Goal 1.

To describe the clinical characteristics of nonsyndromic disorders of testicular development.

Goal 2.

To review the genetic causes of nonsyndromic disorders of testicular development and conditions that may be in the differential diagnosis.

Goal 3.

To provide an evaluation strategy to identify the genetic cause of nonsyndromic disorders of testicular development (when possible).

Goal 4.

To inform genetic risk assessment in family members of a proband.

Goal 5.

To inform management regarding sex of rearing, medical/surgical intervention (when appropriate), hormone therapy, and psychosocial aspects of care.

Clinical Manifestations of Nonsyndromic 46,XY DSD

External genitalia can range over the following spectrum:

• Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee
• Microphallus
• Abnormalities of scrotal formation
• Normal-appearing female

Müllerian structures can range over the following spectrum upon ultrasound examination, MRI, and/or laparoscopy:

• Absent
• Fully developed uterus and fallopian tubes

Gonadal findings, as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination; see Note), can range over the following spectrum:

• Normal testis
• Ovotestis
• Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells)
• Streak gonad

Note: Results may be inaccurate because of biopsy sampling error; gonadal biopsy may harm the future growth and development of the gonad.

Clinical Manifestations of Nonsyndromic 46,XY CGD

Clinical manifestations of nonsynromic 46,XY CGD include:

• External genitalia. Normal female
• Müllerian structures. Uterus and fallopian tubes present
• Gonadal findings. Streak gonads or dysgenetic testes

Nomenclature

The nomenclature for disorders of sex development (DSD) was revised in 2006 to reflect the genetic causes and pathogenesis of these conditions [Houk et al 2006].

• The term "differences of sex development" is often used to replace "disorders of sex development," although "disorders of sex development" is still appropriate to use among medical providers.
• The term "disorders of sex development" has replaced the term "intersex."
• The term "46,XY DSD" has replaced the following terms:
  • Male pseudohermaphrodite
  • Undervirilization of an XY male
  • Undermasculinization of an XY male
  • Mixed gonadal dysgenesis
  • Partial gonadal dysgenesis
• The term "46,XY CGD" has replaced the terms "46,XY sex reversal" and "46,XY female."
• The term "46,XY ovotesticular DSD" has replaced "46,XY true hermaphrodite."

Chromosome Analysis

One genetic testing strategy is to perform a karyotype using conventional staining methods of a sufficient number of cells to detect mosaicism for sex chromosome aneuploidy (i.e., 45,X / 46,XY) and fluorescence in situ hybridization (FISH) for the presence of SRY.

Another genetic testing strategy is to perform a chromosomal microarray (CMA), as this will determine the sex chromosome complement, evaluate for the presence or absence of SRY, and screen for deletion/duplication syndromes in which individuals may have genital anomalies within the DSD spectrum (see Tables 1, 2, and 3). If the karyotype is already known, CMA may still be pursued, particularly for individuals in whom a syndromic diagnosis is being considered.

Note: (1) If the individual has a 46,XY chromosome complement but is SRY negative, the cause of the individual's nonsyndromic disorder of testicular development has been determined. (2) If CMA detects a deletion of SRY, a limited karyotype can be considered to determine if the deletion was caused by a translocation or a complex rearrangement of genetic material.

Molecular Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which genes are likely involved, whereas genomic testing does not. Individuals with distinctive hormonal, gonadal, and/or imaging findings described in Clinical Characteristics may be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other disorders of sex development are more likely to be diagnosed using genomic testing (see Option 2).

Mode of Inheritance

Nonsyndromic disorders of testicular development can be inherited in a sex-limited autosomal recessive, sex-limited autosomal dominant, Y-linked, or X-linked manner depending on the causative genetic alteration.

• Sex-limited autosomal recessive inheritance: mutation of DHH
• Sex-limited autosomal dominant inheritance: intragenic mutation of DMRT1, DHX37, MAP3K1, or NR5A1; complete or partial deletion of DMRT1
• Y-linked inheritance: mutation of SRY
• X-linked inheritance: duplication at Xp21

Sex-Limited Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an individual with a DHH-related nonsyndromic disorder of testicular development are presumed to be heterozygous for a DHH pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a DHH pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are usually asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for a DHH pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial pathogenic variants.
• XY sibs who inherit biallelic pathogenic variants will have clinical features.
• Heterozygotes (carriers) are usually asymptomatic.

Offspring of a proband

• Individuals with sex-limited autosomal recessive 46,XY nonsyndromic disorder of testicular development are frequently unable to reproduce.
• If assisted reproductive technology enables an individual with a sex-limited autosomal recessive nonsyndromic disorder of testicular development to have children, all offspring will be heterozygous for a pathogenic variant in DHH and will therefore be carriers and usually asymptomatic.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DHH pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the DHH pathogenic variants in the family.

