Children with differences in sex development (DSD) may present at various stages of life, but most commonly during the neonatal period or at puberty.
In newborns, the most frequent physical sign is atypical genitalia. If you work in a neonatal unit, you’re likely to encounter this presentation. Atypical genitalia may signal an important underlying diagnosis, so timely recognition and investigation are essential to ensure the baby’s safety. This is also an area in which many clinicians feel uncertain—both about the investigations themselves and about how best to communicate with parents and families.
We’ll look at
- The definitions of atypical genitalia
- The underlying physiology
- Some of the more common conditions which can cause this presentation
- Approach to assessment, investigation, and management
- Tips on how to communicate with families
Disclaimer: Although this blog is intended to be educational, its content may affect each reader in different ways.
If you, someone close to you, or someone you care for in your clinical practice is affected by this content, please be aware that support is available.
In the UK, the charitable organisations DSDfamilies and YoungMinds provide resources and signposting for young people, parents, and professionals.
What are atypical genitalia?
Atypical genitalia, also known as ambiguous genitalia (AG), is a condition in which a baby’s biological sex cannot clearly be determined by examination of their genitals. Differences in (or disorders of) sex development (DSD) are an umbrella term for a group of inborn conditions where the development of chromosomal, gonadal, or anatomical sex is atypical. AG may indicate an underlying DSD.
Atypical genitalia are relatively rare, although incidence varies with the specific criteria used. Depending on how AG is defined, between 1 in 300 and 1 in 5,000 children are identified as having AG.
The definition of atypical genitalia (AG) is often unclear, leading to confusion. However, certain features on examination are widely accepted indicators. If any of the following are present, the child is generally considered to have atypical genitalia.
Micropenis – a penis that is significantly smaller than average for a newborn male. Specifically, a stretched penile length of 1.9 centimetres (0.75 inches) or less is commonly considered indicative of micropenis.
Bilateral undescended testicles – when neither testicle can be found in the scrotum or in the inguinal canal (a tubelike passage in the groin that the testicle passes through during the development of the baby).
Severe hypospadias – a condition in which the location of the opening through which a child urinates (the urethral meatus) is not present at its typical location at the tip of the penis. In severe hypospadias (20-25% of cases), it is located significantly further down (penoscrotal, scrotal or perineal).
Clitoromegaly – an enlarged clitoris, usually with a length >6 mm and somewhat resembling a small penis.
Other ambiguity – this includes any combination of the above-listed features or other findings, such as fused labioscrotal folds (so-called genital swellings)
Background – overview of the HPG axis and sex hormone synthesis
Before we discuss the causes of atypical genitalia, it helps to understand how the body develops and controls the reproductive system. This involves a group of organs and hormones working together, known as the hypothalamic-pituitary-gonadal (HPG) axis.
The hypothalamic-pituitary-gonadal axis structure
The HPG axis comprises three interconnected components that regulate reproductive function.
- The hypothalamus (found in the brain) releases the initial signal. It contains specialised nerve cells that produce gonadotropin-releasing hormone (GnRH).
- The anterior pituitary (aka the “front” lobe of the master gland) acts as the relay station. It responds to GnRH by releasing two gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
- Finally, the gonads (testes in males and ovaries in females) produce sex hormones in response to signals from the gonadotropins (LH and FSH).
How are the sex hormones made?
Sex hormones are steroid hormones produced through a process called steroidogenesis, which primarily occurs in the gonads but also in the adrenal glands (hormone-producing glands atop the kidneys) and in fat tissue.
The hormones we are referring to are split into three main groups:
- Oestrogens (the feminising hormones)
- Androgens (the masculinising hormones)
- Progestogens (also involved in female reproductive functions).
The main building block for the sex hormones is cholesterol – the same fatty substance you hear about in foods and blood.
The simplified major steps
- Cholesterol entry: cholesterol is brought into specific parts of the cell (the mitochondria – the “powerhouse” of the cell).
- First reaction: cholesterol is turned into pregnenolone. This is the “base chemical” for all steroids.
- Downstream options: depending on what hormone is needed, the body uses different enzymes to change pregnenolone into:
- Progesterone
- Testosterone (main male sex hormone) – pregnenolone is first converted into other intermediates and then into testosterone
- Oestrogen (main female sex hormone) – testosterone or a related chemical is converted into oestrogen through an enzyme called aromatase.
