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 reduced 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.

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).

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

• Shorter-than-average stature has been described.
• Three individuals without genital ambiguity were incidentally diagnosed while being evaluated for developmental delay or gender dysphoria [Sutton et al 2011, Vetro et al 2015] (see Differential Diagnosis for discussion of syndromic forms of 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 reduced 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.

Allelic Nonsyndromic Disorders

Nonsyndromic 46,XX testicular and 46,XX ovotesticular (defined as the presence of both testicular and ovarian tissue in an individual) disorders/differences of sex development (DSD) may represent the same genetic entity, as both phenotypes are represented in families with 46,XX males. However, it is critical to differentiate them, as their potential outcomes differ, requiring different management. The presence of ovarian tissue, however minimal, in a self-identified boy may lead to feminization of physical characteristics (reduced hair, gynecomastia, menstrual flow), a possible indication for surgical excision of the ovarian portion of the gonad. Conversely, the presence of testicular tissue in a self-identified girl could eventually lead to unwanted hirsutism and may increase tumor risk.

Differences between 46,XX ovotesticular DSD and 46,XX testicular DSD include the following:

• Individuals with ovotesticular DSD (formerly known as "true hermaphrodites") have both testicular and ovarian tissue either as an ovotestis or as an ovary and a contralateral testis, whereas the gonads of individuals with 46,XX testicular DSD consist only of testicular tissue. The type of gonadal tissue can be established by gonadal biopsy. The possibility of bias of sampling of a gonadal biopsy that may miss the ovarian portion of the gonads needs to be considered.
• Ovotesticular DSD may be associated with the presence of a uterus or a hemi-uterus; individuals with nonsyndromic 46,XX testicular DSD have no müllerian structures.
• Endocrine investigations may reveal estrogen production in individuals with ovotesticular DSD.

All known genetic causes of nonsyndromic 46,XX testicular DSD can also lead to 46,XX ovotesticular DSD:

• NR5A1. Heterozygous pathogenic variants that lead to the predicted p.Arg92Trp protein change are associated with variable phenotypes, including ovotesticular DSD.
• SOX3. 46,XX ovotesticular DSD was reported in one individual with a 774-kb insertion translocated from chromosome 1 to a region 82 kb distal to SOX3, resulting in upregulation of SOX3 expression [Haines et al 2015]. In this individual, ultrasound of bilateral descended gonads in a rugated scrotum suggested the gonads were testes; on biopsy, one of the gonads contained ovarian tissue, resulting in a diagnosis of ovotesticular DSD [Haines et al 2015]. The translocation involving SOX3 was inherited from a fertile mother. The discrepancy in phenotypes between the mother and proband could be attributed to differential X inactivation in the developing gonad, but this could not be demonstrated. Testicular DSD was suspected in the other five individuals with SOX3-associated 46,XX DSD reported to date, but histologically demonstrated in only one [Sutton et al 2011].
• SOX9. SOX9-associated duplications appear to be more frequently associated with ovotesticular DSD than with testicular DSD. The two phenotypes have not been reported in the same family.
• SRY. SRY translocations are much more frequently associated with nonsyndromic 46,XX testicular DSD than with ovotesticular DSD.
• WT1. Testicular DSD appears to be more frequent than ovotesticular DSD in 46,XX individuals with pathogenic variants affecting the ZF4 domain of WT1; of the nine individuals reported to date, four have histologically demonstrated testicular DSD (with two suspected) and two have documented ovotesticular DSD (with one suspected).

Table 2 summarizes allelic nonsyndromic DSD conditions.

Allelic Syndromic Disorders

SOX3. Larger duplications of approximately six megabases (Mb) have been described in two individuals with 46,XX testicular DSD associated with developmental delay [Sutton et al 2011, Vetro et al 2015].

Table 3 summarizes allelic syndromic conditions.

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.

Treatment of Manifestations

Surveillance

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.

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.

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.

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].

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

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