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46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis

Includes: DHH-Related 46,XY DSD and 46,XY CGD; NR0B1-Related 46,XY DSD and 46,XY CGD; NR5A1-Related 46,XY DSD and 46,XY CGD; SRY-Related 46,XY DSD and 46,XY CGD; WNT4-Related 46,XY DSD and 46,XY CGD
, MD
Human Genetics Program
Department of Pediatrics
New York University School of Medicine
New York, New York

Initial Posting: ; Last Revision: September 15, 2009.

Summary

Disease characteristics. 46,XY disorder of sex development (46,XY DSD) is characterized by a 46,XY karyotype, ambiguous genitalia with mild to severe penoscrotal hypospadias with or without chordee, dysgenetic testes, reduced to no sperm production, and müllerian structures that range from absent to presence of a fully developed uterus and fallopian tubes. 46,XY complete gonadal dysgenesis (46,XY CGD) is characterized by a 46,XY karyotype, normal female external genitalia, completely undeveloped (”streak”) gonads, no sperm production, and presence of normal müllerian structures.

Diagnosis/testing. The diagnosis of 46,XY DSD and 46,XY CGD relies on clinical findings, gonadal histology, chromosome analysis, and testing to detect changes in one of the following five genes: SRY (deletion or sequence variant), NR5A1 (SF1) (sequence variant), DHH (sequence variant), NR0B1 (DAX1 duplication), or WNT4 (duplication).

Management. Treatment of manifestations: Individuals with 46,XY CGD are raised as females. Individuals with 46,XY DSD may be raised as males or females; some individuals require surgery to repair the external genitalia and to create and/or enlarge the vagina. Abdominal dysgenetic gonads are at increased risk for gonadal tumors (most commonly dysgerminoma) and should be surgically removed; streak gonads and dysgenetic gonads are at increased risk for gonadoblastoma and should be surgically removed. Typically, hormone replacement therapy (HRT) is required from puberty onward. Women with 46,XY CGD and with 46,XY DSD and müllerian structures may become pregnant through zygote donation. Males with 46,XY DSD may possibly donate gametes via intracytoplasmic sperm insemination (ICSI).

Surveillance: Streak gonads and dysgenetic testes that have not been removed require monitoring for gonadoblastoma with annual abdominal sonograms.

Genetic counseling. 46,XY DSD with abnormally developed, dysgenetic gonads and 46,XY CGD with streak gonads can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner depending on the gene involved. Prenatal diagnosis for pregnancies at increased risk (including those conceived through assisted reproductive technology [ART]) for a mutation in a gene associated with 46,XY DSD or 46,XY CDG is possible if the mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

46,XY disorder of sex development (46,XY DSD) is diagnosed in individuals with the following:

  • A 46,XY karyotype using conventional staining methods or fluorescence in situ hybridization (FISH)
  • Ambiguous genitalia with mild to severe penoscrotal hypospadias with or without chordee
  • Defective embryonic development of the gonads (”dysgenetic gonads”) with testicular elements
  • Reduced to no sperm production
  • Müllerian structures: absent to fully developed uterus and fallopian tubes

46,XY complete (pure) gonadal dysgenesis (46,XY CGD) is diagnosed in individuals with the following:

  • A 46,XY karyotype using conventional staining methods or FISH
  • Normal female external genitalia
  • Completely undeveloped (”streak”) gonads
  • No sperm production
  • Müllerian structures: uterus and fallopian tubes

Testing

Endocrine studies usually show the following for both 46,XY DSD and 46,XY CGD:

  • Hypergonadotropic hypogonadism secondary to gonadal failure:
    • Basal serum concentration of LH and FSH are moderately to significantly elevated (in adult males normal range for LH: 7-24 mLU/mL; for FSH: 1.5-12.4 mLU/mL).
    • Serum testosterone concentration is usually decreased, typically lower than 300 ng/dL in adults (in adult males normal range: 300-1000 ng/dL).
    • Human chorionic gonadotropin (hCG) stimulation test typically shows little or no elevation of serum testosterone concentration after IM injection of hCG.
  • Normal hypothalamic-pituitary axis. Gonadotropin releasing hormone (GnRH) stimulation test shows a normal LH and FSH response to an IM injection of GnRH. (Such testing is not warranted for diagnosis.)

Diagnostic imaging

  • A uterus is visualized by sonography, MRI, or laparoscopy in 46,XY CGD.
  • A uterus may or may not be visualized in 46,XY DSD.

