When a girl is born with both male and female reproductive organs, this condition is called intersex or differences/disorders of sex development (DSD). The medical term for when a girl has both a penis and vagina is ambiguous genitalia. There are various intersex conditions that can cause a girl to be born with both sets of genitalia. The most common cause is congenital adrenal hyperplasia (CAH), where the adrenal glands produce excessive virilizing hormones that cause masculinization of the genitals. Other potential causes include androgen insensitivity syndrome, 5-alpha reductase deficiency, ovotesticular DSD, and chromosome abnormalities like Klinefelter syndrome.
What Causes Intersex in Girls?
There are several different intersex conditions that can lead to a girl being born with both male and female reproductive organs:
Congenital Adrenal Hyperplasia (CAH)
CAH is the most common cause of intersex in girls, accounting for about 1 in 1300 to 1 in 1500 births. It is caused by inherited genetic mutations that lead to impaired cortisol production by the adrenal glands. The lack of cortisol triggers the pituitary gland to produce excess adrenocorticotropic hormone (ACTH), which causes the adrenal glands to oversecrete androgens like testosterone. The high levels of androgens virilize or masculinize the genitals, leading to ambiguous genitalia in girls. There are two main types of CAH – 21-hydroxylase deficiency makes up about 90-95% of cases, while 11β-hydroxylase deficiency accounts for 5-8% of cases.
Androgen Insensitivity Syndrome (AIS)
AIS occurs when a genetic female (XX chromosomes) is resistant to the effects of androgens like testosterone due to mutations in the androgen receptor gene. Although the child has testes and makes normal levels of androgens, the body cannot respond to these hormones. As a result, they develop female external genitalia, but do not develop female internal reproductive structures like a uterus and fallopian tubes. AIS is classified into three categories depending on the degree of androgen insensitivity:
- Complete AIS (CAIS) – complete resistance to androgens, female external genitalia
- Partial AIS (PAIS) – partial resistance, ambiguous external genitalia
- Mild AIS (MAIS) – slight resistance, predominantly male genitalia
PAIS and MAIS can result in a genetic female being born with both male and female external genitals.
5-Alpha Reductase Deficiency
This condition is caused by deficiency of the enzyme 5-alpha reductase type 2, which converts testosterone into the more potent androgen dihydrotestosterone (DHT). Because DHT levels are low, the external genitalia do not virilize normally in utero. As a result, genetic males (XY) can be born with ambiguous genitalia such as a small phallus and labioscrotal folds. However, they undergo virilization at puberty when testosterone levels rise.
Ovotesticular Disorders of Sex Development (DSD)
Individuals with ovotesticular DSD have both ovarian and testicular tissues. The karyotype is most often 46,XX, meaning they have two X chromosomes. However, there is also tissue from the Y chromosome present that leads to partial or incomplete testicular development. This results in intermediate or ambiguous external genitalia. The gonads are often asymmetric, with one ovary on one side and one testis on the other.
Klinefelter Syndrome (XXY)
This condition occurs when a male has an extra X chromosome resulting in a 47,XXY karyotype. The external genitalia are usually normal male, but the condition can sometimes lead to ambiguous or intermediate genitalia. The extra X chromosome results in hypogonadism and small, abnormal testes that produce lower levels of testosterone.
Other rare causes of ambiguous genitalia in girls include:
- Exposure to high levels of androgens from medications during pregnancy
- Metabolic conditions like congenital lipoid adrenal hyperplasia and P450 oxidoreductase deficiency
- Certain genetic syndromes like Smith-Lemli-Opitz syndrome
Diagnosis of Ambiguous Genitalia
Diagnosing the cause of ambiguous genitalia involves:
- Medical history – pregnancy history, family history of intersex conditions, medications, etc.
- Physical exam – inspection of the genitalia, internal reproductive organs
- Hormone tests – testosterone, DHT, cortisol, ACTH, AMH, etc.
- Genetic tests – karyotyping, testing for gene mutations
- Imaging – pelvic ultrasound, MRI
The results of these tests help identify the specific DSD condition causing the ambiguous genitalia. Accurately determining the diagnosis guides appropriate gender assignment and management.
