Description

• Genital ambiguity occurs when it is not possible to categorize the gender of the child based on outward genital appearance.
• Can result from various disorders of sexual development (DSD), a generic term defined as a congenital condition in which development of chromosomal, gonadal, or phenotypic sex is atypical
  • General DSD categories are sex chromosome DSD; 46,XX DSD; 46,XY DSD; ovotesticular DSD; 46,XX testicular DSD; and 46,XY complete gonadal dysgenesis. Specific diagnoses (when available) are preferable to these broad categories.
  • Previous terms such as "intersex," "pseudohermaphroditism," or "sex reversal" should be avoided.
• Criteria that suggest that a child may have a DSD include the following:
  • Bilateral nonpalpable testes
  • Micropenis (stretched length <2.5 cm at full term)
  • Severe hypospadias or mild hypospadias with a unilateral undescended testis
  • Clitoromegaly (width >6 mm or length >9 mm), posterior labial fusion
  • An inguinal/labial mass
  • Family history of a DSD
  • Discordance between genital appearance and prenatal karyotype
• Note: The term "DSD" also comprises sex chromosome disorders including Turner (45,X) and Klinefelter syndromes (47,XXY). However, these usually do not present as ambiguous genitalia.

Epidemiology

• Genital anomalies at birth have a prevalence as high as 1 in 300.
• Genital ambiguity has a prevalence of approximately 1 in 5,000 births.
• Congenital adrenal hyperplasia (CAH) is the most common cause of DSD. CAH is discussed in detail in a separate chapter.
• Partial androgen insensitivity syndrome (PAIS) is the next most common cause of DSD (classified as a 46,XY DSD).
• Disorders causing genital ambiguity are congenital and usually present in the newborn period.
• Later presentations can occur in older children and young adults. Examples:
  • 46,XY individuals with complete 17α-hydroxylase/17,20-lyase deficiency may present in adolescence with hypertension and delayed puberty.
  • Women with complete androgen insensitivity syndrome (CAIS) may present during adolescence with primary amenorrhea.
  • Children with 5α-reductase deficiency may become virilized during puberty.

Pathophysiology

• 46,XY DSD
  • Incomplete masculinization of the male fetus can be caused by disorders of T synthesis (e.g., CAH, 5α-reductase deficiency), unresponsiveness to T action (androgen insensitivity syndromes), or defects in testicular development (complete or partial gonadal dysgenesis).
• 46,XX DSD
  • Masculinization of the female fetus is caused by exposure to androgens, either endogenous or exogenous. The most common cause is CAH in which the fetal adrenal glands overproduce androgens in an attempt to produce cortisol.
  • The ovaries and müllerian derivatives are normal, and the sexual ambiguity is limited to masculinization of the external genitalia.
• Ovotesticular DSD
  • Presence of both ovarian and testicular elements. Combinations may include one ovary and one testis, two ovotestes, or one ovotestis with either an ovary or a testis. Differentiation of internal and external genitalia often coincides with the gonad on the ipsilateral side.
  • Karyotypes are 46,XX most commonly; the molecular basis of this disorder may not be known; 46,XX/46,XY and 46,XX/47,XXY reported.
• Gonadal dysgenesis
  • Mixed gonadal dysgenesis (MGD) (classically 45,X/46,XY) involves a streak gonad on one side and a testis, often dysgenetic, on the other side. Phenotype is highly variable and ranges from female external genitalia through all stages of ambiguous genitalia to a normal male.
  • Pure (complete) gonadal dysgenesis (46,XX, 46,XY, or a Turner syndrome karyotype) involves replacement of gonads by streak gonads. Neonates have female external genitalia and often present later in life with delayed puberty and primary amenorrhea.

History

Obtain a careful gestational and family history addressing the following:

• Drug ingestions or exposure to teratogens
• Infections during the pregnancy
• Androgenic changes in the mother
• Family history of DSDs may not be known or disclosed, but hypospadias, amenorrhea, or infertility in the family may be more commonly known.
• History of consanguinity

Physical Exam

Notable features include phallic structure size, labial fusion, symmetry of external genitalia, presence and location of palpable gonads, and presence of additional anomalies.

