, typically smaller than average for age
  • Absence of dysmorphic features and congenital anomalies outside of the genitourinary system
  • Normal cognitive development

Supportive laboratory findings

  • A 46,XX karyotype using conventional staining methods
  • Azoospermia
  • Endocrine studies that demonstrate hypergonadotropic hypogonadism secondary to testicular failure:
    • Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (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: 350-1,030 ng/dL in adult males).
    • Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG.
  • Preservation of the hypothalamic-pituitary axis. Gonadotropin-releasing hormone (GnRH) stimulation testing shows a normal LH and FSH response.
    Note: Such testing is not required for diagnosis.
  • Testicular biopsy shows a decrease in size and number of seminiferous tubules, peritubular fibrosis, absence of germ cells, and hyperplasia of Leydig cells.
    Note: Such testing is not required for diagnosis.

Imaging findings. No evidence of müllerian structures on pelvic ultrasound or MRI

Establishing the Diagnosis

The diagnosis of nonsyndromic 46,XX testicular DSD is established in a 46,XX proband who has the clinical findings listed in Suggestive Findings and/or one of the following on molecular genetic testing (see Table 1):

  • Presence of SRY, frequently detected through chromosomal microarray (CMA), fluorescence in situ hybridization (FISH) for SRY, or polymerase chain reaction (PCR) for SRY
    Note: Some individuals will be diagnosed solely by CMA when there is evidence for two X chromosomes, no Y chromosome, and presence of SRY.
  • Small copy number variants in or around SOX3 or SOX9 affecting only either SOX3 or SOX9, respectively, on CMA or genome sequencing
    Note: (1) Depending on the microarray platform used and the probe coverage in and around SOX3 and SOX9, these variants may not be detected by CMA. (2) It is important to verify with the testing laboratory that they will report variants in the gene desert around SOX9, as these may be overlooked and thus not reported.
  • Specific heterozygous pathogenic variants in NR5A1 or WT1 (See Table 1 and Molecular Genetics.)

In a phenotypic male or an individual with ambiguous genitalia in whom a 46,XX karyotype is already established, molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, genome sequencing).

Gene-Targeted Testing

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

If SRY is not present, the following can be considered next:

  • Sequence analysis of NR5A1 and WT1 to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants.
    Note: Only a specific pathogenic variant in NR5A1 and pathogenic variants in a specific subdomain of WT1 are known to be causative of nonsyndromic 46,XX testicular DSD at this time (see Table 1 and Molecular Genetics).
  • A DSD multigene panel that includes NR5A1, WT1, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive Genomic Testing

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (sometimes including the regulatory regions around SOX3 and SOX9) that cannot be detected by sequence analysis, and small chromosomal rearrangements that may not be detected by karyotype.

Note: A balanced chromosomal translocation involving the 17q24.3 region has also been reported [Croft et al 2018b], but this should be detectable on karyotype.

Genome sequencing does not require the clinician to determine which gene is likely involved. Unlike exome sequencing, genome sequencing may able to detect copy number and single-nucleotide variants that are in noncoding areas of the genome, including in regulatory regions.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development by Phenotype

Gene 1, 2Proportion of Nonsyndromic 46,XX Testicular DSD by Phenotype Attributed to Pathogenic Variants in or around GeneProportion of Pathogenic Variants 3 Detectable by Method
Typical male genitaliaAmbiguous genitaliaSequence
analysis 4
CMA 5GS 6FISH for
SRY
NR5A1 Very rare 7Rare 7100% 8None reported 9100% 8NA
SOX3 Rare 10Very rare 11None reported<100% 12UnknownNA
SOX9 Very rare 10Rare 10None reported<100% 12, 13UnknownNA
SRY 80% 14Rare100% 15100%100%100%
WT1 Very rare 16Very rare 16100% 17None reported 9100% 17NA
UnknownNA

CMA = chromosomal microarray; DSD = disorders/differences of sex development; FISH = fluorescent in situ hybridization; NA = not applicable; GS = genome sequencing

1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on variants detected in these genes.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. Sequencing will typically detect presence of a gene but not chromosomal location.

5.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the regions surrounding SOX3 and SOX9. CMA will typically detect presence or absence of a chromosomal region but not the location of that region in relationship to other chromosomal regions.

6.

Genome sequencing is typically performed by next-generation sequencing of sheared genomic DNA. Genome sequencing techniques have nonstandardized, highly variable coverage. Unlike exome sequencing, genome sequencing has the ability to identify structural variants and chromosome breakpoints in noncoding regions. The coverage of the genome is less than 100% and varies by laboratory.

7.
8.

To date, the only pathogenic variants in NR5A1 identified as causing nonsyndromic 46,XX testicular DSD affect the Arg92 codon.