Findings on routine and specialized cytogenetic studies in 46,XY DSD and 46,XY CGD. Routine cytogenetic studies usually demonstrate a normal 46,XY chromosomal constitution:

  • Some cases have cytogenetic deletions of 9p, 2q, or 10q or duplications of 1p (WNT4) or of Xp21 [NR0B1 (DAX1)] [Ostrer 2004].
  • FISH may demonstrate a submicroscopic deletion of SRY (sex-determining region Y).
  • Array genomic hybridization (aGH) has been introduced as a discovery tool to identify de novo chromosomal duplications and deletions [Salman et al 2004]. Depending on probe location and density, aGH may identify duplications of NR0B1 (DAX1) or WNT4; deletions of SRY, NR5A1 (SF1), DHH; deletions of genes that map to 9p, 2q, or 10q; or other duplications or deletions [Ostrer 2004, Barbaro et al 2007] (see Table 1).

Histology. On gonadal biopsy:

  • 46,XY DSD. Dysgenetic gonads with decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells
  • 46,XY CGD. Completely undeveloped streak gonads

Note: Gonadal biopsy is generally required for diagnosis.

Molecular Genetic Testing

Genes. Mutations of SRY, NR5A1 (SF1), and DHH are known to be associated with 46,XY DSD and 46,XY CGD. Duplication of NR0B1 (DAX1) and WNT4 are associated with 46,XY DSD.

  • SRY mutations and deletions have been identified in approximately 1% of individuals with 46,XY DSD and 15% of individuals with 46,XY CGD [Veitia et al 1997; Ken McElreavey, personal communication]. Heritable mutations in SRY that are mosaic in transmitting fathers or penetrant only on certain genetic backgrounds occur in some families [Sarafoglou & Ostrer 2000]; the frequency is not known.

    Note: Based on the presence or absence of SRY, the individual’s disorder can be characterized as SRY-positive or SRY-negative.
  • NR5A1 (formerly known as SF1), or nuclear receptor subfamily 5, group A, member 1. Mutations in NR5A1 have been identified in 13% of individuals with 46,XY DSD and 46,XY CGD [Lin et al 2007].
  • DHH. Heterozygous DHH mutations have been identified in up to 20% of individuals with 46,XY DSD. Homozygous or compound heterozygous DHH mutations have been identified in up to 50% of individuals with 46,XY CGD [Canto et al 2005].
  • NR0B1 and WNT4. The prevalence of duplications involving NR0B1 or WNT4 in individuals with 46,XY DSD and 46,XY CGD appears to be low [Domenice et al 2004]. Heritable duplications involving NR0B1 occur in some families [Sarafoglou & Ostrer 2000, Barbaro et al 2007].

Other loci. At least one more as-yet unknown gene on chromosome 5q11 is implicated in SRY-positive 46,XY DSD and 46,XY CGD [Jawaheer et al 2003].

Clinical testing

Sequence analysis. Analysis of the entire coding region of SRY, NR5A1 (SF1), and DHH detects the presence of single base-pair mutations and small deletions and insertions.

Deletion/duplication analysis. Several different methods are used to detect the following:

  • Deletion of SRY
    • A commercially available FISH probe specifically detects deletion of SRY from the Y chromosome in individuals with SRY-negative 46,XY DSD.
    • Polymerase chain reaction (PCR) of SRY is used in lieu of FISH to detect an SRY deletion and most likely has a greater sensitivity than FISH in detection of small deletions (~ <2 kb) within SRY.
  • Duplication of NR0B1 or WNT4. Duplications of NR0B1 or WNT4 are detectable by FISH, quantitative PCR, and other methods that reliably detect copy number changes (see Table 1, footnote 1).

Table 1. Summary of Molecular Genetic Testing Used in 46,XY DSD and 46,XY Complete Gonadal Dysgenesis

Gene SymbolProportion of 46,XY DSD and 46,XY Complete Gonadal Dysgenesis Attributed to Mutations in This GeneTest MethodMutations Detected
46,XY DSD46,XY CGD
SRY1% 115% 2FISH or deletion/duplication testing 2Size of deletion detected depends on method
Sequence analysisSequence variants
NR5A1 (SF1)13%0%Sequence analysisSequence variants
DHH~20% 3~50% 4Sequence analysisSequence variants
NR0B1 (DAX1)RareRareFISH Gene duplication 5
WNT4RareRareDeletion/duplication testing 2Gene duplication

1. Courtesy of Ken McElreavey, Institut Pasteur, based on results of sequence analysis in 400 individuals with 46,XY DSD or 45,XY CGD

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. (See Testing, Findings on routine and specialized cytogenetic studies.)

