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Nonsyndromic Disorders of Testicular Development

, MS, , MD, and , MD, PhD.

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Initial Posting: ; Last Update: June 2, 2016.

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

Nonsyndromic disorders of testicular development are a group of conditions characterized by the following:

  • A generally normal physical examination with absence of clinical findings involving organ systems other than the reproductive organs
  • A normal 46,XY karyotype by conventional staining
  • External genitalia that range from ambiguous to normal female
  • Internal genitalia that range from absent müllerian structures to a fully developed uterus and fallopian tubes
  • Gonads that are characterized as normal testis, ovotestis, dysgenetic testis, or streak

Based on the particular features seen in any given individual, the clinical diagnosis may be designated as 46,XY disorder of sex development (DSD) or 46,XY complete gonadal dysgenesis (CGD).

Diagnosis/testing.

Nonsyndromic 46,XY DSD and 46,XY CGD must be distinguished from syndromic forms, in which additional organ systems, growth, and cognitive development may also be affected. Biallelic pathogenic variants in DHH, heterozygous pathogenic variants in MAP3K1 and NR5A1, hemizygous pathogenic variants in SRY, hemizygous duplication of NR0B1, and heterozygous deletion of DMRT1 are causative of nonsyndromic 46,XY disorders of testicular development.

Genetic counseling.

Nonsyndromic disorders of testicular development can be inherited in a sex-limited autosomal recessive (DHH), sex-limited autosomal dominant (MAP3K1, NR5A1, and heterozygous deletion of DMRT1), Y-linked (SRY), or X-linked manner (hemizygous duplication of NR0B1). Genetic counseling and risk assessment depend on determination of the specific cause and the sex chromosome complement of the individual who harbors the pathogenic variant(s).

Management.

Treatment of manifestations: Evaluation and long-term management is best performed 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; all individuals should receive a sex of rearing; surgical decisions should be made after detailed discussion with the family regarding risks, benefits, and limitations of any proposed surgery; surgical intervention (hypospadias repair, orchiopexy, scrotoplasty, and phalloplasty in males and clitoroplasty, vaginoplasty, and urogenital sinus mobilization in females) should focus on functionality; whenever possible, removal of tissue and irreversible procedures should be avoided; streak gonads and nonfunctional dysgenetic gonads should be removed to decrease the risk for gonadoblastoma; dysgenetic gonads with residual function that are not removed require tumor surveillance; if gonads are retained, surveillance for the development of contrasexual puberty is warranted if sex of rearing is discordant with gonadal sex; sex steroid therapy (testosterone in males and estrogen or estrogen/progesterone in females) is important for the development of secondary sexual characteristics and for normal adolescent bone mass accrual; 46,XY individuals with a heterozygous pathogenic variant in NR5A1 should be monitored for adrenal insufficiency; most affected individuals are infertile, although assisted reproductive technologies may help achieve pregnancy in some cases.

Surveillance: Regular follow up with an interdisciplinary DSD team including endocrinology, genetics, obstetrics/gynecology, psychology, and urology.

GeneReview Scope

Nonsyndromic Disorders of Testicular Development: Included Phenotypes
  • 46,XY disorder of sex development (DSD)
  • 46,XY complete gonadal dysgenesis (CGD)

For synonyms and outdated names see Nomenclature.

Definition

Nonsyndromic disorders of testicular development are a group of disorders characterized by:

  • Normal general physical examination AND absence of clinical findings involving other organ systems (i.e., nonsyndromic);
  • Clinical and gonadal findings of a 46,XY disorder of sex development (DSD) or 46,XY complete gonadal dysgenesis (CGD) (see Clinical manifestations of nonsyndromic 46,XY DSD and Clinical manifestations of nonsyndromic 46,XY CGD);
  • A normal 46,XY karyotype by conventional staining (see Evaluation Strategy).

Clinical manifestations of nonsyndromic 46,XY DSD

  • External genitalia that 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 that on US examination, MRI, and/or laparoscopy can range over the following spectrum:
    • 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:), that 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

  • 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 "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."

Causes

Most genetic causes of nonsyndromic disorders of testicular development are not known. Approximately half of affected individuals will have an underlying genetic etiology identified through molecular genetic testing (Table 1) [Barseghyan et al 2015].

