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

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Nonsyndromic 46,XX Testicular Disorders of Sex Development

Synonyms: 46,XX Testicular DSD

, PhD and , MD, PhD, FACMG.

Author Information
, PhD
Departments of Human Genetics and Pediatrics
University of California School of Medicine
Los Angeles, California
, MD, PhD, FACMG
Departments of Human Genetics, Pediatrics, and Urology
University of California School of Medicine
Los Angeles, California

Initial Posting: ; Last Update: May 7, 2015.

Summary

Clinical characteristics.

Nonsyndromic 46,XX testicular disorders of sex development (46,XX testicular DSD) are 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 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 (CMA). Rearrangements in or around SOX9 and SOX3 detected by CMA, or rarely karyotype, have recently been reported in a few cases; at least one more as-yet-unknown gene at another locus is implicated.

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. Providers are encouraged to anticipate the need for further psychological support.

Surveillance: Monitor for testosterone effects during testosterone replacement therapy, including prostate size and prostate-specific antigen (PSA) in adults; routine monitoring of hematocrit, lipid profile, and liver function tests; 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 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.

Autosomal dominant inheritance has been documented for familial cases thought to be caused by CNV in or around SOX9.

The mode of inheritance of other 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.

GeneReview Scope

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

For synonyms and outdated names see Nomenclature.

Diagnosis

Algorithms have been developed for the evaluation and diagnosis of disorders of sex development (DSD), including nonsyndromic 46,XX testicular DSD [Barseghyan et al, in press].

Suggestive Findings

The diagnosis of a nonsyndromic 46,XX testicular disorder of sex development (46,XX testicular DSD) may be suggested by the following clinical findings and/or laboratory findings.

Clinical findings

  • Male external genitalia that range from typical to ambiguous (penoscrotal hypospadias with or without chordee)
  • Two testicles
  • No evidence of Müllerian structures

Laboratory findings

  • A 46,XX karyotype using conventional staining methods
  • Azoospermia
  • Endocrine studies that demonstrate 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 gonadotropin (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.
  • Preservation of the hypothalamic-pituitary axis:
    • GnRH stimulation testing shows a normal LH and FSH response.
      Note: Such testing is not warranted for diagnosis.
  • Testicular biopsy that 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.

Establishing the Diagnosis

The diagnosis of a nonsyndromic 46,XX testicular DSD is established in a proband who has the above clinical features and an XX sex chromosome complement. A genetic diagnosis is established if there is evidence of either SRY (the gene encoding the sex-determining region Y) or copy number variants or rearrangements in or around SOX9 or SOX3.

Molecular genetic testing approaches rely on fluorescence in situ hybridization (FISH) for SRY and/or chromosomal microarray (CMA).

  • FISH for SRY. This is a standard test that is often sent concurrently with karyotype in individuals for whom a DSD diagnosis is being entertained. This test, however, cannot detect copy number variants or rearrangements in or around SOX9 or SOX3.
  • Chromosome microarray (CMA) can detect SRY and copy number variants or rearrangements in or around SOX9 or SOX3.

SRY-positive 46,XX testicular DSD is established in individuals with evidence of SRY.

SRY-negative 46,XX testicular DSD is established in individuals with no evidence of SRY on CMA or FISH and evidence of copy number variants or rearrangements in or around SOX9 or SOX3:

Molecular Genetic Testing Strategy

In an individual with ambiguous genitalia in whom no chromosome study has been performed

  • One testing option is to perform karyotype with FISH for SRY first. If the karyotype is normal 46,XX and FISH for SRY is negative, proceed to chromosomal microarray (CMA).
  • An alternative option is to perform CMA first, which will give information about the sex chromosome complement, the presence of SRY, and other copy number variants of clinical relevance.

    If the CMA is normal female without any clinically significant copy number variants in or around SRY, SOX9, and SOX3, consider karyotype as a next step to evaluate for balanced rearrangements.

In a phenotypic male or an individual with ambiguous genitalia in whom a 46,XX karyotype is already established

  • FISH of an SRY probe to metaphase chromosomes should be performed to determine the presence and, if positive, 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.
  • If SRY by FISH is not positive, CMA should be the next step. CMA may reveal the presence of SRY not detected by FISH, including mosaicism. It will also identify copy number variants in and around SOX9 and SOX3.