3. Heterozygous mutations

4. Homozygous or compound heterozygous mutations, but based on a small sample from the Mexican population, so may represent an overestimate of prevalence

5. May also be detected by targeted array GH (gene/segment-specific) or full array GH analyses, which detects deletions/duplications across the genome may also include this gene/segment.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

1.

Perform routine cytogenetic analysis.

2.

If cytogenetic studies are normal, perform FISH or deletion testing to determine if SRY is deleted.

3.

If SRY is present, perform sequence analysis for SRY, NR5A1, and DHH.

4.

If sequence analysis of SRY, NR5A1, and DHH is normal, test for duplication of NR0B1 and WNT4.

Carrier testing for relatives at risk for 46,XY DSD and 46,XY CGD requires prior identification of the disease-causing mutation(s) in the family.

Note: Carriers are heterozygotes for an autosomal recessive, X-linked, or Y-linked disorder and may be at risk for mild forms of the disorder.

Prenatal diagnosis

  • For pregnancies at risk because of a positive family history, prior identification of the disease-causing mutation(s) in the family is required.
  • For pregnancies in which discordance is noted between the gender as determined by sonographic appearance of the genitalia and gender as determined by karyotype, testing for confirmation of the diagnosis in a proband (see above: To confirm the diagnosis in a proband) is required.

Clinical Description

Natural History

46,XY complete gonadal dysgenesis (46,XY CGD). Individuals with 46,XY complete gonadal dysgenesis (46,XY CGD) are born with normal female genitalia (see Figure 1 for description of normal gonadal development). The diagnosis may not be suspected in infancy unless cytogenetic analysis has been performed for another reason, such as prenatal diagnosis or family history of a disorder of sex development (DSD).

Figure 1

Figure

Figure 1. Normal development of male and female internal genitalia. In response to SRY expression, the undifferentiated gonad becomes a testis. This produces (1) the hormone testosterone, which causes the differentiation of the wolffian ducts into seminal (more...)

Typically, individuals with 46,XY CGD do not have phenotypic features of Turner syndrome (e.g., short stature, webbed neck, coarctation of the aorta, renal anomalies) unless they have chromosomal mosaicism such as 46,X/46,XY or a deletion of the short arm of the Y chromosome (i.e., SRY-negative 46,XY CGD).

Affected individuals are raised as females and usually are not diagnosed until puberty, when primary amenorrhea is evident because of the lack of estrogen and progesterone production by the streak gonads. With hormone replacement therapy (HRT), these young women go through normal puberty with development of breasts and axillary and pubic hair and regular menstrual cycles (see Treatment of Manifestations). These women are infertile but may become pregnant through zygote donation.

If gonads are removed early in life to prevent gonadal tumors (most commonly dysgerminoma), life span is not reduced. The cumulative risk of developing gonadoblastoma is 30% by age 40 years. The risk of malignancy for individuals with streak gonads and those with dysgenetic gonads appears to be the same.

46,XY disorder of sex development (46,XY DSD). By contrast, 46,XY DSD is associated with ambiguous genitalia, which may include hypospadias with chordee, incomplete fusion of the labial-scrotal folds, and presence of a urogenital sinus (see Figure 2 for description of normal genital development). The diagnosis of 46,XY DSD may be suspected during pregnancy on the basis of a sonogram that demonstrates small phallic size and/or gender discordance with prenatal cytogenetic analysis. Alternatively, the diagnosis is considered in a newborn with ambiguous genitalia.

Figure 2

Figure

Figure 2. Normal development of the external genitalia. In response to signaling by dihydrotestosterone, the genital tubercle becomes the glans penis, the folds become the phallus, and the swellings become the scrotum. In the absence of this signaling, (more...)

The choice of gender of rearing for individuals with 46,XY DSD is based on expert opinion, including judgment about the degree of hypospadias and the quantity of erectile tissue in the phallus [Houk et al 2006]:

  • When male gender is chosen, surgery is often required to repair hypospadias, chordee, or other genitourinary abnormalities.
  • When female gender is chosen, the surgery necessary to adequately femininize the external genitalia usually requires fewer operations and has fewer urologic difficulties than the surgery needed to adequately masculinize the external genitalia.

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 female and male gender vary.

