Ambiguous genitalia

Disease Description (Causes and Symptoms)

• Definition: Ambiguous genitalia is a condition in which the external genitalia cannot be clearly classified as male or female, and is included among Disorders/Differences of Sex Development (DSD).
• Pathophysiology and main causes
  • Chromosomal abnormalities (e.g., 45,X Turner syndrome, 46,XX, 46,XY, deletions, duplications, etc.)
  • Abnormal development of the gonads (testes and ovaries) (gonadal malformation, gonadal dysgenesis)
  • Abnormal hormone synthesis (e.g., congenital adrenal hyperplasia [CAH] caused by 21-hydroxylase deficiency)
  • Abnormalities in androgen metabolism or receptors (e.g., 5α-reductase deficiency, Androgen Insensitivity Syndrome)
  • Developmental timing factors: a discrepancy between the effects of genetic factors such as SRY and hormone exposure during gonadal differentiation around the 7th week of fetal development
• Main symptoms (clinical findings)
  • Ambiguity of the external genitalia: clitoromegaly (in girls), partial labial fusion, micropenis in children, hypospadias, and external genitalia with features that are difficult to classify as male or female
  • Whether both testes can be palpated (not palpable), amenorrhea (after puberty), and fertility problems
  • Detection of hormonal or chromosomal abnormalities during neonatal testing

Treatment Methods and Precautions

• Treatment principles
  • Multidisciplinary approach: pediatric endocrinology, pediatric urology/gynecology, medical genetics, child psychiatry/psychosocial support, sex education specialists, ethics committees, etc.
  • After identifying the cause, establish a treatment plan that includes sex assignment — considering age, fertility potential, risk of gonadal malignancy, anatomical status, hormonal function, and family and cultural context
• Medical and surgical treatment (varies according to the cause and assigned sex)
  • Endocrine treatment
    • In cases such as CAH, administer glucocorticoids (cortisol analogues) and, if necessary, mineralocorticoids
    • If male sex is assigned, attempt to increase penile size in cases of a small penis using testosterone injections (intramuscular injections); monitoring of bone age and adverse effects is essential
    • When the testes have not descended (cryptorchidism): attempt hormonal treatment (such as vasopressin-related agents), followed by orchiopexy if unsuccessful
  • Surgical correction
    • Masculinization goals: removal of unnecessary uterine and ovarian tissue, urethral reconstruction (hypospadias repair), phalloplasty, etc.
    • Feminization goals: removal of testicular tissue (to reduce the risk of malignancy), clitoral reduction (considering infection and urination problems), vaginoplasty (if necessary)
    • Timing of surgery: in the past, early correction during infancy was recommended (e.g., within 12 months of birth for feminization); however, recent guidelines tend to recommend delaying non-emergency, cosmetic surgery until the patient can participate in the decision, considering patient autonomy and psychological outcomes
  • Cancer risk management: gonadal abnormalities (including dysgenetic gonads and testicular tissue) carry a risk of seminoma and gonadoblastoma, so appropriate follow-up or prophylactic removal should be considered
• Psychosocial management
  • Family counseling, psychosocial support, and long-term follow-up (gender identity, sexual function, mental health)
• Complications and precautions
  • Surgical complications (urinary leakage or stenosis, loss of sensation, scarring), and adverse effects of hormone therapy (accelerated bone age, acne, etc.)
  • Sexual and identity-related issues, possible infertility, and the possibility of gonadal cancer
  • If the assigned sex does not match the person’s identity, the psychological burden can be significant — multidisciplinary counseling and sufficient information must be provided during decision-making
• Prognosis
  • Varies depending on the cause and the appropriateness of procedures and treatment. Fertility, sexual function, and cancer risk differ by cause. Early, accurate diagnosis and multidisciplinary follow-up are important for improving the prognosis

Outpatient Visit Checklist (Including Items to Bring, Test Records, and Example Questions)

• Recommended items to bring
  • List of currently used medications (including steroids and hormones) and allergy history
  • Birth and neonatal records (whether full-term, neonatal weight, etc.)
  • Family history records (differences of sex development, genetic diseases, congenital adrenal hyperplasia, etc.)
  • Previous test results (karyotype, blood hormone test results, umbilical/pelvic ultrasound, abdominal/pelvic CT/MRI, biopsy/laparoscopy findings)
  • Timeline of symptom changes (changes in appearance, urination problems, growth and pubertal changes, etc.)
  • If possible, photographs of the external genitalia (for convenience when consulting with medical staff) — confirm personal information protection when taking and storing them
• Items to check during the outpatient visit
  • Physical examination (including photographing the external genitalia) and confirmation of whether the testes are palpable
  • Necessary blood tests (electrolytes, 17-OH progesterone, etc.), hormone panel, and whether karyotype testing should be requested
  • Imaging tests (pelvic/abdominal ultrasound and MRI if necessary)
  • Counseling on the need for genetic testing and gene panels
• Example questions (items for patients and guardians to consider before the outpatient visit)
  • When were the current symptoms first observed?
  • Does anyone in the family have a similar condition or a genetic disease?
  • The child’s behavior and expressions of gender identity (when possible, observations appropriate to the child’s age)

Examples of General Questions to Ask the Doctor

• "How likely is this cause, and what additional tests are needed?"
• "What are the long-term adverse effects and expected outcomes of treatment (surgery and hormone therapy)?"
• "What is the risk of cancer in my child’s gonads, and is prophylactic removal necessary?"
• "What is the outlook for future fertility (pregnancy and sperm production), and what options for preservation are available?"
• "How can psychosocial support be obtained?"

Examples of Condition-Specific Questions

• "Based on my child’s karyotype (chromosome test) and hormone test results, what sex assignment is recommended, and what is the basis for it?"
• "If surgery is considered, what is the recommended timing and what types of surgery are expected (e.g., clitoral reduction vs. vaginoplasty vs. urethral repair), and what are the recovery process and risks of complications?"

(Note: Reference value for evaluating penile length in newborns — in a full-term male infant, a penile length of less than approximately 2.0–2.5 cm may raise suspicion of a small penis, but it must be distinguished from a buried penis, in which the penis is concealed by surrounding tissue. Karyotype, hormone testing, imaging, and tissue examination are essential for diagnosing differences of sex development, and decisions are made while considering age (e.g., the possibility that gender identity may become established after 18–30 months of age).)