Nonsyndromic Disorders Of Testicular Development

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.

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.