People with 46,XY DSD require HRT to go through normal puberty. As a result of HRT:

  • Those persons assigned a female gender who have müllerian structures have regular menstrual cycles. They may become pregnant through zygote donation.
  • Those persons assigned a male gender are commonly infertile but may donate gametes via intracytoplasmic sperm insemination (ICSI).

Abdominal dysgenetic gonads are at increased risk for gonadal tumors (most commonly dysgerminoma) and should be surgically removed. If located in the inguinal canal, dysgenetic gonads may be placed in the scrotum following an hCG stimulation test that indicates testicular function.

The cumulative risk of developing gonadoblastoma is 30% by age 40 years. The risk of malignancy for individuals with streak gonads and those with dysgenetic gonads appears to be the same.

If gonads are removed early in life to prevent gonadal tumors (most commonly gonadoblastoma), life span is normal.

Genotype-Phenotype Correlations

SRY

  • Deletion of SRY or mutations that cause complete loss of function of SRY are associated with 46,XY CGD, not 46,XY DSD.
  • Other mutations in SRY may be associated with either 46,XY CGD or 46,XY DSD.
  • The coexistence of fathers with 46,XY DSD and offspring with 46,XY CGD harboring the same SRY mutation is taken as evidence for modifying genes of these mutations [Sarafoglou & Ostrer 2000].

NR5A1 (SF1). Certain mutations in NR5A1 are associated only with 46,XY DSD; others are associated with both 46,XY DSD and AHC.

DHH

  • Heterozygous DHH mutations are associated with 46,XY DSD; homozygous DHH mutations are associated with 46,XY CGD.
  • No information is available on the mutation type that is associated with variation in phenotype.

NR0B1 and WNT4. No genotype-phenotype correlations are known.

Penetrance

The penetrance of germline (i.e., non-mosaic) SRY deletions is 100%. The penetrance of other SRY mutations is unknown.

The penetrance of mutations in NR5A1 and DHH is unknown.

Nomenclature

The nomenclature for disorders of sex development (DSD) was revised in 2006 to reflect the genetics 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 term “46,XY sex reversal.”

Prevalence

Collectively, the prevalence of 46,XY DSD and 46,XY CGD is 1:20,000 [Ostrer 2000].

Differential Diagnosis

The diagnosis of a specific disorder of sex development is made by the evaluation of the newborn, which may reveal other congenital malformations indicating that the disorder of sex development (DSD) is part of a more complex genetic syndrome:

  • Medical history. Investigation of exposure to maternal androgens (as a source of virilization of female fetuses)
  • Family history
    • Existence of similarly affected relatives who have a specific genetic diagnosis
    • Inquiry about relatives with ambiguous genitalia at birth, early infant death (from congenital adrenal hyperplasia or genetic syndrome), delayed onset of puberty, primary amenorrhea (females), and infertility (males)
  • Physical examination with attention to the following:
    • Phallic size and appearance in relation to gender and age:
      • Hypospadias. A male with hypospadias may have a single midline frenulum, i.e., several irregularly spaced fibrous bands that extend between the perineum and the penile shaft resulting in chordee or a bend in the phallus.
      • Clitoral size. A female with clitoral hypertrophy has two paramedian frenula.
    • Labial-scrotal folds. Appearance and presence of gonads
    • Introitus. Assessment of the vagina with a small flexible endoscope to determine if it ends in a blind pouch or a cervix
    • Gonad size, consistency, and location
      • A normal testis tends to feel more compliant than a dysgenetic testis or an ovary.
      • A gonad in the inguinal canal or labioscrotal fold is likely to be a testis or ovotestis.
  • Non-genital malformations, which would indicate a high probability of an underlying syndrome as the cause of DSD (rather than one of the disorders discussed in this section)
  • Laboratory testing
    • Chromosome analysis, including a full karyotype
      Note: In newborns, cord blood can be analyzed without cell culture, providing a same-day test result.
    • Fluorescence in situ hybridization (FISH) to determine the sex chromosome constitution and the presence or absence of SRY
    • Hormonal testing to evaluate for a biosynthetic defect that is either confined to the androgen synthetic pathway or affects the glucocorticoid and mineralocorticoid pathways (e.g., 21-OHD) (The latter may require stimulation with ACTH or hCG to unmask the defect.)
    • Molecular genetic testing to identify mutations in genes associated with 46,XY gonadal dysgenesis and androgen receptor defects resulting from mutations in AR.
  • Diagnostic imaging. Sonography can identify the presence of an estrogen-stimulated uterus in a newborn. MRI may provide better imaging of the uterus, especially after the newborn period, and is less invasive than laparoscopy.

