What is Ambiguous Genitalia and Disorders of Sexual Differentiation?
When a baby is born with unclear physical gender characteristics, it can lead to a range of challenging issues, including medical, surgical, ethical, and social dilemmas for the child and their parents. The physical gender of a person comes from the development of internal and external reproductive organs influenced by hormones and other factors. However, sometimes there’s a mismatch among these processes (chromosomal, gonadal, and phenotypic sex determination), leading to a condition called a disorder of sexual development (DSD).
DSD is a more current and respectful term that replaces older ones like hermaphrodite, pseudo-hermaphrodite, and intersex, which can be offensive and outdated. DSDs are conditions present from birth that involve unusual development of chromosomal, gonadal, or anatomic sex.
Normal sexual development in the womb depends on a precise sequence of various factors working together. Any changes from the usual development pattern can result in DSDs. This process involves two distinct steps. The first is sex determination, where the reproductive organs (gonads) in a baby develop into either male testes or female ovaries. The next step involves these newly formed gonads releasing hormones that control the formation of internal and external reproductive organs.
The physical signs of DSDs can vary greatly, and could include conditions such as undescended testes, severe hypospadias (a condition where the opening of the urethra is not at the tip of the penis), an enlarged clitoris, a fusion of the outer vaginal lips, female genitalia with a palpable gonad, or mismatched genitalia and sex chromosomes. It remains a topic of debate whether conditions where there is no mismatch between the genitalia and gonads, such as Turner syndrome and Klinefelter syndrome, should be included as DSDs.
Regardless of how a DSD presents or its severity, it’s crucial that individuals with these conditions receive care from a diverse team of professionals. This collaborative approach is necessary to improve their quality of life and ensure the best possible outcomes.
What Causes Ambiguous Genitalia and Disorders of Sexual Differentiation?
Sexual development in mammals, including humans, goes through two steps:
1. Sex determination, which is set by the X and Y chromosomes we receive at conception. If we get a Y chromosome and the SRY gene on it is expressed, the developing embryo moves towards becoming male and starts to develop testes. If there’s no Y chromosome, then the embryo develops female-specific ovaries.
2. Sex differentiation, where certain hormones guide the development and maturation of the genitals and reproductive system.
In males, certain cells produce testosterone and a hormone called anti-mullerian factor, which leads to the development of male sex organs and also prevents female sex organs from developing. When these hormones aren’t present, female sexual organs will start to develop.
These steps are guided by a complex dance of our genes, each doing a specific job. Here’s a breakdown of some key genes involved:
1. SRY gene: This gene on the Y chromosome kickstarts male development.
2. SOX9 gene: This gene is expressed after the SRY gene and contributes to the development of Sertoli cells, which are cells in the testes.
3. NR5A1/SF-1: Codes for a protein that’s crucial for male development and hormone production.
4. DHH gene: This gene plays a part in the differentiation of testes.
5. DAX/NROB1: This gene promotes the development of ovaries.
6. WT1: This is a gene important for the development of kidneys and reproductive organs. If there’s a mutation, it may result in abnormal genitourinary development.
7. Wnt4 and Wnt 7a: These genes suppress male sexual differentiation and the production of male hormones in ovaries.
Mutations in any of these genes can cause different disorders in sexual development. If genes involved in male development aren’t functioning properly, a person may appear physically female despite having XY chromosomes.
The hormones testosterone and anti-Mullerian factor need to be present and properly balanced for normal sexual development. Testosterone helps strengthen certain structures in males, while anti-Mullerian hormone prevents the development of certain female structures. Dihydrotestosterone, another hormone, is necessary for the normal development of external male genitals.
If female genitals are exposed to an excess of androgens, which are male hormones, they can take on male characteristics. If an enzyme called aromatase is lacking, which is responsible for converting the male hormone into the female hormone, it leads to increased levels of testosterone and lowered levels of estrogen. This can result in physically ambiguous genitalia in individuals with XX chromosomes, although they usually have normal internal reproductive organs.
Risk Factors and Frequency for Ambiguous Genitalia and Disorders of Sexual Differentiation
Disorders of sexual development (DSD) are not very common in children, showing up in about 1 in every 1,000 to 4,500 live births. The most common cause is a condition known as congenital adrenal hyperplasia (CAH), followed by androgen insensitivity and mixed gonadal dysgenesis.
Signs and Symptoms of Ambiguous Genitalia and Disorders of Sexual Differentiation
It’s very important to thoroughly check the medical history and conduct a physical examination for newborn babies who have undetectable testes and severe hypospadias, a condition where the opening of the urethra is on the underside of the penis. This should be done irrespective of how unclear their genitalia appears, as they may have what is known as a Disorder of Sex Development (DSD). Around 17% to 50% of newborns who have hypospadias and undescended testes have a DSD.