Physical Exam of Ambiguous Genitalia
On physical exam of the external genitalia, findings that are considered ambiguous or intermediate include:
- Enlarged clitoris looking like a small penis (clitoromegaly)
- Labia that are fused and appear scrotal (labioscrotal folds)
- A small vaginal opening
- Partial fusion of the labioscrotal folds, resembling a hypospadic penis
Internal reproductive organs may include:
- Ovaries, uterus and upper vagina on one side
- Testis and seminal vesicles on the other side
- Ovotestes containing both ovarian and testicular tissue
Hormone tests help determine the underlying cause:
- High testosterone, DHT, 17-OHP – suggests CAH
- High testosterone, low DHT – suggests 5-alpha reductase deficiency
- High testosterone, normal DHT – suggests AIS
- Low testosterone – suggests gonadal dysgenesis
Genetic tests like karyotyping detect chromosome abnormalities like Klinefelter syndrome. Gene mutation testing can identify mutations causing CAH, AIS, 5-ARD deficiency, etc.
Pelvic ultrasound and MRI evaluate internal reproductive anatomy like the presence of ovaries, testes or ovotestes.
Gender Assignment in Ambiguous Genitalia
Determining the appropriate sex assignment is a complex process in disorders of sex development. Factors that influence gender assignment include:
- Appearance of external genitalia
- Internal reproductive structures
- Hormonal function and potential for pubertal virilization
- Fertility potential and sexual function
- Cultural influences
- Social circumstances
- Family wishes
A multidisciplinary team including endocrinologists, surgeons, mental health providers, social workers, and ethicists work together with the family to make a decision. In many cases, the child is initially assigned a male or female sex, but this may change later in life. Ongoing counseling helps the affected individual establish their gender identity.
Gender Assignment in Specific DSDs
Typical gender assignment for some conditions includes:
- CAH – Female gender in 46,XX DSD
- AIS – Female gender identity
- 5-alpha reductase deficiency – Varies, depending on country. Male in US, female in other countries.
- Ovotesticular DSD – Case-by-case based on genital appearance, internal organs, hormones, etc.
- Klinefelter syndrome (XXY) – Male gender identity
Treatment of Ambiguous Genitalia
Treatment aims to:
- Assign appropriate gender
- Replace deficient hormones
- Surgically create typical male or female genital appearance
- Provide fertility options in adulthood
- Provide psychosocial support and counseling
Hormone replacement is given to correct hormone deficiencies or excesses:
- Glucocorticoids like hydrocortisone in CAH
- Estrogen replacement in Turner syndrome, complete AIS
- Testosterone in Klinefelter syndrome, hypogonadism
Timing of hormone therapy depends on the DSD condition and assigned gender.
Surgery is sometimes done to normalize genital appearance. Procedures may include:
- Clitoroplasty to reduce enlarged clitoris size
- Vaginoplasty to create or enlarge vaginal opening
- Hypospadias repair to correct abnormal urinary opening on underside of penis
- Gonadectomy to remove dysgenic gonads with malignancy risk
Ideally, surgery should be postponed until adolescence or later so the individual can give informed consent and participate in decision-making.
Ongoing psychological counseling and support helps patients and families cope with the diagnosis and develop a healthy gender identity. Support groups can provide peer support.
Prognosis for Ambiguous Genitalia
The prognosis depends on the specific DSD condition:
- CAH – Normal life expectancy with glucocorticoid treatment
- AIS – Normal fertility in mild cases. Infertility in complete AIS.
- 5-ARD – Good prognosis. Most live as males.
- Ovotesticular DSD – Reduced fertility potential.
- Klinefelter syndrome – Small increased risk of certain cancers, osteoporosis.
With appropriate treatment, most individuals with intersex conditions have good psychosocial outcomes and quality of life. Open communication, ongoing counseling and support facilitates positive adaptation.
Ambiguous genitalia in girls is most often caused by intersex conditions like CAH, AIS, 5-alpha reductase deficiency, ovotesticular DSD, and Klinefelter syndrome. Diagnosis involves hormone tests, genetic tests, imaging of internal organs, and a detailed physical exam. Multidisciplinary care leads to appropriate gender assignment, hormone replacement, surgical reconstruction, and psychological support. With modern management, girls born with ambiguous genitalia due to DSD can have good outcomes and lead fulfilling lives.