Sex-Limited Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• An individual with a sex-limited autosomal dominant disorder of testicular development caused by a DMRT1, DHX37, MAP3K1, or NR5A1 pathogenic variant or a DMRT1 deletion may have inherited the genetic alteration from their mother or mildly affected father.
• Some individuals with a sex-limited autosomal dominant disorder of testicular development have a de novo genetic alteration.
• Testing of the parents for the genetic alteration identified in the proband is recommended to allow reliable recurrence risk counseling.
• If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological relatedness, the following possibilities should be considered:
  • The proband has a de novo genetic alteration.
  • The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with a sex-limited autosomal dominant nonsyndromic disorder of testicular development may appear to be negative because of a milder phenotypic presentation in a parent or the appearance of reduced penetrance due to the sex-limited expression of the genetic variant. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents and the sex chromosome complement of the sib:

• If a parent of the proband has the genetic alteration identified in the proband, the risk to sibs of inheriting the genetic alteration is 50%.
  • 46,XY sibs who inherit the genetic alteration will have clinical features.
  • In general, individuals with a 46,XX chromosome complement and a heterozygous DMRT1, DHX37, MAP3K1, or NR5A1 pathogenic variant or a heterozygous DMRT1 deletion do not show clinical findings; however, some females with a heterozygous pathogenic variant in NR5A1 develop primary ovarian insufficiency [Fabbri-Scallet et al 2020].
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a proband

• Individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development are frequently unable to reproduce. Some pathogenic variants in NR5A1 may allow for male fertility but assisted reproductive technologies may be needed.
• If assisted reproductive technology enables individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development to have children, each child would have a 50% chance of inheriting the genetic alteration. 46,XY offspring would show clinical features. 46,XX offspring would generally be unaffected, although some 46,XX individuals with a heterozygous NR5A1 pathogenic variant could be at risk for primary ovarian insufficiency.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the genetic alteration identified in the proband, family members of the heterozygous parent may be at risk.

Y-Linked Inheritance – Risk to Family Members

Parents of a proband

• Most individuals with an SRY-related nonsyndromic disorder of testicular development have a de novo pathogenic variant.
• Rarely, individuals with an SRY-related nonsyndromic disorder of testicular development have a paternally inherited SRY pathogenic variant. In these families, the father has EITHER:
  • Somatic (and presumably germline) mosaicism for an SRY pathogenic variant [Isidor et al 2009];
    OR
  • Incomplete penetrance of an SRY pathogenic variant [Isidor et al 2009].
• The frequency of paternal mosaicism and SRY pathogenic variants with reduced penetrance is not known.
• The mother of an individual with an SRY-related nonsyndromic disorder of testicular development does not require evaluation/testing.

Sibs of a proband. The risk to XY sibs depends on the genetic status of the father (XX sibs are not at risk):

• Because probands with an SRY-related nonsyndromic disorder of testicular development usually have a de novo pathogenic variant, the risk to XY sibs of a proband is presumed to be low.
• If the father of the proband has germline mosaicism or an SRY pathogenic variant with reduced penetrance, he may transmit an SRY pathogenic variant to XY sibs of the proband.

Offspring of a proband

• Individuals with an SRY pathogenic variant are unlikely to reproduce.
• If assisted reproductive technologies can enable individuals with an SRY pathogenic variant to have children, such individuals will pass the pathogenic variant to all of their XY offspring and none of their XX offspring.

Other family members. The risk to other family members depends on the genetic status of the proband's father.

X-Linked Inheritance – Risk to Family Members

Parents of a proband

• In a family with more than one individual with an Xp21 duplication-related nonsyndromic disorder of testicular development, the mother of an affected individual is an obligate heterozygote (carrier) of the duplication. Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her DNA, she most likely has germline mosaicism.
• If only one family member is affected (i.e., a simplex case), the mother may be a heterozygote (carrier), the proband may have a de novo Xp21 duplication (in which case the mother is not a carrier), or the mother may have somatic/germline mosaicism.
  Too few affected individuals have been reported to provide an accurate rate of de novo duplication; however, most of the affected individuals who have a small duplication inherited it from an unaffected carrier mother [Barbaro et al 2012].
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• The father of an affected male will not have the disorder nor will he be hemizygous for the NR0B1 duplication; therefore, he does not require further evaluation/testing.

Sibs of a proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an Xp21 duplication, the chance of transmitting it in each pregnancy is 50%. 46,XY sibs who inherit the duplication will be affected; 46,XX sibs who inherit the duplication will be heterozygous and will usually not be affected.
• If the proband represents a simplex case and if the Xp21 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

• Individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development are unlikely to reproduce.
• If assisted reproductive technology enables individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development to have children, such individuals will pass the duplication to all of their XX offspring and none of their XY offspring.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the Xp21 duplication, and their offspring, depending on their sex chromosome complement, may be at risk of being heterozygous for the Xp21 duplication or of being affected.

Heterozygote detection. Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the Xp21 duplication in the proband.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers), or who are at increased risk of being heterozygotes (carriers) or affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the genetic cause of a nonsyndromic disorder of testicular development has been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk 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.

Treatment of Manifestations

A consensus statement on the management of disorders of sex development (DSD) was developed under the sponsorship of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pædiatric Endocrinology [Lee et al 2006]. Further consensus guidelines for the care of children with DSD were developed by León et al [2019] (full text; purchase or subscription required) and Wisniewski et al [2019] (full text).