Table 1.

Molecular Genetics of Nonsyndromic Disorders of Testicular Development

Gene/Pathogenic MechanismProportion of Nonsyndromic Disorders of Testicular Development Attributed to Variants in GeneMode of
Inheritance
46,XY DSD46,XY CGD
DHHRare 1Rare 1AR
MAP3K110%-18% 210%-18% 2AD
NR5A110%-15% 3Rare 4AD
SRYRare 515% 5YL
160-kb heterozygous duplication at Xp21 6, 7Rare 8Rare 8XL
Heterozygous DMRT1 9 deletionRare 10Rare 10AD

AD = autosomal dominant; AR = autosomal recessive; XL = X-linked; YL = Y-linked

1.

Biallelic pathogenic variants were found in paraffin-embedded gonadal tissue in three individuals with CGD; however, the data are based on a small sample size from the Mexican population, and no functional data were reported [Canto et al 2004]. One additional individual with 46,XY DSD and neuropathy and a homozygous pathogenic missense variant (p.Met1Thr) in DHH was reported [Umehara et al 2000].

2.
3.
4.

The first two affected individuals reported with heterozygous pathogenic variants in NR5A1 had 46,XY CGD and adrenal failure [Achermann et al 1999, Achermann et al 2002]. Subsequently, heterozygous pathogenic variants in NR5A1 were reported in five of 15 adolescents with a 46,XY chromosome complement who had primary amenorrhea and low serum testosterone concentrations, but only one had a CGD phenotype with a uterus present [Philibert et al 2010].

5.

Hemizygous pathogenic variants in SRY primarily cause 46,XY CGD phenotype [Hawkins et al 1992, Cameron & Sinclair 1997, Veitia et al 1997].

6.

Genes involved in the duplication include MAGEB, NR0B1, CXorf21, GK, and a portion of MAP3K7IP3. However, NR0B1 (DAX1) is presumed to be the gene responsible for the phenotype, although this has not been definitively proven [Barbaro et al 2012].

7.

Hemizygous deletions and pathogenic variants in NR0B1 are known to cause a different phenotype (X-linked adrenal hypoplasia congenita).

8.
9.

DMRT1 is presumed to be the gene responsible for the phenotype, although this has not been definitively proven [Quinonez et al 2013].

10.

Deletions of 9p24 are a recurrent cause of 46,XY DSD and 46,XY CGD. While most reports are of individuals who have larger deletions of this chromosome region leading to syndromic features (see Table 3), reports of rare individuals who have nonsyndromic 46,XY disorders of testicular development with small deletions encompassing DMRT1 alone or including several neighboring genes have been published [Ledig et al 2010, Tannour-Louet et al 2010].

Conditions Not Discussed in the GeneReview

Table 2.

Additional Nonsyndromic DSD Conditions to Consider in the Differential Diagnosis of Ambiguous Genitalia and/or Sex Chromosome-Phenotype Discordance

