Ambiguous Genitalia



  • Genitalia can be defined as ambiguous when it is not possible to categorize the gender of the child based on outward genital appearance.
  • Ambiguous genitalia 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 DSD include the following:
    • Bilateral nonpalpable testes
    • Micropenis (stretched length <2.5 cm)
    • Perineal 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
  • DSDs also comprise sex chromosome disorders including Turner (45,X) and Klinefelter syndromes (47,XXY), which usually do not present as ambiguous genitalia.


  • Genital anomalies at birth may have a prevalence as high as 1 in 300.
  • External genitalia ambiguity has a prevalence of approximately 1 in 5,000 births.
  • Congenital adrenal hyperplasia (CAH) is the most common cause of DSD (classified as a 46,XX DSD) and 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 sexual ambiguity are congenital and usually present in the newborn period.
  • Later presentations in older children and young adults can occur. 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.


  • Several single-gene disorders causing gonadal dysgenesis have been described. However, only 15–20% of patients with DSDs are diagnosed at the molecular level.
  • 46,XY DSD may be associated with mutations in the following genes:
    • Genes involved in testicular development: sex-determining region on Y (SRY), SOX9, steroidogenic factor 1 (SF-1), Wilms tumor suppressor gene (WT1), WNT4 duplication, and DAX1 duplication.
    • Genes involved in steroid hormone action or synthesis (autosomal recessive, except for the androgen receptor)
      • LH/choriogonadotropin receptor (LHCGR) gene leading to Leydig cell hypoplasia and decreased testosterone
      • Genes encoding adrenal steroidogenic enzymes: 17α-hydroxylase (CYP17A1), 3β-hydroxysteroid dehydrogenase, (HSD3B2), P450 oxidoreductase, and StAR protein (lipoid hyperplasia)
      • Gene encoding 5α-reductase (SRD5A2), leading to defective conversion of testosterone (T) to dihydrotestosterone (DHT). DHT is necessary for the development of male external genitalia in utero.
      • Androgen receptor (AR) gene located on the X chromosome (X-linked recessive), leading to impaired androgen action
  • 46,XX DSD may be associated with mutations in the following genes:
    • Genes involved in ovarian development and leading to gonadal dysgenesis: FSH receptor (FSHR), SF-1
    • Genes involved in testicular development: presence of SRY, SOX9 duplication
    • Genes encoding steroidogenic enzymes, involved in cortisol biosynthesis, leading to virilizing CAH: 21-hydroxylase (CYP21A), the most common form; 11β-hydroxylase (CYP11B1); 3β-hydroxysteroid dehydrogenase (HSD3B2)
    • Aromatase gene (CYP19A1), leading to impaired placental conversion of fetal adrenal androgens to estrogens
  • Sex chromosome DSD (45,X; 47,XXY; 45,X/46,XY; and 46,XX/46,XY) are caused by meiotic or mitotic nondisjunction.


  • 46,XX DSD
    • Masculinization of the female fetus is caused by androgens produced by the fetus or transferred across the placenta. The most common cause is CAH in which the fetal adrenal glands overproduce androgens in an attempt to correct cortisol deficiency.
    • The ovaries and müllerian derivatives are normal, and the sexual ambiguity is limited to masculinization of the external genitalia.
  • 46,XY DSD
    • Incomplete masculinization of the male fetus can be caused by enzyme disorders of testosterone synthesis (e.g., CAH, 5α-reductase deficiency), unresponsiveness to testosterone action (androgen insensitivity syndromes), or defects in testicular development (complete or partial gonadal dysgenesis).
  • Ovotesticular DSD
    • Includes patients with both ovarian and testicular elements. Combinations include one ovary and one testis, two ovotestes, or one ovotestis with either an ovary or a testis. Often, differentiation of internal and external genitalia 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 (classically 45,X/46,XY) involves a streak gonad on one side and a testis, often dysgenetic, on the other side. The clinical 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 look female at birth and often present later in life with delayed puberty and primary amenorrhea.


  • Ambiguous genitalia in the neonate should be treated as an emergency, and diagnostic evaluation undertaken as soon as possible.
  • CAH, the most common cause of DSD, can be life threatening when accompanied by salt wasting. Also, DSD is disturbing for families and calls for immediate investigation, counseling, and support.


Obtain a careful pregnancy and family history addressing the following:

  • Drug ingestions
  • Teratogen exposures
  • Infections during the pregnancy
  • Androgenic changes in the mother
  • Family history suggestive of CAH or androgen insensitivity
  • History of consanguinity

Physical Exam

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

  • Palpable gonads: imply the presence of Y-chromosome material
  • 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.
  • Presence of a vagina
  • Position of the urethra
  • Length and diameter of penis/clitoris: stretched penile length at term usually ≥2.5 cm; clitoral length is usually ≤1 cm.
  • Development of the scrotum
  • Asymmetry of external genitalia: suggests ovotesticular or 45,X/46,XY DSDs
  • Other dysmorphic features
  • Hypertension is seen with 17α-hydroxylase and 11-hydroxylase deficiencies.
  • Features of the classic disorders of adrenal steroidogenesis

Diagnostic Tests and Interpretation


Initial evaluation should be targeted to help with sex assignment and assessment of gonadal and adrenal steroids. A 1st-line investigation includes the following:

  • Karyotype, or fluorescence in situ hybridization (FISH) (X- and Y-specific probes)
  • Measurement of 17α-hydroxyprogesterone (17-OHP), testosterone, anti–müllerian hormone (AMH) (reliable indicator of testicular tissue), and serum electrolytes

Second-line investigations depend on the karyotype, the presence of palpable gonads, and the 17-OHP levels. These can be ordered after the 1st-line tests or ordered simultaneously, depending on the clinical situation.