Things to consider when taking a medical history include: checking if the mother was exposed to androgen hormones such as danazol during pregnancy, monitoring if the mother experienced virilization or took exogenous hormones, oral contraceptives, or certain foods like soy during pregnancy, and also keeping track of family history, especially relating to urological abnormalities, precocious puberty, amenorrhea, infertility, or neonatal deaths. The probability of unclear genitalia could increase if parents are closely related, which is a known risk factor for diseases passed on through the parents’ genes like congenital adrenal hyperplasia. A history of neonatal deaths might also indicate this disease. Sisters with primary amenorrhea (missed periods) and an XY chromosome pattern could indicate X-linked Androgen Insensitivity Syndrome.
- Physical exams are critical to make the right diagnosis
- A good exam includes checking and touching the genitalia
- The baby should be examined in a warm room, on their back, with legs free to move, to check if the testes have descended to the correct place
- Doctors should note the size of the penis or clitoris, the number of perineal openings, and the presence of testes in specific areas
- in a newborn boy, the size of the stretched penis varies between 2.8cm to 4.2cm, based on their gestational age and race. A small penis is not necessarily a sign of a disorder in sexual development. In some cases, the doctor may find undescended testes, scrotal or perineal hypospadias, or hypospadias with an undetectable gonad
- in a full-term female infant, the clitoris size averages 3.3mm to 6.5mm. A clitoris longer than 9mm could indicate clitoromegaly. Other observations are fused vaginal lips, inguinal masses, and a urogenital sinus
- A uterus can be found during a rectal examination as a structure that feels like a cord in the centre, towards the front
- Other abnormalities and unusual physical features need to be written down. Smith-Lemli-Opitz syndrome patients can have unclear genitalia, small head size, ears that are low and tilted backwards, and fused second and third toes. Additional findings could include a short, wide neck, widely spaced nipples, and absence of the iris in the eye.
Testing for Ambiguous Genitalia and Disorders of Sexual Differentiation
Let’s talk about if a patient might be living with a disorder of sexual development (DSD). To try and shed light on the issue, doctors usually kick off their evaluation with a test called karyotyping. It’s most often done using peripheral leukocytes, which are a type of white blood cell. This test helps sort patients into three categories: 46XX DSD, 46XY DSD, and mixed chromosome DSD.
Another important test used in this context is fluorescent in situ hybridization (FISH) for the SRY gene. This gene plays a key role in developing male sex characteristics. If the SRY gene is missing in a 46XY karyotype where it should typically be present, it could lead to DSD that could range from uncertain sexual characteristics to complete sex reversal.
It’s crucial not to overlook potential congenital adrenal hyperplasia (CAH). This is because delayed diagnosis could result in salt-wasting, which can cause significant ill-health and potentially death. Therefore, levels of a hormone called 17hydroxyprogesterone should be measured in all newborns with unusual external genitalia and no apparent swellings in the groin, to rule out classic CAH. Testing for other hormones (dehydroepiandrosterone, 17-hydroxypregnenolone, and 11-deoxycortisol) can assist in diagnosing less common causes of CAH.
The patient’s testosterone levels after stimulation and their gonadotropin levels must also be assessed. Additionally, imaging tools such as ultrasound and MRI can be used to examine the structure and appearance of reproductive organs, like gonads (ovaries or testes), the uterus, and the vagina. Vaginoscopy, which allows doctors to see the inside of the vagina clearly, is also essential.
The type of treatment depends on the patient’s karyotype and whether the SRY gene is present or not. Patients with a 46 XX DSD typically need to undergo an FISH test for the SRY gene. If the SRY gene is present, this can result in uncertain sex characteristics due to the movement of the SRY gene. If the SRY gene is absent, doctors generally measure the concentration of 17 hydroxyprogesterone. Raised levels of this hormone suggest that CAH might be behind female fetuses developing male sex characteristics. In people with 46 XY DSD, the presence or absence of the SRY gene helps determine next steps. The absence of the SRY gene is usually due to deletion.
With patients that have SRY positivity, there are many possible causes for investigation, including CAH leading to an ‘under-virilized’ (less clearly male) 46XY fetuses.
People with DSD related to sex chromosomes usually have karyotypes showing either a 45 X/46 XY mosaicism or 46 XX/46XY mosaicism. Those with no atypical genitalia, such as Turner syndrome or Klinefelter syndrome, are also included in this group.