9.

Due to the mechanism of disease causation, copy number variants in this gene are unlikely to lead to nonsyndromic 46,XX testicular DSD.

10.
11.
12.

Depending on the microarray platform used and the probe coverage in and around SOX3 and SOX9, these variants may not be detected by CMA.

13.

It is important to verify with the testing laboratory that they will report variants in the gene desert around SOX9, as these may be overlooked and thus not reported.

14.
15.

As implied by the title of this table, sequence analysis that detects the present of SRY only leads to nonsyndromic 46,XX DSD in individuals with a known 46,XX chromosome complement and not to those with a 46,XY chromosome complement.

16.
17.

The only pathogenic variants described in individuals with this phenotype specifically affect the ZF4 domain (see Genetically Related Disorders and Molecular Genetics).

Clinical Characteristics

Clinical Description

By definition, nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are not associated with dysmorphic features, congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues.

Approximately 85% of males with a 46,XX sex chromosome complement present after puberty with typical male pubic hair and penile size but small testes, gynecomastia, and sterility resulting from azoospermia [Zenteno-Ruiz et al 2001]. These typically represent individuals with nonsyndromic 46,XX testicular DSD, but ovotesticular DSD cannot be excluded as testicular biopsy is not clinically warranted and thus rarely performed.

Differences of the penis. Most affected individuals have an orthotopic urethral meatus and no abnormalities of phallic size (i.e., typical male external genitalia).

  • Approximately 15% of individuals have ambiguous genitalia, typically penoscrotal hypospadias with or without chordee, noted at birth [Zenteno-Ruiz et al 2001].
  • Anterior/distal hypospadias (atypical urethral opening) is also uncommon.

Testes. At birth, testes are typically descended but may be smaller and softer than usual. The testes may become firmer with age. A minority have cryptorchidism (undescended testes).

There has only been one case report of a germ cell tumor in an individual with nonsyndromic 46,XX testicular DSD who presented with ambiguous genitalia [Carcavilla et al 2008]. Leydig cell tumors have rarely been reported [Kim et al 2010, Osaka et al 2020]. As these appear to be rare events, no consensus tumor screening protocol has been recommended to date for individuals with 46,XX testicular DSD.

Decreased testosterone production. The natural history of individuals with nonsyndromic 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

Gynecomastia. Affected individuals frequently develop gynecomastia during puberty, the risk of which is related to the underlying cause (see Phenotype Correlations by Gene). Breast reduction surgery can be offered if the condition is of concern to the individual.

Fertility. Individuals with 46,XX testicular DSD are infertile, as they lack the AZF loci on the long arm of the Y chromosome (Yq) that allow normal spermatogenesis. Even in SRY-positive individuals, only genetic material from the short arm of the Y chromosome (Yp) is translocated onto another chromosome (most commonly the short arm of the X chromosome).

Gender roles 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.

Phenotype Correlations by Gene

SRY-positive nonsyndromic 46,XX testicular DSD

  • Typically, these individuals do not have hypospadias.
  • The finding of ambiguous genitalia is uncommon.
  • Gynecomastia is much less common compared to those who have SRY-negative nonsyndromic 46,XX testicular DSD [Ergun-Longmire et al 2005].

SRY-negative nonsyndromic 46,XX testicular DSD of unknown cause

  • Affected individuals 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.
  • Affected individuals may have shorter-than-average height.

SOX3-related nonsyndromic 46,XX testicular DSD

SOX9-related nonsyndromic 46,XX testicular DSD. As gonadal biopsy is not routinely performed, it is unclear what percentage of individuals with copy number variants in and around SOX9 have testicular (vs ovotesticular) DSD (see Genetically Related Disorders).

WT1-related nonsyndromic 46,XX testicular DSD. Of six reported individuals with WT1-related testicular DSD, only one had palpable gonads and typical male genitalia [Gomes et al 2019, Eozenou et al 2020, Sirokha et al 2021].

Penetrance

Heterozygous pathogenic variants in NR5A1 that lead to the predicted p.Arg92Trp protein change demonstrated incomplete penetrance in 46,XX individuals, with fertile XX phenotypic females described [Bashamboo et al 2016, Baetens et al 2017, Knarston et al 2019].

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 names "XX male syndrome" and "true hermaphrodite" be replaced by the names "46,XX testicular DSD" and "46,XX ovotesticular DSD," respectively [Lee et al 2006]. Recent evolutions suggest that the DSD acronym should be taken to mean "differences of sex development" in an effort to lessen stigma often associated with these conditions [Délot & Vilain 2021].

Prevalence

The prevalence of nonsyndromic 46,XX testicular DSD is estimated at 1:20,000 males.