Table 1.

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

Gene 1Test Method Proportion of 46,XX Testicular DSD Accounted for by Mutation of This Gene
Normal Male GenitaliaAmbiguous Male Genitalia
SRYCMA or FISH 280% 3 Rare
SOX9CMA<10% 4<10% 4
SOX3CMARare 4 Rare 5
Unknown 6NA

Clinical Characteristics

Clinical Description

Approximately 85% of individuals with a nonsyndromic 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 [Zenteno-Ruiz et al 2001]; up to 90% of these individuals are SRY positive [McElreavey et al 1993]. 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 15% of individuals with a nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia, typically penoscrotal hypospadias with or without chordee [Zenteno-Ruiz et al 2001]; only a minority of these individuals are SRY positive [Fechner et al 1993, McElreavey et al 1993, Boucekkine et al 1994].

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

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

SRY-positive nonsyndromic 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
  • Azospermia

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 nonsyndromic 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.

SOX9-related nonsyndromic 46,XX testicular DSD. Of the limited number of individuals with confirmed SOX9-related 46,XX testicular DSD reported to date, none presented in the newborn period with ambiguous genitalia, one was ascertained at age four years with small testes as the sole finding, and three presented as adults with infertility and azoospermia.

A primary presentation of delayed puberty has not been reported.

As gonadal biopsy is not routinely performed, it is unclear what percentage of individuals with copy number variants in and around SOX9 have testicular DSD versus ovotesticular DSD, an allelic disorder.

SOX3-related nonsyndromic 46,XX testicular DSD. Shorter-than-average stature, small testes with azoospermia and low testosterone are seen in affected individuals.

Only one of five affected individuals presented at birth with atypical male genitalia. One affected individual was diagnosed in adulthood because of infertility. In the other three individuals, SOX3-related 46,XX testicular DSD without genital ambiguity was discovered during consultation for developmental delay or gender dysphoria (see Differential Diagnosis for discussion of syndromic forms of DSD).

Genotype-Phenotype Correlations

In nonsyndromic 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 nonsyndromic 46,XX testicular DSD have typical male external genitalia [Vilain et al 1994, Zenteno et al 1997, Kolon et al 1998, Vernole et al 2000, Abusheikha et al 2001]. This number may increase as larger cohorts of adults undergoing evaluation for fertility problems are tested. A recent study found three individuals with a 46,XX karyotype among 555 infertile adult Taiwainese males; two of the three individuals were SRY positive [Chiang et al 2013].

Due to the small number of individuals reported with SOX9-related 46,XX testicular DSD and SOX3-related 46,XX testicular DSD, genotype-phenotype correlations are not yet available.

Penetrance

Penetrance in those with a known genetic etiology is believed to be 100%, but no data are available.

One report of a small duplication in the SOX9 promoter region in a newborn with a 46,XX karyotype and ambiguous genitalia states that the duplication was found not only in the proband’s 46,XY fertile father and phenotypically normal male brothers, but also in his paternal 46,XX (fertile) grandmother [Benko et al 2011].

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 disorders of sex development" and “46,XX ovotesticular DSD” respectively [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 forms of 46,XX testicular DSD

  • Syndromic forms of 46,XX testicular DSD – characterized by palmoplantar keratosis and predisposition to squamous cell carcinoma of the skin – have been shown to be associated with pathogenic variants in R-Spondin 1 (RSPO1) [Parma et al 2006, Tomaselli et al 2008] (OMIM 610644).
  • 46,XX testicular DSD may be associated with microphthalmia and linear skin defects when the X/Y abnormal interchange results in microdeletion of Xp [Lindsay et al 1994, Kotzot et al 2002, Anguiano et al 2003].
  • Facial dysmorphic features were found in association with 46,XX testicular DSD in the reported cases of balanced translocation involving the SOX9 region, 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 2014].
  • Developmental delay was associated with 46,XX testicular DSD (without ambiguous genitalia) in the two individuals with de novo large (5.6 and 6 Mb) duplications of the Xq27 region, including SOX3 and several other genes. The most likely etiology for the developmental issues in these individuals is deletion of multiple genes around SOX3.