Treatment Options for Ambiguous Genitalia and Disorders of Sexual Differentiation
Managing individuals with conditions that affect sexual development can be complicated. Various elements, including cultural norms, genetics, hormones, and family dynamics, play a crucial role in a person’s sexual development. Old guidelines recommended early genital surgery based on anticipated fertility and functioning. However, emerging evidence suggests that this approach may not always lead to satisfactory long-term outcomes.
Management now focuses on initial stabilization, an accurate diagnosis, and carefully deciding the person’s gender and planning for possible surgery or hormonal treatment. This is important for conditions like congenital adrenal hyperplasia, the most common cause of ambiguous genitalia (when it’s not clear whether a baby is male or female), that may cause life-threatening crises due to salt loss. In such cases, early diagnosis and treatment with specific medications, like glucocorticoids, is crucial.
An accurate diagnosis is essentially important. Though in some situations, the diagnosis might be clear, a specialized center should handle complex cases. It’s also important to discuss with parents the idea of delaying the decision on gender until a confirmed diagnosis is given.
The decision about the individual’s gender should be based on available evidence and a thorough consideration of factors such as type of condition, hormone exposure, possible fertility and sexual functioning, and psychosocial aspects. There are differing views regarding when this decision should be made. Some suggest immediately after birth to avoid potential conflicts, while others believe it should be a shared decision made during puberty, as no one can predict the person’s future gender identity or sexual orientation. Key factors in this decision are the anatomical and functional capability of the person’s genitals, the cause of the condition, and the family’s values and desires.
Surgical procedures, if deemed necessary, should always aim for optimal cosmetic results, preserving sexual functioning and fertility when possible, and minimizing the risk of cancer in the abnormal gonad (ovary or testis). Delaying the surgery until the individual can confirm their gender identity themselves is often advocated.
Treatment largely depends on the nature of the condition. For instance, in congenital adrenal hyperplasia 46XX, surgery could correct the position of the vagina and urethra and fix fistulas (abnormal connections) between the vagina and the urogenital sinus.
For individuals with 46 XY DSD with a deficiency of specific enzymes, assigning a male gender is usually recommended. Surgeries and hormonal treatments may be used to stimulate growth and correct abnormalities.
Lastly, some conditions increase the risk of gonadal cancer. In these situations, the timing of a gonadectomy (removal of gonads) depends on the risk, the assigned gender, and the functionality of the gonad. Besides, both parents and children with such conditions should be provided with psychosocial support and education to help them understand and manage the situation.
What else can Ambiguous Genitalia and Disorders of Sexual Differentiation be?
Doctors often suspect Disorders of Sex Development (DSD) after they do a physical check of the genital area. However, other conditions could also be the cause, such as:
- Cloaca
- Urogenital sinus
- Rectovaginal fistula
- Caudal duplication, a type of birth defect
Additionally, conditions like undescended testes, a hole in the underside of the penis (penile hypospadias), or a smaller-than-average penis (micropenis) might seem like DSD. But in these cases, there’s no mismatch between the person’s physical features and their sex chromosomes, which is a key feature of true DSD.
What to expect with Ambiguous Genitalia and Disorders of Sexual Differentiation
Even though the outlook is generally positive, the disease can significantly impact a person’s mental and social well-being. Also, related medical and surgical conditions can have an effect on the overall outlook.
Possible Complications When Diagnosed with Ambiguous Genitalia and Disorders of Sexual Differentiation
The most extreme issue in newborns with congenital adrenal hyperplasia (CAH), a genetic disorder, can be a condition called neonatal salt wasting. An early diagnosis is very important to prevent severe illness or even death in newborns. People with malformed gonads, or sex glands, have a risk of developing gonadal tumors, especially those with a Y chromosome. Surgery and treatments might not completely restore sexual functionalities. Also, the chances for these individuals to have children remain less than average.
Common Issues:
- Neonatal salt wasting in newborns with Congenital Adrenal Hyperplasia (CAH)
- Serious illness or death in newborns if not diagnosed early
- Risk of developing gonadal tumors in people with malformed sex glands, especially those with a Y chromosome
- Possibility of unsatisfactory restoration of sexual functionalities post-surgery and treatments
- Suboptimal chances for having children
Preventing Ambiguous Genitalia and Disorders of Sexual Differentiation
When caring for a patient dealing with a condition that affects their sexual development, a patient-centered and team-based approach is needed. It’s important to have a detailed conversation about potential results and to hold off on determining the patient’s gender until the condition has been properly diagnosed. These days, it’s advised to postpone any surgical procedures. Doing so can reduce the chances of the patient experiencing distress about their gender and also help to ensure the best possible results in terms of their physical functioning.