    Note: Sonography cannot be relied on to visualize undescended gonads.
  • Laparoscopy and gonadal biopsy may be required to confirm the anatomy of the internal genitalia and the histology of the gonad.

    Note: Gonadal biopsy may not be required if the diagnosis of a specific disorder can be made by other means.

Disorders Characterized by 46,XY DSD or 46,XY CGD

45,X/46,XY chromosomal mosaicism or related chromosomal disorders, which may include the features of Turner syndrome, i.e., webbed neck, shield chest, coarctation of the aorta, renal anomalies, and short stature. Occurrence is sporadic.

Campomelic dysplasia (CD), a skeletal malformation syndrome, includes bowing of the tibias, small scapulae, abnormalities of the pelvis and spine, eleven pairs of ribs, cleft palate, micrognathia, flat face, and ocular hypertelorism. Most affected individuals die from respiratory distress in the neonatal period. Mutations in SOX9 are causative. Inheritance is autosomal dominant.

WT1-related disorders (see Wilms Tumor Overview):

  • Frasier syndrome (FS) is characterized by focal and segmental glomerulosclerosis of the kidney and 46,XY CGD. Germline WT1 mutations that diminish the +KTS isoform cause FS [Hastie 1992, Little et al 1993, Barbaux et al 1997]. Inheritance is autosomal dominant.
  • Denys-Drash syndrome (DDS) is characterized by mesangial sclerosis of the kidney, Wilms tumor, and 46,XY DSD. Germline mutations in WT1 cause DDS. Inheritance is autosomal dominant.

Alpha-thalassemia X-linked mental retardation (ATRX) syndrome is characterized by small head circumference, telecanthus or ocular hypertelorism, small nose, tented upper lip, prominent or everted lower lip, and coarsening of facial features over time. Genital anomalies range from hypospadias to ambiguous genitalia with undescended testes. Affected individuals have developmental delay from infancy. Some never walk independently or develop speech. Mutations in ATRX are causative. Inheritance is X-linked.

Other Disorders of Sex Development

46,XX ovotesticular DSD (formerly “true hermaphroditism”) presents with testicular and ovarian tissue, either in separate gonads or, more commonly, as unilateral or bilateral ovotestes in which the testicular and ovarian components are adjacent to each other, usually in an end-to-end fashion. A unicornuate or bicornuate uterus is present. The external genitalia tend to be ambiguous. Approximately two thirds of true hermaphrodites are raised as males:

SRY-negative 46,XX testicular disorder of sex development presents with small testes and signs of androgen deficiency, often with ambiguous genitalia. Occurrence is usually sporadic.

Hormonal Biosynthetic Defects

Defects in androgen biosynthesis can lead to normal testis development in 46,XY individuals with abnormalities in the differentiation of the internal and external genitalia. Depending on the quantity of testosterone produced, these androgen biosynthesis defects can lead to ambiguous or completely feminized genitalia. The androgen biosynthetic defects may be confined to the testes, may involve both the testes and the adrenal glands, or may affect the peripheral conversion of testosterone to dihydrotestosterone.

Androgen biosynthetic defects resulting from deficiency of 17-ketosteroid dehydrogenase affect only the synthesis of testosterone [Andersson et al 1996].

Androgen biosynthetic defects resulting from 3-beta-hydroxysteriod dehydrogenase (HSD3B2; encoded by HSD3B2) deficiency, cholesterol desmolase (P450scc; encoded by CYP11A1) deficiency, 17-alpha-hydroxylase (P450C17; encoded by CYP17A1) deficiency, and combined P450C17 and P450C21 (encoded by CYP21A2) deficiency resulting from oxidoreductase (POR) deficiency (see Cytochrome P450 Oxidoreductase Deficiency) involve both testes and the adrenal glands, leading to the development of congenital adrenal hyperplasia with androgen and glucocorticoid deficiencies and potentially with abnormalities of mineralocorticoid synthesis.

Individuals with P450scc or HSD3B2 deficiencies may lose salt whereas individuals with P450C17 may retain salt and develop hypertension. Individuals with cytochrome P450 oxidoreductase deficiency may also have Antley-Bixler syndrome (ABS), including craniosynostosis and other craniofacial anomalies, skeletal anomalies, renal anomalies, and reduction of cognitive function and developmental delay.