Differential Diagnosis

Nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) must be differentiated from ovotesticular DSD as their potential outcomes differ, thus affecting management; see Genetically Related Disorders.

Other disorders to consider in the differential diagnosis of nonsyndromic 46,XX testicular DSD are summarized in Table 4. Sex chromosome aneuploidies, which represent the most common disorders in the differential diagnosis, can be distinguished from 46,XX testicular DSD by karyotype and by FISH testing.

Table 4.

Disorders to Consider in the Differential Diagnosis of Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

Differential
Category
EtiologyPhenotype
Sex
chromosome
aneuploidies
47,XXY (& variants:
48,XXXY; 49,XXXXY; 46XY/47,XXY mosaicism)
  • Klinefelter syndrome (males w/hypogonadism, small testes, gynecomastia)
  • Unlike 46,XX testicular DSD, Klinefelter syndrome is often characterized by normal or tall stature, speech delay, learning disorders, & behavioral issues.
46,XX/46,XYMay present w/external genitalia ranging from typical male to ambiguous to typical female
45,X/46,XYAffected persons often present as male & may have short stature; may be clinically indistinguishable from 46,XX testicular DSD.
Syndromic
forms of
46,XX
testicular
DSD
RSPO1 Biallelic pathogenic variants are assoc w/palmoplantar hyperkeratosis with squamous cell carcinoma of skin & 46,XX testicular DSD. 1
Yp translocation assoc w/partial or complete Xp monosomyRare 46,XX males in whom the translocation of Y material to the X chromosome has resulted in loss of X material may present w/syndromic form associating an XX karyotype & male or ambiguous genitalia w/characteristics of partial monosomy Xp, as in microphthalmia with linear skin defects syndrome (MIDAS complex), an X-linked disorder generally lethal in XY persons.
Balanced translocation involving SOX9 246,XX testicular DSD w/dysmorphic facial features
Deletion of multiple genes around SOX3 or Mb-size duplications incl SOX3 346,XX testicular DSD & DD (w/o ambiguous genitalia)
NR2F2 Frameshift variant in or deletion of NR2F can cause testicular or ovotesticular DSD assoc w/cardiac malformations. 4
Prenatal
exposure of
46,XX fetuses
to androgens
CYP21A2
  • Biallelic pathogenic variants are assoc w/21-hydroxylase deficiency (most common cause of congenital adrenal hyperplasia); excessive adrenal androgen biosynthesis results in virilization in all persons & salt wasting in some.
  • Virilized females may have an enlarged clitorophallic structure & urogenital sinus; uterus & ovaries are normal.
Externally administered androgens (e.g., danazol) or androgens endogenously produced by the motherVirilization resulting in an infant w/ambiguous genitalia that may look similar to those of a male w/46,XX testicular DSD & ambiguous genitalia

DD = developmental delay; Mb = megabase

1.

See OMIM 610644.

2.

46,XX,t(12;17)(q14.3;q24.3) [Refai et al 2010] and 46,XX,t(11;17)(p13;q24.3) [Vetro et al 2015]

3.
4.

See OMIM 618901.

Management

No clinical practice guidelines for nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of the condition and needs in an individual diagnosed with nonsyndromic 46,XX testicular DSD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

System/ConcernEvaluationComment
Constitutional Measurement of length/heightTo assess for short stature
Endocrinology Measurement of LH, FSH, & total testosterone levelsIn those age >10 yrs
Assessment of libido, energy, erectile function, acne, breast tenderness, & presence of gynecomastiaIn adolescents & adults
Baseline DXA scan in adolescents & adultsTo assess bone mineral density
Urology Physical exam for evidence of undervirilizationIncl assessment of length & width of phallus; location of urethral meatus; location of gonads through palpation & size measurement w/orchidometer
Digital rectal exam & measurement of PSA 1In adults, prior to initiating testosterone replacement therapy 1 (See Table 6.)
Psychology Assessment of mood & gender identityBy mental health professional
Genetic
counseling
By genetics professionals 2To inform affected persons & their families re nature, MOI, & implications of nonsyndromic 46,XX testicular DSD to facilitate medical & personal decision making
Individual &
family support/
resources
Assess need for:

DSD = disorders/differences of sex development; DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; PSA = prostate-specific antigen

1.

Abnormalities in either of these may indicate the presence of prostate cancer; in this scenario, supplemental testosterone therapy may be contraindicated.

2.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Table 6.