The most common disorders in the differential diagnosis of nonsyndromic 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. Depending on the relative ratio of XX and XY cells, individuals with 46,XX/46,XY chimerism may present with external genitalia ranging from typical male to ambiguous to typical female. In addition, evidence suggests that some XX individuals who are masculinized show some low-level hidden, tissue-specific 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 may be 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.

46,XX ovotesticular DSD. 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. Possible 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 46,XX testicular DSD have no Müllerian structures. Endocrine investigations may reveal estrogen production in individuals with ovotesticular DSD.

Testicular and ovotesticular DSD may represent the same genetic entity, as both phenotypes may be represented in families with 46,XX males. However, it is critical to differentiate them, as their potential outcomes differ, thus affecting 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. While 46,XX ovotesticular DSD has been associated with the presence of SRY (most likely in either mosaic or chimeric form) and with copy number variants in and around SOX9, to date it has not been reported in association with SOX3 copy number variants.

Prenatal exposure of 46,XX fetuses to androgens

  • Congenital adrenal hyperplasia. 21-hydroxylase deficiency (21-OHD) 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 classic 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals 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). Molecular genetic testing of CYP21A2 for a panel of nine common pathogenic variants and gene deletions detects approximately 80%-98% of disease-causing alleles in affected individuals and carriers. Inheritance is autosomal recessive. Rarer genetic causes of CAH (less common 21-OHD variants and variants in other genes) exist and testing may also be available for these variants.
  • Prenatal exposure of a fetus with an XX karyotype to externally administered androgens such as Danazol or to androgens endogenously produced 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 ambiguous genitalia.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a 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
  • Medical genetics consultation

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 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 newer hydroalcoholic gels [Kühnert 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. Providers are encouraged to anticipate the need for further psychological assistance.

Surveillance

Monitoring during testosterone replacement therapy should include the following:

  • 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
  • Ongoing psychosocial support

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 nonsyndromic 46,XX testicular disorders of sex development (46,XX testicular DSD) are generally not inherited as they result 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.

SOX9-related 46,XX testicular disorders of sex development (which results from 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) are inherited in a sex-limited autosomal dominant manner [Huang et al 1999, Refai et al 2010, Cox et al 2011, Vetro et al 2011, Xiao et al 2013, Lee et al 2014, Vetro et al 2014, Kim et al 2015].

The inheritance of SOX3-related 46,XX testicular DSD (which results from microdeletions just upstream of the open reading frame of SOX3 [Sutton et al 2011] or microduplications in SOX3 [Sutton et al 2011, Moalem et al 2012]) is not known.

The mode of inheritance of other 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 with SRY-positive 46,XX ovotesticular DSD. 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 or ovotesticular DSD. 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 or ovotesticular DSD. XY sibs will not be affected.

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

Risk to Family Members — SOX9-Related 46,XX Testicular DSD

Parents of a proband

  • A proband with SOX9-related 46,XX testicular DSD may have the disorder as the result of a de novo rearrangement/duplication.
  • The parents of individuals with 46,XX testicular DSD are unaffected.
    • Fathers of individuals with a SOX9-related 46,XX testicular DSD are 46,XY typical fertile males who may have a heterozygous copy number variant (CNV) in or around SOX9.
    • Mothers of individuals with a SOX9-related 46,XX testicular DSD are 46,XX non-carrier typical females.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s father.
  • If the father has a CNV in or around SOX9, the risk to the sibs of inheriting the CNV is 50%.
    • Individuals with a 46,XX karyotype who inherit the CNV are at risk of having 46,XX testicular (or ovotesticular) DSD.
    • Individuals with a 46,XY karyotype will be typical fertile males.

Offspring of a proband. Individuals with SOX9-related 46,XX testicular DSD are infertile.

Risk to Family Members — SOX3-Related 46,XX Testicular DSD

Parents of a proband

  • To date, all individuals with SOX3-related 46,XX DSD have been simplex cases (i.e., a single occurrence in a family). No parents have been affected.
  • In the two affected individuals where parents were available for testing, the copy number variant was de novo.

Sibs of a proband

  • To date, all individuals with SOX3-related 46,XX DSD have been simplex cases (i.e., a single occurrence in a family). No sibs have been affected.

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

Risk to Family Members — SRY-Negative 46,XX Testicular DSD Not Caused by SOX9 or SOX3 Variants

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. Individuals with SRY-negative 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 [Lissens et al 2002].