Evaluation and long-term management should be provided at a center with an interdisciplinary care team (including clinical geneticists, endocrinologists, surgeons, and mental health professionals) experienced in the diagnosis and management of DSD conditions.

The general concepts of care include the following.

Sex assignment

• All individuals should receive a sex of rearing.
• Sex assignment in newborns with ambiguous genitalia should not be decided prior to an evaluation by experts.
• The choice of sex of rearing for individuals with 46,XY DSD is based on the underlying diagnosis, expert opinion, and parental beliefs [Houk et al 2006].

Surgical decisions should be made after detailed discussion with the family about risks, benefits, and limitations of any proposed surgery. Many surgeries are not medically necessary and thus consideration should be given to delaying surgery in order to allow the affected individual to participate in the decision-making process.

• Surgical intervention in minors with DSD is controversial, particularly in those being reared female. Surgical intervention should focus on functionality; whenever possible, removal of tissue and irreversible procedures should be avoided.
• When male sex of rearing is chosen, surgical options may include hypospadias repair, orchiopexy, scrotoplasty, and phalloplasty. Removal of müllerian remnants may be considered.
• When female sex of rearing is chosen, surgical options may include clitoroplasty, vaginoplasty, and urogenital sinus mobilization. Vaginal dilatation is also used for creation/expansion of the vagina.

Note: (1) No controlled clinical trials of the efficacy of different surgical techniques have been conducted. The long-term data regarding the quality of life and sexual function among those assigned male and female sex vary. (2) There is no consensus on the appropriate timing of the surgical procedures listed.

Management of gonads

• Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional.
  • In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
  • Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
  • A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
  • A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
  Note: Hormonal evaluation cannot distinguish between one versus two functioning gonads.
• If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results indicate some testicular function. However, this gonad will need to undergo surveillance for gonadoblastoma. There are no current guidelines on surveillance; one option would be yearly ultrasound of the gonad.
• Removal of gonads that are not consistent with the assigned sex of rearing is controversial.
  • Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
  • Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
    If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
  • In some states, removal of potentially functional gonads in a minor requires a court order.

Hormone therapy. Sex steroid therapy is important for the development of secondary sexual characteristics and for normal adolescent bone mass accrual.

• If an individual is given a male sex assignment:
  • A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
  • Testosterone therapy is typically required to initiate and sustain puberty.
• If an individual is given a female sex assignment:
  • Estrogen therapy is used to initiate breast development and puberty.
  • If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
• 46,XY individuals with a heterozygous pathogenic variant in NR5A1 may need to be managed for adrenal insufficiency.

Psychosocial aspects of care. As noted in Lee et al [2006], "The initial contact with the parents of a child with a DSD is important, because first impressions from these encounters often persist. . . . Ample time and opportunity should be made for continued discussion with review of information previously provided."

• Open communication with affected individuals and families, including their active participation in the decision-making process, is critical.
• Providers need to address the concerns of the affected individual and family respectfully and in strict confidence.
• Assigned sex of rearing may not be congruent with gender identity, which is determined by the individual over time.

Fertility

• Most individuals with a nonsyndromic DSD are infertile due to dysgenetic or streak gonads. Some pathogenic variants in NR5A1 are associated with normal testicular development in individuals with a 46,XY chromosome complement, which may allow for fertility, although assisted reproductive technology may be required.
• Women with 46,XY DSD or 46,XY CGD with müllerian structures may become pregnant through oocyte donation.

Surveillance

Regular follow up with an interdisciplinary DSD team including endocrinology, medical genetics, obstetrics/gynecology, psychology, and urology is indicated.

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 disorder.

Author History

Patricia Fechner, MD (2016-present)
Catherine E Keegan, MD, PhD (2016-present)
Lauren Mohnach, MS (2016-present)
Harry Ostrer, MD; New York University School of Medicine (2008-2016)

Author Notes

Website: www.mottchildren.org/conditions-treatments/peds-sex-development

Revision History

• 18 August 2022 (ma) Comprehensive update posted live
• 2 June 2016 (ma) Comprehensive update posted live; reconfigured as an overview
• 15 September 2009 (cd) Revision: deletion/duplication analysis no longer available clinically for NR0B1; FISH available
• 24 July 2008 (cd) Revision: testing for mutations in NR5A1 available clinically
• 21 May 2008 (me) Posted live
• 19 December 2007 (ho) Original submission

Published Guidelines / Consensus Statements

• Accord Alliance. DSD Guidelines. Available online. 2008. Accessed 10-28-22.
• Houk CP, Hughes IA, Ahmed SF, Lee PA; Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics. 2006;118:753-7. [PubMed]
• 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. Pediatrics. 2006;118:e488-500. [PubMed]
• León NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 2019;7:560-74. [PubMed]
• Wisniewski AB, Batista RL, Costa EM, Finlayson C, Sircili MHP, Dénes FT, Domenice S, Mendonca BB. Management of 46,XY differences/disorders of sex development (DSD) throughout life. Endocr Rev. 2019;40:1547-72. [PubMed]

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