Treatment of Manifestations in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

Manifestation/ConcernTreatmentConsiderations/Other
Short stature Growth hormone therapy may be considered.Referral to endocrinologist recommended
Low or absent serum
testosterone levels 1
  • Low-dose testosterone replacement therapy can be initiated after age 14 yrs. 2, 3
  • Testosterone enanthate 4 is given IM 5 every 3-4 wks, starting at 100 mg & ↑ by 50 mg every 6 mos to 200-400 mg.
  • In adulthood, treatment should plateau at best possible dosage, typically 50-400 mg every 2-4 wks.
  • If person has short stature & is eligible for growth hormone therapy, testosterone therapy should be either delayed or given at lower doses initially to maximize growth potential.
  • Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings.
Gynecomastia Reduction mammoplasty may be considered if gynecomastia is causing psychological distress.Regression of gynecomastia may occur w/testosterone replacement therapy.
Osteopenia Standard treatment per endocrinologistMay incl calcium, exercise, vitamin D, biphosphonates, or calcitonin
Undervirilization Standard therapy per urologistMay incl orchidopexy &/or hypospadias repair
Psychological
distress
Referral to mental health professionalSensitivity is necessary when conveying information to persons w/nonsyndromic 46,XX testicular DSD about genetic cause of the disorder & assoc sterility.

IM = intramuscularly

1.

Prior to initiating treatment with supplemental testosterone in adults, perform a digital rectal examination and measurement of prostate-specific antigen (PSA), abnormalities of which would be a contraindication to the treatment.

2.

Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy.

3.

Initial high doses of testosterone should be avoided to prevent priapism.

4.

Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage.

5.

Alternative delivery systems that result in more stable dosing include transdermal patches (scrotal and nonscrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of newer hydroalcoholic gels.

Surveillance

Table 7.

Recommended Surveillance for Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

System/ConcernEvaluationFrequency
Short stature Measurement of length/heightAt each visit
Low testosterone
levels
Assessment of mood, libido, energy, erectile function, acne, breast tenderness, & presence or progression of gynecomastiaAt each visit in adolescence & adulthood
For those on
testosterone
replacement
therapy
Measurement of serum testosterone levels
  • Every 3 mos (prior to next injection) to evaluate nadir testosterone concentrations 1
  • Once optimal dose is established, annual measurements are sufficient.
Digital rectal exam & measurement of PSA in adults 23, 6, & 12 mos after initiation of testosterone therapy; then annually
Measurement of hematocrit 33, 6, & 12 mos after initiation of testosterone therapy; then annually
Lipid profile & liver function testsAnnually
Osteopenia DXA scanEvery 3-5 yrs after puberty or annually if osteopenia has been identified

DXA = dual-energy x-ray absorptiometry; PSA = prostate-specific antigen

1.

Concentrations lower than 200 ng/dL or higher than 500 ng/dL may require adjustment of total dose or frequency.

2.

To evaluate for the presence of an overt prostate cancer, which would be a contraindication to supplemental testosterone treatment.

3.

Increased hematocrit may lead to risk of hypoxia and sleep apnea.

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 in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance and Risk to Sibs of a Proband

The mode of inheritance and recurrence risk to sibs of a proband with a nonsyndromic 46,XX testicular disorder/difference of sex development (DSD) depend on the molecular diagnosis in the proband and the genetic status of the parents (see Table 8). The reports of cryptic mosaic/chimeric translocations of SRY to the X chromosome seen only in gonads but not blood [Inoue et al 1998, Queipo et al 2002] complicate evaluation of recurrence risk and genetic counseling.

Table 8.

Mode of Inheritance and Recurrence Risk for Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