Family planning. The optimal time for determination of genetic risk and discussion of the availability 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, allelic variants, 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 requires conventional cytogenetic analysis and FISH of an SRY probe. If SRY by FISH is not positive, PCR for SRY may be performed.

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.

  • Accord Alliance
    531 Route 22 East
    #244
    Whitehouse Station NJ 08889
    Phone: 908-349-0534
    Fax: 801-349-0534
  • InterNational Council on Infertility Information Dissemination, Inc. (INCIID)
    5765 F Burke Centre Pkwy
    Box 330
    Burke VA 22015
    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 of Sex Development: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SRYYp11​.31Sex-determining region Y proteinSRY databaseSRY

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 Nonsyndromic 46,XX Testicular Disorders 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 as a 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.

SRY

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

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

SOX3

Gene structure. SOX genes share an SRY-related HMG-box. SOX3 is a single-exon gene, structurally and functionally similar to SRY but is not normally expressed in the developing gonad. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. None

Pathogenic allelic variants. Microdeletions just upstream of the SOX3 open reading frame [Sutton et al 2011] or microduplications of SOX3 [Sutton et al 2011, Moalem et al 2012] have been associated with a minority of cases of nonsyndromic 46,XX testicular DSD.

Normal gene product. SOX3 is a 446-amino acid protein, with a single HMG-box that binds to the minor groove of DNA in a highly sequence-specific manner.

Abnormal gene product. Abnormal expression of SOX3 in gonadal tissue is thought to be the mechanism underlying nonsyndromic 46,XX testicular DSD seen in some individuals [Sutton et al 2011].

SOX9

Gene structure. SOX9 is a single-exon gene, structurally and functionally similar to SRY but is not normally expressed in the developing gonad. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. None.

Pathogenic allelic variants. Approximately 10% of individuals with nonsyndromic SRY-negative 46,XX testicular DSD have been found to have small duplication or triplication of the promoter region of SOX9; balanced chromosomal translocations involving the 17q24.3 region; or large duplications of the entire SOX9 (in mosaic and non mosaic form).

Normal gene product. SOX9 encodes a single HMG-box 509-amino acid protein, activated by SRY in the male sex-determination cascade.

Abnormal gene product. In the absence of SRY, gonadal activation of SOX9 is necessary and sufficient to trigger the male sex-determination cascade. Copy number variants in the promoter of SOX9 are thought to result in such activation in 46,XX testicular DSD.