Males with 5-alpha-reductase deficiency have incomplete virilization of the genitalia because of the requirement of dihydrotestosterone for fusion of the labioscrotal folds and normal growth of the phallus.

Males with Smith-Lemli-Opitz syndrome (SLOS) resulting from 7-dehydrocholesterol (7-DHC) reductase deficiency have prenatal and postnatal growth retardation, microcephaly, moderate to severe intellectual disability, and multiple major and minor malformations, including underdeveloped external genitalia.

Androgen Receptor Defects

Androgen insensitivity syndrome (AIS), most commonly caused by mutations in AR encoding the androgen receptor, can be either partial or complete (see Androgen Insensitivity Syndrome). Depending on the residual activity of the androgen receptor, affected individuals can have female external genitalia or incomplete masculinization of the external genitalia. The testes of these individuals produce müllerian inhibitory substance (MIS), and thus the müllerian structures (uterus, fallopian tubes, upper one-third of the vagina) are not present. The testes in such individuals are at increased risk for gonadoblastoma and should be removed during the first decade of life. Inheritance is X-linked.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 46,XY disorder of sex development (DSD) or 46,XY complete gonadal dysgenesis (CGD), the following measurements/evaluations are recommended:

  • Blood pressure
  • If the diagnosis is 46,XY DSD, hCG stimulation test
  • Serum concentration of adrenal steroids as a baseline and possibly following ACTH stimulation
  • Abdominal and renal sonogram
  • If genitalia are ambiguous, vaginal examination using a flexible scope
  • Laparoscopy with gonadal biopsy
  • If phenotypic features of Turner syndrome are present, echocardiogram

Treatment of Manifestations

A consensus statement on the management of DSDs was developed under the sponsorship of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology [Houk et al 2006].

The general concepts of care include the following:

  • Avoiding gender assignment in newborns with ambiguous genitalia prior to evaluation by experts
  • Evaluation and long-term management at a center with a multidisciplinary team (including medical geneticists, endocrinologists, surgeons, and mental health professionals) experienced in the diagnosis and management of DSDs
  • Gender assignment for all individuals
  • Open communication with patients and families, including their participation in decision-making
  • Addressing patient and family concerns respectfully and in strict confidence

As noted in the 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.” [Houk et al 2006].

The treatment of an individual with a DSD is determined by the specific diagnosis:

  • Some individuals require surgery to repair the external genitalia and to create and/or enlarge the vagina.
  • HRT is typically required from puberty onward.
  • Abdominal dysgenetic gonads are at increased risk for gonadal tumors (most commonly dysgerminoma) and should be surgically removed.

    Note: If located in the inguinal canal, dysgenetic gonads may be placed in the scrotum when results of an hCG stimulation test indicate testicular function.
  • Streak gonads and dysgenetic gonads are at increased risk for gonadoblastoma and should be surgically removed.
  • Women with 46,XY CGD and with 46,XY DSD and müllerian structures may become pregnant through zygote donation.
  • Males with 46,XY DSD may possibly donate gametes via ICSI.

Surveillance

If streak gonads or dysgenetic testes have not been removed, annual abdominal sonograms are recommended to evaluate for gonadoblastoma.

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

46,XY disorder of sex development (DSD) with abnormally developed, dysgenetic gonads and 46,XY complete gonadal dysgenesis (46,XY CGD) with streak gonads can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner depending on the gene involved:

  • Mutations in SRY are inherited in a Y-linked manner.
  • Mutations in NR5A1 are inherited in an autosomal dominant manner.
  • Heterozygous mutations in DHH resulting in 46,XY DSD are inherited in an autosomal dominant manner.
  • Homozygous (or compound heterozygous) mutations in DHH resulting in 46,XY CGD are inherited in an autosomal recessive manner.
  • NR0B1 duplications are inherited in an X-linked manner.
  • WNT4 duplications are inherited in an autosomal dominant manner.

Risk to Family Members – Y-Linked Inheritance

Parents/father of a proband

  • Because males with 46,XY DSD and 46,XY CGD with a mutation in SRY are generally infertile, the mutations are usually de novo and thus not present in the father of the proband.
  • Individuals with 46,XY partial gonadal dysgenesis with a mutation in SRY may have inherited the mutation from their father.
  • The father of the proband could have germline mosaicism or a constitutional mutation in SRY.

Sibs/brothers of a proband. Because individuals with 46,XY DSD or 46,XY CGD with a mutation in SRY are infertile, the mutation is usually de novo, and the risk to the brothers of a proband is low. On occasion, the brothers of a proband may be at risk because of a constitutional mutation or germline mosaicism in the father.