Molecular Diagnosis in ProbandGenetic MechanismGenetic Status of Proband's ParentsRecurrence Risk in Sibs of a Proband
SRY-positive 46,XX testicular DSD Almost all probands have a de novo translocation of SRY to an X chromosome. Karyotype of the father of a proband can be evaluated for rare possibility that the father has an extra X-linked copy of SRY. 1Parents are unaffected & are not carriers.Low (<1%)
The XY father has 2 copies of SRY (1 translocated to the X chromosome & 1 on the Y chromosome).XX sibs will have 46,XX testicular or ovotesticular DSD; XY sibs will not be affected.
SRY translocation to an autosome. An unaffected father may carry the translocation. Carrier status of the father should be assessed to evaluate recurrence risk.Parents are unaffected & are not carriers.Not ↑ over empiric risk in general population 2
The father is a carrier of a translocated SRY.XX sibs have a 50% chance of inheriting the translocated SRY & having 46,XX testicular or ovotesticular DSD; XY sibs will not be affected.
NR5A1-related 46,XX testicular DSD Recurrent missense variant p.Arg92Trp, de novo or inherited in an AD fashion, w/incomplete penetrance & variable expressivity. Genetic status of both parents should be assessed to guide genetic counseling about recurrence risk.At least 1 fertile 46,XY father has transmitted the variant to affected children. Heterozygous pathogenic variants in NR5A1 are often inherited from XX mothers.If a fertile parent is heterozygous, they will pass the variant to 50% of their offspring, who are at risk of testicular or ovotesticular DSD if XX. At least 1 sib w/46,XY karyotype has been reported, with a phenotype of gonadal dysgenesis & female anatomy.
SOX3-related 46,XX testicular DSD Microdeletions just upstream of the open reading frame of SOX3 or microduplications in SOX3. These alterations have been de novo in all persons reported to date.To date, all reported parents are unaffected & are not carriers.To date, no sibs have been affected.
SOX9-related 46,XX testicular DSD Rearrangement/duplication involving SOX93 Transmission through an unaffected 46,XY father has been demonstrated in at least 2 families w/testicular DSD & 3 w/ovotesticular DSD. Carrier status of the father should be assessed to evaluate recurrence risk.Parents are unaffected & are not carriers.Not ↑ over empiric risk in general population 2
The father is heterozygous for a CNV in or around SOX9. All reported 46,XY carriers have been fertile, anatomically typical males. One such XY father (the father of a proband w/ovotesticular DSD) was reported to have inherited the duplication from his fertile 46,XX mother.The risk to the sibs of inheriting the CNV is 50%. Persons w/46,XX karyotype who inherit the CNV are at risk of having 46,XX testicular (or ovotesticular) DSD. Persons w/46,XY karyotype will be typical fertile males.
WT1-related 46,XX testicular DSD Frameshift & missense variants affecting the ZF4 domain of WT1. These alterations have been de novo in all persons reported to date.To date, all reported parents are unaffected & not carriers.One XY sib w/the recurrent p.Arg500Gln variant presented w/Meacham syndrome, male external genitalia, anorchia, & diaphragmatic hernia. No recurrences have been reported in the other 7 families to date.
SRY-negative 46,XX testicular DSD not caused by SOX9, SOX3, NR5A1, or WT1 pathogenic variants UnknownIf the family history suggests an AR 4 MOI, both parents are presumed to be carriers of 1 causative pathogenic variant.In AR inheritance, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, & a 25% chance of being unaffected & not a carrier.

AD = autosomal dominant; AR = autosomal recessive; CNV = copy number variant; DSD = disorders/differences of sex development; MOI = mode of inheritance

1.

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 with SRY-positive 46,XX ovotesticular DSD.

2.

This risk could be theoretically increased in case of paternal germline mosaicism.

3.

Small duplication or triplication of the promoter region of SOX9; a balanced chromosomal translocation involving the 17q24.3 region; or duplication of the entire SOX9 gene (reviewed in Croft et al [2018b]).

4.

Although recurrence in sibs has suggested autosomal recessive inheritance (e.g., McElreavey et al [1993]), it is not known if autosomal recessive inheritance is the correct explanation for the recurrence pattern observed.

Offspring of a proband. Individuals with nonsyndromic 46,XX testicular DSD are infertile.

Related Genetic Counseling Issues

Management of infertility. A management option for infertility in couples where the male has 46,XX testicular DSD is artificial insemination of the female partner with donor sperm.

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

Prenatal Testing and Preimplantation Genetic Testing

Pregnancies known to be at increased risk. Once the genetic cause of 46,XX testicular DSD has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Pregnancies not known to be at increased risk. In most cases, the suspicion of 46,XX testicular DSD arises during pregnancy when the karyotype (done for an unrelated reason) or the result of a noninvasive prenatal test 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;
  • The phenotypic variability associated with most known etiologies;
  • 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.

  • MedlinePlus
  • Accord Alliance
    Phone: 602-492-4144
  • Differences of Sex Development - Translational Research Network
  • InterNational Council on Infertility Information Dissemination, Inc. (INCIID)
    Phone: 703-379-9178
    Fax: 703-379-1593
    Email: INCIIDinfo@inciid.org
  • RESOLVE: The National Infertility Association
    7918 Jones Branch Drive
    Suite 300
    McLean VA 22102
    Phone: 703-556-7172
    Fax: 703-506-3266
    Email: info@resolve.org

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.

Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development (View All in OMIM)

184757NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 1; NR5A1
27885046,XX SEX REVERSAL 2; SRXX2
30083346,XX SEX REVERSAL 3; SRXX3
313430SRY-BOX 3; SOX3
40004546,XX SEX REVERSAL 1; SRXX1
480000SEX-DETERMINING REGION Y; SRY
607102WT1 TRANSCRIPTION FACTOR; WT1
608160SRY-BOX 9; SOX9
61748046,XX SEX REVERSAL 4; SRXX4

Molecular Pathogenesis

Approximately 80% of individuals with nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have the condition due to the presence of a small Y chromosome fragment (including SRY) in the genome that resulted from an abnormal terminal X-Y exchange during paternal meiosis. This abnormal recombination involves highly homologous loci (recombination hot spots) on the sex-specific part of the X and Y chromosomes [Weil et al 1994].