References

Literature Cited

  1. 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]
  2. Abusheikha N, Lass A, Brinsden P. XX males without SRY gene and with infertility. Hum Reprod. 2001;16:717–8. [PubMed: 11278224]
  3. Andersson M, Page DC, de la Chapelle A. Chromosome Y-specific DNA is transferred to the short arm of X chromosome in human XX males. Science. 1986;233:786–8. [PubMed: 3738510]
  4. Anguiano A, Yang X, Felix JK, Hoo JJ. Twin brothers with MIDAS syndrome and XX karyotype. Am J Med Genet A. 2003;119A:47–9. [PubMed: 12707958]
  5. Barseghyan H, Délot E, Vilain E. New genomic technologies: an aid for diagnosis of disorders of sex development. Horm Metab Res. In press.
  6. Benko S, Gordon CT, Mallet D, Sreenivasan R, Thauvin-Robinet C, Brendehaug A, Thomas S, Bruland O, David M, Nicolino M, Labalme A, Sanlaville D, Callier P, Malan V, Huet F, Molven A, Dijoud F, Munnich A, Faivre L, Amiel J, Harley V, Houge G, Morel Y, Lyonnet S. Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. J Med Genet. 2011;48:825–30. [PubMed: 22051515]
  7. 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]
  8. de la Chapelle A. Analytic review: nature and origin of males with XX sex chromosomes. Am J Hum Genet. 1972;24:71–105. [PMC free article: PMC1762158] [PubMed: 4622299]
  9. de la Chapelle A. The etiology of maleness in XX men. Hum Genet. 1981;58:105–16. [PubMed: 6945286]
  10. Chiang HS, Wu YN, Wu CC, Hwang JL. Cytogenic and molecular analyses of 46,XX male syndrome with clinical comparison to other groups with testicular azoospermia of genetic origin. J Formos Med Assoc. 2013;112:72–8. [PubMed: 23380608]
  11. Cox JJ, Willatt L, Homfray T, Woods CG. A SOX9 duplication and familial 46,XX developmental testicular disorder. NEJM. 2011;364:91–3. [PubMed: 21208124]
  12. 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]
  13. Evans HJ, Buckton KE, Spowart G, Carothers AD. Heteromorphic X chromosomes in 46,XX males: evidence for the involvement of X-Y interchange. Hum Genet. 1979;49:11–31. [PubMed: 572812]
  14. 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]
  15. Ferguson-Smith MA, Cooke A, Affara NA, Boyd E, Tolmie JL. Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination. Hum Genet. 1990;84:198–202. [PubMed: 2298458]
  16. Grigorescu-Sido A, Heinrich U, Grigorescu-Sido P, Jauch A, Hager HD, Vogt PH, Duncea I, Bettendorf M. Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis. J Pediatr Endocrinol Metab. 2005;18:197–203. [PubMed: 15751609]
  17. 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]
  18. Hughes IA, Houk C, Ahmed SF, Lee PA., Lawson Wilkins Pediatric Endocrine Society/European Society for Paediatric Endocrinology Consensus Group. Consensus statement on management of intersex disorders. J Pediatr Urol. 2006;2:148–62. [PubMed: 18947601]
  19. Kasdan R, Nankin HR, Troen P, Wald N, Pan S, Yanaihara T. Paternal transmission of maleness in XX human beings. N Engl J Med. 1973;288:539–45. [PubMed: 4685451]
  20. Kim GJ, Sock E, Buchberger A, Just W, Denzer F, Hoepffner W, German J, Cole T, Mann J, Seguin JH, Zipf W, Costigan C, Schmiady H, Rostásy M, Kramer M, Kaltenbach S, Rösler B, Georg I, Troppmann E, Teichmann AC, Salfelder A, Widholz SA, Wieacker P, Hiort O, Camerino G, Radi O, Wegner M, Arnold HH, Scherer G. Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development. J Med Genet. 2015;52:240–7. [PubMed: 25604083]
  21. Kolon TF, Ferrer FA, McKenna PH. Clinical and molecular analysis of XX sex reversed patients. J Urol. 1998;160:1169–72. [PubMed: 9719302]
  22. Kotzot D, Hoffmann K, Kujat A, Holland H, Froster UG, Mücke J. Implications of FISH investigations in MIDAS syndrome associated with a 46,XX,t(X;Y) karyotype. Am J Med Genet. 2002;113:108–10. [PubMed: 12400076]
  23. Kühnert B, Byrne M, Simoni M, Kopcke W, Gerss J, Lemmnitz G, Nieschlag E. Testosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trial. Eur J Endocrinol. 2005;153:317–26. [PubMed: 16061839]
  24. Lee PA, Houk CP, Ahmed SF, Hughes IA. International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006;118:e488–500. [PubMed: 16882788]
  25. Lee GM, Ko JM, Shin CH, Yang SW. A Korean boy with 46,XX testicular disorder of sex development caused by SOX9 duplication. Ann Pediatr Endocrinol Metab. 2014;19:108–12. [PMC free article: PMC4114044] [PubMed: 25077096]
  26. Lim J, Tu X, Choi K, Akiyama H, Mishina Y, Long F. BMP-Smad4 signaling is required for precartilaginous mesenchymal condensation independent of Sox9 in the mouse. Dev Biol. 2015;400:132–8. [PMC free article: PMC4361319] [PubMed: 25641697]