Disease MechanismDisease NameGeneOMIMMOI 1Distinguishing Feature(s) 2
Hormone biosynthetic defectsLipoid adrenal hyperplasiaSTAR201710ARSevere deficiency of adrenal & gonadal steroids; all XY individuals phenotypically female; severe salt wasting
P450scc (formerly cholesterol desmolase) deficiencyCYP11A1613743ARAcute adrenal insufficiency; ↑ ACTH & plasma renin, ↓ or absent adrenal steroids; XY individuals phenotypically female
3-beta-hydroxysteroid dehydrogenase deficiencyHSD3B2201810ARAcute adrenal insufficiency w/↑ pregnenolone, 17-hydroxypregnenolone & DHEA; XY individuals have severe hypospadias w/micropenis.
17-alpha-hydroxylase deficiency/17,20-lyase deficiencyCYP17A1202110ARHypertension, hypokalemic alkalosis, ↑ ACTH, LH & FSH; XY individuals have absent or incomplete virilization of external genitalia
Cytochrome P450 Oxidoreductase DeficiencyPOR613571ARCombined deficiency of p450c17 & p450c21 causing accumulation of steroid metabolites; ambiguous genitalia in XX individuals & incomplete virilization in XY individuals
17-beta-hydroxysteroid dehydrogenase deficiencyHSD17β3264300ARInterferes w/conversion of androstenedione to testosterone; XY individuals have absent or incomplete virilization of external genitalia but may virilize at puberty.
5-alpha-reductase deficiencySRD5A2264600ARInterferes w/conversion of testosterone to dihydrotestosterone; possible virilization at puberty; XY individuals may appear phenotypically female or have ambiguous genitalia w/hypospadias & blind vaginal pouch.
Aldo-keto reductase deficiencyAKR1C2, AKR1C4614279ARAlternative pathway for DHT synthesis in fetal testis; XY individuals may appear phenotypically female or have ambiguous genitalia
LH receptor defectsLeydig cell hypoplasiaLHCGR238320ARLeydig cell hypoplasia or agenesis; T levels low; LH/FSH ↑; ↓ response to hCG stimulation testing
LH deficiencyKallmann syndromeKAL1300836XLSee Isolated Gonadotropin-Releasing Hormone Deficiency; XY individuals typically have micropenis w/normally formed scrotum.
Androgen receptor defectsAndrogen Insensitivity SyndromeAR300068XLLack of virilization due to impaired androgen binding or transactivation; incl complete & partial defects; T levels normal or ↑
CBX2-related complete gonadal dysgenesisCBX2613080AROne case reported 3; phenotypic female w/46,XY karyotype, uterus & histologically normal ovarian tissue

ACTH = adrenocorticotropic hormone; DHT = dihydrotestosterone; FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone; MOI = mode of inheritance; T = testosterone

1.

Typical MOI; exceptions occur.

2.

The majority of the conditions in Table 2 can be differentiated from 46, XY CGD by the absence of müllerian structures.

3.

The phenotype was proposed to be caused by biallelic pathogenic variants in CBX2 [Biason-Lauber et al 2009].

Table 3.

Additional Syndromic DSD Conditions to Consider in the Differential Diagnosis of Ambiguous Genitalia and/or Sex Chromosome-Phenotype Discordance

Disease NameGene(s)OMIMMOI 1Clinical Features
Alpha-thalassemia X-linked mental retardation syndromeATRX301040XLDistinctive craniofacial features, genital anomalies, hypotonia, severe ID, mild-to-moderate anemia secondary to alpha-thalassemia
Antley-Bixler syndrome with disordered steroidogenesisPOR201750ARCraniosynostosis, hydrocephalus, distinctive facies, choanal stenosis or atresia, low-set dysplastic ears w/stenotic external auditory canals, skeletal anomalies, renal anomalies, ↓ cognitive function, DD
Campomelic dysplasiaSOX9114920ADDistinctive facies, Pierre Robin sequence w/cleft palate, shortening & bowing of long bones, club feet, laryngotracheomalacia w/respiratory compromise
GATA4-related disordersGATA4615542ADTesticular anomalies & congenital heart defects
Smith-Lemli-Opitz syndromeDHCR7270400ARPre- & postnatal growth retardation, microcephaly, moderate-to-severe ID, distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, 2-3 syndactyly of the toes. Caused by deficiency of the enzyme 7-dehydrocholesterol.
X-linked lissencephaly with ambiguous genitaliaARX300215XLLissencephaly w/severe ID; genitalia of XY individuals can range from ambiguous to phenotypically female.
WT1-related disorders (see Wilms Tumor Overview and WT1 Disorder)WT1ADFraiser syndrome. Focal & segmental glomerulosclerosis of the kidney & 46,XY CGD
Denys-Drash syndrome. Mesangial sclerosis of the kidney, Wilms tumor, & 46,XY DSD
9p24 deletions 2DMRT1 3154230ADTrigonocephaly, dysmorphic features (widely spaced eyes, arched eyebrows, low-set ears, long philtrum, thin vermilion of the upper lip), congenital heart defects, underdeveloped external genitalia in males, ID
11p13 microdeletion 4, 5WT1194072ADWilms tumor, aniridia, genitourinary anomalies, & mental retardation (i.e., ID) syndrome (WAGR)

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

Typical MOI; exceptions occur.

2.