Offspring of a proband

  • Individuals with 46,XY CGD are unlikely to reproduce without the use of assisted reproductive technologies (ARTs).
  • With the use of ARTs, individuals with 46,XY DSD may be able to have children. Such individuals will pass the disease-causing mutation to all of their sons and none of their daughters.

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

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • A proband with 46,XY DSD or 46,XY CGD with a mutation in NR5A1 and a proband with 46,XY DSD with a mutation in DHH typically have a new gene mutation.
  • A parent of some individuals with 46,XY partial gonadal dysgenesis with a mutation in DHH may have the mutation but no clinical findings.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The incidence of germline mosaicism is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include genetic testing for that mutation. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health-care professionals to recognize the syndrome and/or a milder phenotypic presentation. 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.
  • If a parent of the proband is affected or has a causative mutation, the risk to the sibs is 50%.
  • When the parents are unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Individuals with 46,XY DSD or 46,XY CGD are unlikely to reproduce without the use of ARTs.
  • With the use of ARTs, individuals with 46,XY DSD may be able to have children. Each child of an individual with 46,XY DSD partial gonadal dysgenesis with a mutation in DHH or NR5A1 has a 50% chance of inheriting the mutation.

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

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an individual with 46,XY CGD associated with homozygous or compound heterozygous DHH mutations are obligate heterozygotes of a DHH mutation.
  • Heterozygotes (carriers) may be asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual 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) may be asymptomatic.

Offspring of a proband

  • Individuals with 46,XY CGD are unlikely to reproduce without the use of ARTs.
  • With the use of ARTs, individuals with 46,XY CGD may be able to reproduce. Each child of an individual with DHH-related 46,XY CGD will be a carrier of a DHH mutation.

Risk to Family Members – X-Linked Inheritance

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has an NR0B1 duplication, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.
  • If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, 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 duplication causing 46,XY DSD or 46,XY CGD are unlikely to reproduce without the use of ARTs.
  • With the use of ARTs, individuals with 46,XY DSD or 46,XY CGD may be able to have children. Males will pass the NR0B1 duplication to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing for family members at risk for autosomal recessive or X-linked 46,XY DSD or 46,XY CGD is possible once the mutation(s) have been identified in the family.

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.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies, conceived through ART, that are at increased risk for 46,XY DSD or 46,XY CGD is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for pregnancies conceived through ART and at risk of resulting in a child with 46,XY DSD or 46,XY CGD.

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.

  • Intersex Society of North America (ISNA)
    Rohnert Park CA 94928
  • InterNational Council on Infertility Information Dissemination, Inc. (INCIID)
    PO Box 6836
    Arlington VA 22206
    Phone: 703-379-9178
    Fax: 703-379-1593
    Email: inciidinfo@inciid.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. 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis: Genes and Databases

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 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis (View All in OMIM)

184757NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 1; NR5A1
23342046,XY SEX REVERSAL 7; SRXY7
300473NUCLEAR RECEPTOR SUBFAMILY 0, GROUP B, MEMBER 1; NR0B1
40004446,XY SEX REVERSAL 1; SRXY1
480000SEX-DETERMINING REGION Y; SRY
600982MITOGEN-ACTIVATED KINASE KINASE KINASE 1; MAP3K1
603490WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 4; WNT4
605423DESERT HEDGEHOG; DHH
60708046,XY GONADAL DYSGENESIS, PARTIAL, WITH MINIFASCICULAR NEUROPATHY
61376246,XY SEX REVERSAL 6; SRXY6

SRY

Normal allelic variants. SRY is an intronless gene with a transcript length of 897 nucleotides (reference sequence NM_003140.1).

Pathologic allelic variants. Mutations that cause Y-linked XY-gonadal dysgenesis include gene deletion, missense and nonsense mutations, and frameshifts caused by small deletions or insertions.

Normal gene product. SRY encodes sex-determining region Y protein, a 204-amino acid protein. Sex-determining region Y protein is a transcription factor that is a member of the high mobility group (HMG)-box family of DNA-binding proteins. This protein is the testis-determining factor (TDF), which initiates male sex determination (reference sequence NP_003131.1).

Abnormal gene product. Most mutations in SRY disrupt either its ability to bind DNA, to bend DNA, or to be translocated in the nucleus. Mutation of SRY prevents testes differentiation from occurring, resulting in gonadal dysgenesis.