  27. Lindsay EA, Grillo A, Ferrero GB, Roth EJ, Magenis E, Grompe M, Hultén M, Gould C, Baldini A, Zoghbi HY, Ballabio A. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization. Am J Med Genet. 1994;49:229–34. [PubMed: 8116674]
  28. Lissens W, Liebaers I, Van Steirteghem A. Male infertility. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Emery and Rimoin's Principles and Practice of Medical Genetics. 4 ed. New York, NY: Churchill Livingston; 2002:963.
  29. 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]
  30. 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]
  31. Parma P, Radi O, Vidal V, Chaboissier MC, Dellambra E, Valentini S, Guerra L, Schedl A, Camerino G. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet. 2006;38:1304–9. [PubMed: 17041600]
  32. Pérez-Palacios G, Medina M, Ullao-Aguirre A, Chávez BA, Villareal G, Dutrem MT, Cahill LT, Wachtel S. Gonadotropin dynamics in XX males. J Clin Endocrinol Metab. 1981;53:254–7. [PubMed: 6788790]
  33. 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]
  34. Ramos ES, Moreira-Filho CA, Vicente YA, Llorach-Velludo MA, Tucci S Jr, Duarte MH, Araújo AG, Martelli L. SRY-negative true hermaphrodites and an XX male in two generations of the same family. Hum Genet. 1996;97:596–8. [PubMed: 8655137]
  35. 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]
  36. Schiebel K, Winkelmann M, Mertz A, Xu X, Page DC, Weil D, Petit C, Rappold GA. Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y-)XY females. Hum Mol Genet. 1997;6:1985–9. [PubMed: 9302280]
  37. Seeherunvong T, Ukarapong S, McElreavey K, Berkovitz GD, Perera EM. Duplication of SOX9 is not a common cause of 46,XX testicular or 46,XX ovotesticular DSD. J Pediatr Endocrinol Metab. 2012;25:121–3. [PubMed: 22570960]
  38. 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]
  39. Solomon NM, Ross SA, Morgan T, Belsky JL, Hol FA, Karnes PS, Hopwood NH, Myers SE, Tan AS, Warne GL, Forrest SM, Thomas PQ. Array comparative genomic hybridisation analysis of boys with X-linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3. J Med Genet. 2004;41:669–78. [PMC free article: PMC1735898] [PubMed: 15342697]
  40. 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]
  41. Tomaselli S, Megiorni F, De Bernardo C, Felici A, Marrocco G, Maggiulli G, Grammatico B, Remotti D, Saccucci P, Valentini F, Mazzilli MC, Majore S, Grammatico P. Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation. Hum Mutat. 2008;29:220–6. [PubMed: 18085567]
  42. Vernole P, Terrinoni A, Didona B, De Laurenzi V, Rossi P, Melino G, Grimaldi P. An SRY-negative XX male with Huriez syndrome. Clin Genet. 2000;57:61–6. [PubMed: 10733237]
  43. Vilain E, Le Fiblec B, Morichon-Delvallez N, Brauner R, Dommergues M, Dumez Y, Jaubert F, Boucekkine C, McElreavey K, Vekemans M, Fellous M. SRY-negative XX fetus with complete male phenotype. Lancet. 1994;343:240–1. [PubMed: 7904700]
  44. Vetro A, Ciccone R, Giorda R, Patricelli G, Mina ED, Forlino A, Zuffardi O. XX males SRY negative: a confirmed cause of infertility. J Med Genet. 2011;48:710–2. [PMC free article: PMC3178810] [PubMed: 21653197]
  45. 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. 2014 Nov 5 [PubMed: 25351776]
  46. 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]
  47. Woods KS, Cundall M, Turton J, Rizotti K, Mehta A, Palmer R, Wong J, Chong WK, Al-Zyoud M, El-Ali M, Otonkoski T, Martinez-Barbera JP, Thomas PQ, Robinson IC, Lovell-Badge R, Woodward KJ, Dattani MT. Over- and underdosage of SOZ3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet. 2005;76:833–49. [PMC free article: PMC1199372] [PubMed: 15800844]
  48. Xiao B, Ji X, Xing Y, Chen Y, Tao J. A rare case of 46,XX SRY-negative male with approximately 74-kb duplication in a region upstream of SOX9. Eur J Med Genet. 2013;56:695–8. [PubMed: 24140641]
  49. Zenteno-Ruiz JC, Kofman-Alfaro S, Méndez JP. 46,XX sex reversal. Arch Med Res. 2001;32:559–66. [PubMed: 11750731]
  50. Zenteno JC, López M, Vera C, Méndez JP, Kofman-Alfaro S. Two SRY-negative XX male brothers without genital ambiguity. Hum Genet. 1997;100:606–10. [PubMed: 9341880]

Chapter Notes

Author Notes

Disorders of Sex Development-Translational Research Network (DSD-TRN)
Emmanuèle Délot, Coordinator
Tel: (310) 825 1319
Email: ude.alcu@tolede
Web: dsdtrn.genetics.ucla.edu

Revision History

  • 7 May 2015 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.

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

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1416PMID: 20301589
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...