Causes of atypical genitalia
Before birth, a baby’s body follows a step-by-step plan for developing sex organs, guided by hormones. If there’s a mix-up in how they are made, sent, or received, the development of the external genitalia can be different from what is typical for a baby’s chromosomes.
There are many reasons this might happen, and they can be grouped based on whether the baby’s genetic pattern is XX (typically assigned at birth as female) or XY (typically assigned at birth as male), or neither of these two options.
For babies with XX chromosomes (typically assigned as female at birth)
The most common cause is a group of genetic disorders under the umbrella term of congenital adrenal hyperplasia (CAH). CAH can be categorised as ‘classic’, and ‘non-classic’.
Classic CAH presents in neonates. Essentially, in classic CAH, there is an enzyme defect which leads to a blockage in one of the hormone-producing pathways in the adrenal gland. Commonly, this means that the body struggles to synthesise cortisol, and sometimes aldosterone. To try and compensate for this, the adrenal glands have a rapid increase in cell number and become bulky. As a result of this change, they produce too much androgen, which can cause a baby with XX chromosomes to become virilised and have an enlarged clitoris, which may look like a penis.
Babies with XX chromosomes can also become virilised by maternal androgens. Virilisation refers to the development of characteristics such as facial hair. If pregnant people have high levels of androgens, these hormones can cross the placenta and influence the baby’s development. This can be caused by tumours or by some medications.
For babies with XY chromosomes (typically assigned as male at birth)
If there is FSH and LH deficiency (which can be part of a wider pituitary problem –panhypopituitarism, the pituitary does not produce gonadotrophins (LH and FSH). If there is an issue with the gonadotrophin production and supply, the gonads do not receive the signal to make enough testosterone, so typical male genitalia might not develop. This is referred to as hypogonadotrophic hypogonadism.
Sometimes, there can be an issue with the pathways that produce testosterone. Normally, an enzyme called 5-alpha reductase helps transform testosterone into its more active form DHT (5-alpha-dihydrotestosterone), which causes a baby with XY chromosomes to develop typically male genitalia. If there is 5-alpha reductase deficiency, this process does not occur.
In a condition like complete androgen insensitivity syndrome (CAIS), the body makes androgens, but the cells don’t respond. These children are likely to have external genitalia that is more consistent with a female baby. The most common early symptom is a protrusion in the groin (inguinal hernia), which results from the presence of underdeveloped testes.
Gonadal dysgenesis
Gonadal dysgenesis means the ovaries or testes don’t develop properly. This condition can affect both babies with XX and XY chromosomes. If the gonads don’t develop properly, hormone production can be affected, which can cause atypical genitalia.
Genetic mosaicism
Genetic mosaicism is when someone has a mix of different genetic instructions in the cells in their body. For example, babies may have some cells with XX and others with XY chromosomes, or they might have some cells with just X, and some cells with XXY. This can be complex, and there is a huge variation in the way children with genetic mosaicism may present.
Assessment
As always, if the baby is acutely unwell or unstable, it is important to start with an ABCDE assessment. If the baby is stable, a thorough assessment should be completed, as detailed below.
History
Start by identifying any concerns raised during the pregnancy, including findings on antenatal scans. Confirm the baby’s birth weight and gestational age at delivery.
Ask whether there were any signs of maternal virilisation during the pregnancy. As noted earlier, certain medications can cause virilisation, so it’s essential to take a thorough medication history.
Atypical genitalia can sometimes be linked to a systemic, inherited condition—particularly when the parents are consanguineous. Certain aspects of the family history may raise suspicion, including previous stillbirths, multiple miscarriages, unexplained infant deaths, or a history of genital abnormalities or surgery. These topics are important to explore, but they should always be approached with sensitivity.
Examination
Key areas to focus on are:
Are there testicles (or what appear to be testicles) present? Are they where you would expect them to be? In other words, are they palpable, and are they descended?
Is there fusion of the labioscrotal folds?
n babies with atypical genitalia, it can be difficult to determine whether the structure is an enlarged clitoris or a small penis. The term genital tubercle is often used to describe either. Measuring the size of the genital tubercle is an important part of assessing the external genitalia score and determining whether specific criteria—such as those for micropenis—are met.
Practical tip: Measure from the pubic bone to the tip. In some babies, a prominent prepubic fat pad can obscure the base, so be sure to press it down to obtain an accurate measurement.