Mechanism of disease causation

  • NR5A1. The NR5A1 c.274C>T (p.Arg92Trp) pathogenic variant has been shown to repress the female-specific WNT signaling pathways [Knarston et al 2019].
  • SOX3. Duplications or translocation in regulatory regions of SOX3, a gene very structurally similar to SRY and not normally expressed in gonadal tissue, are thought to trigger ectopic expression of SOX3 in XX developing gonadal tissues, leading to a male developmental pathway [Sutton et al 2011].
  • SOX9. Duplications and triplications in the regulatory regions of SOX9 are thought to trigger overexpression of SOX9, the immediate downstream target of SRY in the male developmental pathway, to levels sufficient to override repression of the ovarian pathway and drive the formation of testes or ovotestes in the absence of SRY.
  • SRY is the primary sex-determination gene, triggering the male developmental pathway in the bipotential gonad [Sinclair et al 1990]. Presence of Y chromosome material including SRY, most frequently translocated onto the X chromosome (rare translocations to autosomes have been described), triggers the male gonadal differentiation cascade, but absence of the other Y-chromosome genes results in azoospermia and infertility.
  • WT1 pathogenic variants in the fourth zinc finger domain (ZF4) interfere with the pro-ovarian beta-catenin pathway and activate the pro-testis SOX9-dependent pathway in vitro [Eozenou et al 2020].

Table 9.

Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Gene-Specific Laboratory Considerations

Gene 1Special Consideration
NR5A1
SOX3 None
SOX9 CNVs affecting SOX9 expression are in a gene desert & may not be identified by automated algorithms. 2
SRY
  • Only the presence of a copy of SRY in a 46,XX genome, not single-nucleotide variants in SRY, is relevant to 46,XX testicular DSD etiology.
  • SRY may be present in mosaic form in blood, & cases have been reported where SRY is found in the gonad only, not in blood [Inoue et al 1998, Queipo et al 2002].
WT1 Only variants affecting the ZF4 domain have been assoc w/nonsydromic 46,XX testicular DSD.

CNV = copy number variant; DSD = disorders/differences of sex development

1.

Genes are listed in alphabetic order.

2.

At least one case of a 46,XX individual who was mosaic for SOX9-associated duplications has been reported [Huang et al 1999].

Table 10.

Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Notable Pathogenic Variants by Gene

Gene 1Reference SequencesDNA Nucleotide Change
(Alias 2)
Predicted Protein Change
(Alias 2)
Comment [References]
NR5A1 NM_004959​.5
NP_004950​.2
c.274C>Tp.Arg92TrpRecurrent pathogenic variant [Bashamboo et al 2016, Baetens et al 2017, Igarashi et al 2017, Knarston et al 2019]
WT1 NM_024426​.6
NP_077744​.4
c.1499G>A
(c.1484G>A)
p.Arg500Gln
(p.Arg495Gln)
Recurrent pathogenic variant [Eozenou et al 2020]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Genes are listed in alphabetic order.

2.

Variant designation that does not conform to current naming conventions

Chapter Notes

Author Notes

Eric Vilain is a founder of the NIH-funded DSD-TRN (Disorders/Differences of Sex Development Translational Research Network). Emmanuèle Délot serves as the national coordinator and chair of the Publications & Research committee for the network. Both have investigated the genetics and mechanisms of DSD, including 46,XX testicular DSD, for more than 20 years.

Revision History

  • 26 May 2022 (ma) Comprehensive update posted live
  • 7 May 2015 (me) Comprehensive update posted live
  • 26 May 2009 (me) Comprehensive update posted live
  • 5 April 2006 (me) Comprehensive update posted live
  • 30 October 2003 (me) Review posted live
  • 29 May 2003 (ejv) Original submission