Deletions of 9p24 vary in size, including large, cytogenetically visible deletions or smaller deletions. None of these 9p24 deletions (including ones that lead to apparently nonsyndromic 46,XY disorders of testicular development) is recurrent. See also Table 1.

3.

DMRT1, located at 9p24, is considered the likely involved gene, although this has not been definitively proven [Quinonez et al 2013]. Heterozygous pathogenic variants in DMRT1 have not been found to be a major cause of 46, XY DSD [Ledig et al 2010, Tannour-Louet et al 2010, Quinonez et al 2013].

4.

The 11p13 deletion is a recurrent deletion (ISCA ID: ISCA-37401; standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays [ISCA] Consortium of cytogenetic and molecular genetic clinical laboratories).

5.

Region location: chr11:31,803,509-32,510,988. Genomic coordinates represent the minimum deletion size associated with 11p13 deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the common 11p13 deletion.

Evaluation Strategy

The initial evaluation of an individual suspected of having a nonsyndromic disorder of sex development is to determine the chromosome complement.

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 Table 1 and Conditions Not Discussed in the GeneReview). 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 testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Single-gene testing. Perform serial single-gene testing of the first four genes listed in Table 1 based on the individual's clinical findings and/or the order in which pathogenic variants most commonly occur.

A multigene panel that includes DHH, MAP3K1, NR5A1, SRY, and other genes of interest (see Conditions Not Discussed in the GeneReview) may also be considered. Note: The genes included in the panel and diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing or genome sequencing may be considered if single gene testing (and/or use of a multigene panel that includes the genes in Table 1) fails to confirm a diagnosis in an individual with features of a nonsyndromic disorder of testicular development. Some experts advocate using exome sequencing as second-line testing after a normal CMA [Barseghyan et al 2015].

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

Genetic Counseling

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

Mode of Inheritance

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 gene involved:

Risk to Family Members

Sex-Limited Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an individual with DHH-related autosomal recessive 46,XY complete gonadal dysgenesis (CGD) are obligate heterozygotes.
  • Heterozygotes (carriers) are usually asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of having biallelic pathogenic variants, a 50% chance of being heterozygous for a DHH pathogenic variant, and a 25% chance of being unaffected and not heterozygous. XY sibs with biallelic pathogenic variants will have clinical features.
  • Heterozygotes 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 ART allows individuals 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 unaffected.

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

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

Sex-Limited Autosomal Dominant Inheritance

Parents of a proband

  • Pathogenic variants in MAP3K1 and NR5A1 and heterozygous deletion involving DMRT1 are inherited in a sex-limited autosomal dominant manner. In general, individuals with a 46,XX chromosome complement and a heterozygous MAP3K1 or NR5A1 pathogenic variant or heterozygous deletion of DMRT1 do not show clinical findings; however, some women with a heterozygous pathogenic variant in NR5A1 develop primary ovarian insufficiency [El-Khairi & Achermann 2012].
  • Individuals with a MAP3K1 or NR5A1 heterozygous pathogenic variant or a heterozygous deletion in DMRT1 may have inherited the genetic variant from their mother or they may have a de novo variant.
  • Recommendations for the evaluation of mother of a proband with an apparent de novo genetic variant include testing for the variant identified in the proband.
  • The family history of some individuals diagnosed with sex-limited autosomal dominant nonsyndromic disorder of testicular development may appear to be negative because of 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.
  • If the genetic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo variant in the proband or germline mosaicism in a parent (the incidence of germline mosaicism is unknown).

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 a genetic variant, the risk to XY sibs is 50%. 46,XX sibs who inherit the variant are generally unaffected but would be at increased risk of having an affected child. 46,XX individuals with a heterozygous NR5A1 pathogenic variant may be at risk for primary ovarian insufficiency [El-Khairi & Achermann 2012].
  • The sibs of a proband with clinically unaffected parents are still at increased risk for an autosomal dominant nonsyndromic disorder of testicular development because of the sex-limited nature of the condition.
  • If the MAP3K1 or NR5A1 pathogenic variant or DMRT1 deletion found in the proband cannot be detected in the leukocyte DNA of either parent, 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 a sex-limited autosomal dominant nonsyndromic disorder of testicular development frequently are unable to reproduce, particularly if they have a 46,XY chromosome complement. Some pathogenic variants in NR5A1 may allow for male fertility, but assisted reproductive technologies (ART) may be needed.
  • If ART allows 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 pathogenic variant. 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 is affected or has a MAP3K1 or NR5A1 heterozygous pathogenic variant or a heterozygous DMRT1 deletion, his or her family members may be at risk.