NR5A1

Normal allelic variants. NR5A1 has seven exons and a transcript of 3119 nucleotides in length (reference sequence NM_004959.4).

Pathologic allelic variants. Mutations include missense, nonsense, and frameshifts caused by deletions or indels involving a few nucleotides.

Normal gene product. NR5A1 encodes the steroidogenic factor 1 (SF-1), a transcription factor of 461 amino acids that regulates the expression of a number of genes involved in steroid hormone production and male sexual differentiation (reference sequence NP_004950.2). It falls into the class of orphan nuclear receptors, as a ligand has yet to be identified.

Abnormal gene product. Mutant steroidogenic factor results in impaired transcriptional activation of SF-1-responsive target genes.

DHH

Normal allelic variants. DHH is a member of the hedgehog gene family, which encodes signaling molecules that play an important role in regulating morphogenesis. The gene has three exons (reference sequence NM_021044.2).

Pathologic allelic variants. Missense mutations and small nucleotide deletions of DHH have been reported. Heterozygous DHH mutations have been identified in up to 20% of individuals with 46,XY DSD. Homozygous or compound heterozygous DHH mutations have been identified in up to 50% of individuals with 46,XY CGD (see Table 1).

Normal gene product. Desert hedgehog protein is predicted to be made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signaling activity whereas the C-terminal portion is involved in precursor processing. The protein product of DHH has 396 amino acid residues, including residues 1-22 (signaling sequence), residues 23-396 (proprotein), and residues 23-198 (mature protein) (reference sequence NP_066382.1).

NR0B1

Normal allelic variants. NR0B1 encodes a transcript of 1555 nucleotides comprising two exons (reference sequence NM_000475.3).

Pathologic allelic variants. XY individuals with a duplication of part of the short arm of the X chromosome including NR0B1 with an intact SRY show 46,XY gonadal dysgenesis. The single X chromosome in these individuals does not undergo X-chromosome inactivation; therefore, these individuals presumably carry two active copies of NR0B1. Genes within the duplicated region, such as NR0B1, are therefore not essential for testis development, but, when present in a double dose, interfere with testis formation. Note that individuals with a deletion of this region develop as males.

Normal gene product. NR0B1 encodes a protein of 470 amino acids that contains a DNA-binding domain (reference sequence NP_000466.2). The encoded protein acts as a dominant-negative regulator of transcription, which is mediated by the retinoic acid receptor. This protein also functions as an anti-testis gene by acting antagonistically to Sry.

Nuclear receptor 0B1 plays an important role in the normal development of the adrenal glands, the hypothalamus, the pituitary, and the ovary and testis. The molecular mechanism of action of nuclear receptor 0B1 is poorly understood. No physiologic target gene has been identified. NR0B1 plays a major role in sex determination. NR0B1 has been hypothesized to act as an antagonist of SRY, the main male sex-determining gene. It has also been shown to interact directly with the SF-1 protein.

Abnormal gene product. There is no abnormal NR0B1 gene product, but simply overexpression of the normal gene product.

WNT4

Normal allelic variants. The WNT gene family consists of structurally related genes, which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. WNT4 is a member of the WNT gene family and is the first signaling molecule shown to influence the sex-determination cascade. The WNT4 transcript is 3905 nucleotides in length with five exons (reference sequence NM_030761.4).

Pathologic allelic variants. Duplication of 1p36.23-p35.1 involving the WNT4 gene results in overexpression of the protein, which is associated with 46,XY gonadal dysgenesis in 46,XY individuals.

Normal gene product. The protein products of WNT4 and NR0B1, a gene known to antagonize the testis-determining factor (SRY), play a concerted role in both the control of female development and the prevention of testes formation. Protein Wnt-4 has 351 amino acid residues with a signal peptide (residues 1-22) and a mature peptide (residues 23-351) (reference sequence NP_110388.2).

Abnormal gene product. There is no abnormal WNT4 gene product, but simply overexpression of the normal gene product.

References

Literature Cited

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  2. Andersson S, Geissler WM, Wu L, Davis DL, Grumbach MM, New MI, Schwarz HP, Blethen SL, Mendonca BB, Bloise W, Witchel SF, Cutler GBJ, Griffin JE, Wilson JD, Russel D. Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab. 1996;81:130–6. [PubMed: 8550739]
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Chapter Notes

Author Notes

Web: www.med.nyu.edu/genetics

Revision History

  • 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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