References

Literature Cited

  • Abbas N, McElreavey K, Leconiat M, Vilain E, Jaubert F, Berger R, Nihoul-Fekete C, Rappaport R, Fellous M. Familial case of 46,XX male and 46,XX true hermaphrodite associated with a paternal-derived SRY-bearing X chromosome. C R Acad Sci III. 1993;316:375–83. [PubMed: 8402263]
  • Baetens D, Stoop H, Peelman F, Todeschini AL, Rosseel T, Coppieters F, Veitia RA, Looijenga LH, De Baere E, Cools M. NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. Genet Med. 2017;19:367–76. [PMC free article: PMC5392598] [PubMed: 27490115]
  • Bashamboo A, Donohoue PA, Vilain E, Rojo S, Calvel P, Seneviratne SN, Buonocore F, Barseghyan H, Bingham N, Rosenfeld JA, Mulukutla SN, Jain M, Burrage L, Dhar S, Balasubramanyam A, Lee B. Members of UDN, Dumargne MC, Eozenou C, Suntharalingham JP, de Silva K, Lin L, Bignon-Topalovic J, Poulat F, Lagos CF, McElreavey K, Achermann JC. A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Hum Mol Genet. 2016;25:3446–53. [PMC free article: PMC5179941] [PubMed: 27378692]
  • Boucekkine C, Toublanc JE, Abbas N, Chaabouni S, Ouahid S, Semrouni M, Jaubert F, Toublanc M, McElreavey K, Vilain E, Fellous M. Clinical and anatomical spectrum in XX sex reversed patients. Relationship to the presence of Y specific DNA-sequences. Clin Endocrinol (Oxf). 1994;40:733–42. [PubMed: 8033363]
  • Carcavilla A, Alonso M, Ezquita B, Garcia-Galloway E, Barrio R, Nistal M. An XX male with an intratubular undifferentiated germ cell neoplasia. Fertil Steril. 2008;90:2005.e3–5. [PubMed: 18701099]
  • Croft B, Ohnesorg T, Hewitt J, Bowles J, Quinn A, Tan J, Corbin V, Pelosi E, van den Bergen J, Sreenivasan R, Knarston I, Robevska G, Vu DC, Hutson J, Harley V, Ayers K, Koopman P, Sinclair A. Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9. Nature communications. 2018a;9:5319. [PMC free article: PMC6293998] [PubMed: 30552336]
  • Croft B, Ohnesorg T, Sinclair A. The role of copy number variants in disorders of sex development. Sex Dev. 2018b;12:19–29. [PubMed: 29145200]
  • Délot EC, Vilain E. Towards improved diagnosis of human differences of sex development. Nat Rev Genet. 2021;22:588–602. [PubMed: 34083777]
  • Eozenou C, Gonen N, Touzon MS, Jorgensen A, Yatsenko SA, Fusee L, Kamel AK, Gellen B, Guercio G, Singh P, Witchel S, Berman AJ, Mainpal R, Totonchi M, Mohseni Meybodi A, Askari M, Merel-Chali T, Bignon-Topalovic J, Migale R, Costanzo M, Marino R, Ramirez P, Perez Garrido N, Berensztein E, Mekkawy MK, Schimenti JC, Bertalan R, Mazen I, McElreavey K, Belgorosky A, Lovell-Badge R, Rajkovic A, Bashamboo A. Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene. Proc Natl Acad Sci U S A. 2020;117:13680–8. [PMC free article: PMC7306989] [PubMed: 32493750]
  • Ergun-Longmire B, Vinci G, Alonso L, Matthew S, Tansil S, Lin-Su K, McElreavey K, New MI. Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature. J Pediatr Endocrinol Metab. 2005;18:739–48. [PubMed: 16200839]
  • Fechner PY, Marcantonio SM, Jaswaney V, Stetten G, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz GD, Amrhein JA, Bard PA. The role of the sex-determining region Y gene in the etiology of 46,XX maleness. J Clin Endocrinol Metab. 1993;76:690–5. [PubMed: 8383144]
  • Gomes NL, de Paula LCP, Silva JM, Silva TE, Lerário AM, Nishi MY, Batista RL, Faria Júnior JAD, Moraes D, Costa EMF, Hemesath TP, Guaragna-Filho G, Leite JCL, Carvalho CG, Domenice S, Costa EC, Mendonca BB. A. 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant. Clin Genet. 2019;95:172–6. [PubMed: 30294972]
  • Haines B, Hughes J, Corbett M, Shaw M, Innes J, Patel L, Gecz J, Clayton-Smith J, Thomas P. Interchromosomal insertional translocation at Xq26.3 alters SOX3 expression in an individual with XX male sex reversal. J Clin Endocrinol Metab. 2015;100:E815–20. [PubMed: 25781358]
  • Huang B, Wang S, Ning Y, Lamb AN, Bartley J. Autosomal XX sex reversal caused by duplication of SOX9. Am J Med Genet. 1999;87:349–53. [PubMed: 10588843]
  • Igarashi M, Takasawa K, Hakoda A, Kanno J, Takada S, Miyado M, Baba T, Morohashi KI, Tajima T, Hata K, Nakabayashi K, Matsubara Y, Sekido R, Ogata T, Kashimada K, Fukami M. Identical NR5A1 missense mutations in two unrelated 46,XX individuals with testicular tissues. Hum Mutat. 2017;38:39–42. [PubMed: 27610946]