Y-Linked Inheritance

Parents of a proband

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

Offspring of a proband

  • Individuals with an SRY pathogenic variant are unlikely to reproduce.
  • If assisted reproductive technologies (ART) can allow 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

Parents of a proband

  • 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.
  • In a family with more than one individual with an NR0B1-related nonsyndromic disorder of testicular development, the mother of an affected individual is an obligate carrier of the NR0B1 duplication. If a woman has more than one affected child and the NR0B1 duplication cannot be detected in her DNA, she has germline mosaicism.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo NR0B1 duplication, in which case the mother is not a carrier. 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].

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

  • If the mother of the proband has an NR0B1 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 (i.e., a single occurrence in a family) and if the NR0B1 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 NR0B1-related nonsyndromic disorder of testicular development are unlikely to reproduce.
  • If ART enables individuals with an NR0B1 related nonsyndromic disorder of testicular development to have children, such individuals will pass the NR0B1 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 NR0B1 duplication and the aunts' offspring, depending on their sex chromosome complement, may be at risk of being heterozygotes (carriers) for the NR0B1 duplication or of being affected.

Heterozygote (carrier) detection. Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the NR0B1 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 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 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 and Preimplantation Genetic Testing

Once a DHH, MAP3K1, NR5A1, or SRY pathogenic variant(s), NR0B1 duplication, or 9p24 deletion involving DMRT1 has been identified in an affected family member, prenatal testing and preimplantation genetic testing for a pregnancy at increased risk are possible.

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.

Management

Treatment of Manifestations

A consensus statement on the management of disorders of sex development (DSDs) was developed under the sponsorship of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology [Lee et al 2006]. Further consensus guidelines for the care of children with DSD were developed by the Texas Children's Hospital [Douglas et al 2010] (full text) and others [Parisi et al 2007] (full text).

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

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 delay the 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 dilation 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 gonadoblastoma and should be surgically removed if nonfunctional.
    If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results of an hCG stimulation test indicate some testicular function.
  • 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.
    • 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 standard deviations 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 the Lee et al consensus statement, "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." [Lee et al 2006]

  • 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.

Fertility

  • Most individuals with nonsyndromic disorders of sex development 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.

References

Published Guidelines / Consensus Statements

  • Accord Alliance. DSD Guidelines. Available online. 2008. Accessed 5-4-20.
  • Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Consensus in Guidelines for Evaluation of DSD by the Texas Children's Hospital Multidisciplinary Gender Medicine Team. Int J Pediatr Endocrinol. 2010;2010:919707. [PMC free article: PMC2963131] [PubMed: 20981291]
  • 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: 16882833]
  • 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: 16882788]
  • Parisi MA, Ramsdell LA, Burns MW, Carr MC, Grady RE, Gunther DF, Kletter GB, McCauley E, Mitchell ME, Opheim KE, Pihoker C, Richards GE, Soules MR, Pagon RA. A Gender Assessment Team: experience with 250 patients over a period of 25 years. Available online. 2007. Accessed 5-4-20. [PubMed: 17575501]

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  • Barbaro M, Cook J, Lagerstedt-Robinson K, Wedell A. Multigeneration Inheritance through Fertile XX Carriers of an NR0B1 (DAX1) Locus Duplication in a Kindred of Females with Isolated XY Gonadal Dysgenesis. Int J Endocrinol. 2012;2012:504904. [PMC free article: PMC3299259] [PubMed: 22518125]
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  • 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: 16882833]
  • Ledig S, Hiort O, Scherer G, Hoffmann M, Wolff G, Morlot S, Kuechler A, Wieacker P. Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci. Hum Reprod. 2010;25:2637–46. [PubMed: 20685758]
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Chapter Notes

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)

Revision History

  • 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
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