  • Karyotype is 46,XX and nonpalpable gonads:
    • Most commonly due to CAH
  • Karyotype is 47,XY: Investigations include tests to determine if testes are present and capable of producing normal levels of androgens:
    • LH, FSH, müllerian-inhibiting substance (MIS), T, and DHT
    • hCG stimulation test will help differentiate disorders of abnormal response to androgen from disorders of androgen synthesis.


  • Ultrasonography of the abdomen and pelvis
    • Part of the 1st-line investigation
    • Can help determine the presence of gonads, uterus, and/or vagina
    • Only 50% accurate in showing intraabdominal testes
  • Retrograde urethrogram can help evaluate the urogenital sinus.
  • MRI can further delineate the internal anatomy.

Diagnostic Procedures/Other

  • Cystoscopy/vaginoscopy is gold standard method to assess the urethral and vaginal anatomy.
  • Laparoscopy +/− gonadal biopsy may be required for definitive evaluation of the reproductive structures.

Differential Diagnosis

  • Gonadal dysgenesis
  • Ovotesticular DSD
  • 46,XX DSD
    • CAH causing virilization in female
    • Maternal androgen exposure
    • Exogenous androgens or endogenous production (e.g., maternal virilizing tumor)
  • 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 androgen receptor or postreceptor defects.
  • Multiple congenital anomalies: Ambiguous genitalia can be a part of a spectrum of congenital anomalies involving the rectum and urologic system.
  • Idiopathic


  • Counsel family to not make announcements describing gender until gender assignment is determined.
  • Medical staff should use terms such as “your child” or “the baby” rather than “he” or “she.”
  • Parents should be counseled that the diagnostic information as well as surgical factors, prediction of hormone function, and potential for fertility will be taken together as a whole.
  • Gender assignment should be made through a multidisciplinary team approach with consultations from endocrinology, urology, neonatology, genetics, psychiatry/psychology, and social work. If these services are not available, the child and family may benefit from transfer to a pediatric tertiary care facility that can provide this multidisciplinary approach.

Medication (Drugs)

  • 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 Treatment

General Measures

  • Surgical management
    • If the gender assignment is female, delaying clitoral surgery should be considered given the potential risk for disturbance of sensation. 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.
    • 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 mixed gonadal dysgenesis [MGD] and low in AR), and the optimal age and type of surgery can vary substantially.
  • Psychosocial management
    • Long-term counseling for the child and parents by mental health staff with expertise in DSDs is critical to promote psychosocial adaption at all stages of cognitive and psychological development.
    • The team can facilitate decision-making processes involving gender assignment/reassignment, timing of surgery, and hormonal replacement.

Ongoing Care

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.


The cosmetic outcome from surgery is usually good. The potential for age-appropriate sexual function is usually good with therapy. The potential for reproductive function depends on the diagnosis. Long-term studies of psychological adjustment are underway.

Additional Reading

  1. Barbaro M, Wedell A, Nordenström A. Disorders of sex development. Semin Fetal Neonatal Med. 2011;16(2):119–127.  [PMID:21303737]
  2. Lambert SM, Vilain EJ, Kolon TF. A practical approach to ambiguous genitalia in the newborn. Urol Clin North Am. 2010;37(2):195–205.  [PMID:20569798]
  3. Lee PA, Houk CP, Ahmed SF, et al. Consensus statement on management of intersex disorders. Pediatrics. 2006;118(2):e488–e500.  [PMID:16882788]
  4. MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004;350(4):367–378.  [PMID:14736929]
  5. Murphy C, Allen L, Jamieson MA. Ambiguous genitalia in the newborn: an overview and teaching tool. J Pediatr Adolesc Gynecol. 2011;24(5):236–250.  [PMID:21872773]
  6. Romao RL, Salle JL, Wherrett DK. Update on the management of disorders of sex development. Pediatr Clin North Am. 2012;59(4):853–869.  [PMID:22857833]



  • 752.7 Indeterminate sex and pseudohermaphroditism
  • 255.2 Adrenogenital disorders


  • 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


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


  • Q: Should a child’s sex assignment be consistent with the karyotype?
  • A: This is a major decision that should involve the family and the treatment team. Future potential for sexual, hormonal, and reproductive function, in addition to genetics, are all important factors.
  • Q: What clues can the physical exam give to the timing of in utero events causing sexual ambiguity?
  • A: In the virilized female, labioscrotal fusion results from androgen exposure prior to 12 weeks’ gestation. Thereafter, androgen exposure can cause only clitoromegaly.


Sarah Z. Hatab

J. Nina Ham

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