  • Inoue H, Nomura M, Yanase T, Ichino I, Goto K, Ikuyama S, Takyanagi R, Nawata H. A rare case of 46,XX true hermaphroditism with hidden mosaicism with sex-determinin region Y chromosome-bearing cells in the gonads. Intern Med. 1998;37:467–71. [PubMed: 9652903]
  • Kim JW, Bak CW, Chin MU, Cha DH, Yoon TK, Shim SH. SRY-negative 46,XX infertile male with Leydig cell hyperplasia: clinical, cytogenetic, and molecular analysis and review of the literature. Fertil Steril. 2010;94:753.e5–9. [PubMed: 20227075]
  • Knarston IM, Robevska G, van den Bergen JA, Eggers S, Croft B, Yates J, Hersmus R, Looijenga LHJ, Cameron FJ, Monhike K, Ayers KL, Sinclair AH. NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients. Hum Mutat. 2019;40:207–16. [PMC free article: PMC6492147] [PubMed: 30350900]
  • Lee PA, Houk CP, Ahmed SF, Hughes IA, et al. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006;118:e488–500. [PubMed: 16882788]
  • McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc Natl Acad Sci U S A. 1993;90:3368–72. [PMC free article: PMC46301] [PubMed: 8475082]
  • Moalem S, Babul-Hirji R, Stavropolous DJ, Wherrett D, Bägli DJ, Thomas P, Chitayat D. XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication. Am J Med Genet Part A. 2012;158A:1759–64. [PubMed: 22678921]
  • Osaka A, Ide H, Matsuoka K, Iwahata T, Kobori Y, Ban S, Okada H, Saito K. SRY-positive 46,XX testicular disorder of sexual development with Leydig cell tumor. Am J Mens Health. 2020;14:1557988320970071. [PMC free article: PMC7607790] [PubMed: 33131361]
  • Queipo G, Zenteno JC, Peña R, Nieto K, Radillo A, Dorantes LM, Eraña L, Lieberman E, Söderlund D, Jiménez AL, Ramón G, Kofman-Alfaro S. Molecular analysis in true hermaphroditism: demonstration of low-level hidden mosaicism for Y-derived sequences in 46,XX cases. Hum Genet. 2002;111:278–83. [PubMed: 12215841]
  • Refai O, Friedman A, Terry L, Jewett T, Pearlman A, Perle MA, Ostrer H. De novo 12:17 translocation upstream of SOX9 resulting in 46,XX testicular disorder of sex development. Am J Med Genet. 2010;152A:422–6. [PubMed: 20082466]
  • Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990;346:240–4. [PubMed: 1695712]
  • Sirokha D, Gorodna O, Vitrenko Y, Zelinska N, Ploski R, Nef S, Jaruzelska J, Kusz-Zamelczyk K, Livshits L. A novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD patient results in the retention of intron 9. Biology (Basel). 2021;10:1248. [PMC free article: PMC8698877] [PubMed: 34943163]
  • Suntharalingham JP, Buonocore F, Duncan AJ, Acherman JC. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015;29:607–19. [PMC free article: PMC5159745] [PubMed: 26303087]
  • Sutton E, Hughes J, White S, Sekido R, Tan J, Arboleda V, Rogers N, Knower K, Rowley L, Eyre H, Rizzoti K, McAninch D, Goncalves J, Slee J, Turbitt E, Bruno D, Bengtsson H, Harley V, Vilain E, Sinclair A, Lovell-Badge R, Thomas P. Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Invest. 2011;121:328–41. [PMC free article: PMC3007141] [PubMed: 21183788]
  • Vetro A, Dehghani MR, Kraoua L, Giorda R, Beri S, Cardarelli L, Merico M, Manolakos E, Bustamante AP, Castro A, Radi O, Camerino G, Brusco A, Sabaghian M, Sofocleous C, Forzano F, Palumbo P, Palumbo O, Calvano S, Zelante L, Grammatico P, Giglio S, Basly M, Chaabouni M, Carella M, Russo G, Bonaglia MC, Zuffardi O. Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3. Eur J Hum Genet. 2015;23:1025–32. [PMC free article: PMC4795112] [PubMed: 25351776]
  • Weil D, Wang I, Dietrich A, Poustka A, Weissenbach J, Petit C. Highly homologous loci on the X and Y chromosomes are hot-spots for ectopic recombinations leading to XX maleness. Nat Genet. 1994;7:414–9. [PubMed: 7920661]
  • Zenteno-Ruiz JC, Kofman-Alfaro S, Méndez JP. 46,XX sex reversal. Arch Med Res. 2001;32:559–66. [PubMed: 11750731]
Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2023 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1416PMID: 20301589

Views

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...