• Gonads: Palpable gonads are nearly always testes and the presence of Y-chromosome material, whereas bilateral undescended testes may indicate 46, XX DSD.
• Labial fusion: measurement of the anogenital ratio (distance from anus to posterior fourchette divided by distance from anus to base of phallus). If >0.5, this suggests virilization with posterior labial fusion.
• Position of the urethra
• Length and breadth of penis/clitoris: In term newborns, stretched penile length is usually ≥2.5 cm; clitoral size is usually <1 cm in length and <6 mm breadth.
• Presence of a vagina
• Development of the scrotum: Bifid scrotum suggests undervirilization.
• Inguinal hernia in the presence of female external genitalia: may indicate testes
• Asymmetry of external genitalia: suggests ovotesticular or 45,X/46,XY DSDs
• Hypertension is seen with CAH due to 17α-hydroxylase and 11-hydroxylase deficiencies.
• Other dysmorphic features

Differential Diagnosis

• Gonadal dysgenesis
• 46,XY DSD
  • CAH causing undervirilization of boys
  • 5α-Reductase deficiency prevents in utero formation of male external genitalia.
  • Syndromes of androgen resistance due to abnormalities in AR or postreceptor defects
• 46,XX DSD
  • CAH causing virilization in female
  • Maternal androgen exposure
  • Exogenous androgens or endogenous production (e.g., maternal virilizing tumor)
• Ovotesticular DSD
• Multiple congenital anomalies: Ambiguous genitalia can be a part of a spectrum of congenital anomalies involving the rectum and urologic system.
• Idiopathic

General Measures

• Emphasis is on patient-centered care.
• Medical staff should use terms such as "your child" or "your baby" rather than "he," "she," or "it."
• Counsel family to not make announcements describing gender until gender assignment is determined.
• Parents should be counseled that the diagnostic information, surgical factors, prediction of hormone function, and potential for fertility will be taken together as a whole.
• Gender assignment should be made through a family-centered and multidisciplinary team approach with consultations from endocrinology, urology, neonatology, genetics, psychiatry/psychology, and social work. If these services are not available, the family may benefit from transfer to a pediatric tertiary care facility that can provide this multidisciplinary approach.
• Surgical management
  • If the gender assignment is female, feminizing genitoplasty should be considered in severe virilization. Given the potential risk for disturbance of sensation, clitoroplasty should not be performed for cosmetic purposes alone. Vaginoplasty may be acceptable in infancy given the potential for improved functional outcome.
  • If gender assignment is male, phallic reconstruction can be done when the team and parents are comfortable with the timing. Urethral reconstruction for hypospadias is usually scheduled between 6 and 24 months of age.
  • Reconstructive surgery timing is an area of controversy in recent years. Some advocate for delay in surgery until individual gender identity is established, and the child is fully able to consent. There is no clear consensus as to timing of surgery except for need to engage in fully informed discussion with the family.
  • Gonadectomy or repositioning may be recommended in patients at risk of gonadal malignancy (gonads bearing the Y chromosome). Tumor risk is heterogeneous among DSDs (e.g., high in MGD and low in AR), and the optimal age and type of surgery can vary substantially.

Medication

• With the exception of CAH, most DSD conditions do not require specific medical treatment until puberty.
• At the time of expected puberty, hormonal therapy is usually started in patients with hypogonadism: between 10.5 and 12 years for females and 12.5 and 14 years for males.

Additional Therapies

Psychosocial management

• Long-term counseling for the child and parents by mental health staff with expertise in DSDs is critical to promote psychological adaption at all stages of cognitive and psychosocial development.
• The team can facilitate decision-making processes involving gender assignment/reassignment, timing of surgery, and hormonal replacement.

Follow-up Recommendations

• Long-term follow-up may involve monitoring hormone levels, linear growth, and sexual and psychological development.
• Follow-up also involves monitoring for gonadal malignancy. Surveillance imaging and testicular palpation should be performed in all DSD patients with abdominal or scrotal testes respectively.

Prognosis

• Approach to surgical management has changed over time. Cosmetic and functional outcomes vary; there continues to be, however, a need for further data on long-term outcomes.
• Potential for reproductive function depends on the specific diagnosis.
• Long-term studies of psychological adjustment are underway.

ICD9

• 752.7 Indeterminate sex and pseudohermaphroditism
• 255.2 Adrenogenital disorders

ICD10

• Q56.4 Indeterminate sex, unspecified
• E25.0 Congenital adrenogenital disorders assoc w enzyme deficiency
• Q56.3 Pseudohermaphroditism, unspecified
• Q56.0 Hermaphroditism, not elsewhere classified
• Q56.2 Female pseudohermaphroditism, not elsewhere classified
• Q56.1 Male pseudohermaphroditism, not elsewhere classified

SNOMED

• 21321009 ambiguous genitalia (disorder)
• 237751000 Congenital adrenal hyperplasia (disorder)
• 237821001 Hermaphroditism (disorder)
• 75164001 Pseudohermaphroditism (disorder)
• 111332007 Male pseudohermaphroditism (disorder)
• 8800006 Female pseudohermaphroditism (disorder)