Can you locate the site of the urinary meatus, and is it in the expected location? This isn’t always possible and sometimes needs to be done in theatre.
Calculating the external genitalia score can be a useful objective measure.
It is also good practice to complete a full neonatal top-to-toe examination, looking for any dysmorphic features, or any systemic features which may suggest an underlying diagnosis, such as hyperpigmentation (sometimes seen with CAH), or midline defects such as a cleft palate.
A full set of observations should be completed, including blood pressure.
Investigation
Investigation of a baby with atypical genitalia often takes place in a staged approach. Early discussion with a specialist in paediatric endocrinology is key, as they will advise regarding exactly which investigations are required. However, as a general rule, the investigations below will be completed within the first 24 hours.
Firstly, and most importantly, U&Es and blood sugar.
A relatively common underlying cause of AG is CAH, and these babies can have issues with their pathways that produce cortisol and aldosterone. If not recognised, babies with classic CAH can present with life-threatening electrolyte abnormalities, such as hyperkalaemia (high potassium), hyponatraemia (low sodium), or hypoglycaemia (low blood sugar). It often takes some time to establish a definitive diagnosis, as many of the investigations need to be sent to reference laboratories.
If CAH is suspected, the U&Es and blood sugars need to be monitored regularly. Regularly is defined differently in different sources, but a general consensus is that blood sugars should be checked before feeding, and that U&Es should be checked at least every 24 hours, and potentially more frequently depending on the results.
Following this, the next step is to determine the sex chromosomes – how many X and Y chromosomes the baby has, and if any mosaicism can be identified. Classically, this was done by requesting a karyotype, but now most genetic laboratories use QF-PCR.
Arrange an abdominal and pelvic ultrasound to assess for Müllerian structures—these are typically present in babies with XX chromosomes and develop into female reproductive organs. The scan should also evaluate the presence, position, and appearance of the gonads. While adrenal glands can be difficult to visualise in neonates, bulky adrenal tissue may raise suspicion for congenital adrenal hyperplasia (CAH).
Based on the initial findings and in consultation with paediatric endocrinology, further investigations may be needed depending on the suspected underlying condition.
Some of these investigations assess the baby’s ability to synthesise steroids, which helps us identify defects in that pathway.
The most commonly discussed test is 17-hydroxyprogesterone (17-OHP). As mentioned earlier, congenital adrenal hyperplasia (CAH) is caused by a defect in one of the enzymes needed to synthesise cortisol—and sometimes aldosterone. The most commonly affected enzyme is 21-hydroxylase, which converts 17-OHP into 11-deoxycortisol, a precursor to cortisol.
In 21-hydroxylase deficiency, this conversion cannot occur. As a result, cortisol production drops, leading to the clinical features of classical CAH, and 17-OHP accumulates. A raised 17-OHP level is therefore highly suggestive of CAH due to 21-hydroxylase deficiency.
Timing matters: 17-OHP is naturally elevated in newborns during the first 48 hours of life, even without CAH. To reduce false positives, the test should be performed after the baby is at least 48–72 hours old.
Other investigations can also be useful in assessing steroid synthesis and identifying any possible issues in the pathway. These include DHEAS, androstenedione, testosterone, dihydrotestosterone, and a urine steroid profile.
Renin and aldosterone can be measured directly. Aldosterone production is affected in many babies with CAH. In response to low aldosterone, the RAAS (renin-angiotensin-aldosterone) system will be activated, resulting in high renin.
LH and FSH should also be checked. Low levels may suggest a disruption in the hypothalamic–pituitary–gonadal (HPG) axis, indicating hypogonadotropic hypogonadism, as previously discussed. However, interpreting these results in neonates requires caution, as it is normal for LH and FSH to be very low shortly after birth.
These hormones are more reliably assessed at around 2–3 months of age, during the period known as mini-puberty, when LH and FSH levels naturally rise. A failure to mount this hormonal surge is more indicative of pituitary dysfunction than low levels seen in the immediate neonatal period. For this reason, if LH and FSH are low at birth, repeat testing is often recommended.
Finally, AMH (anti-Mullerian hormone), can be checked. AMH is produced by Sertoli cells in the testicles. It causes Mullerian structures to regress and is a good indicator of functioning testicular tissue.
There are also some further tests that can be considered, depending on the situation:
A short Synacthen test assesses the baby’s ability to produce cortisol in response to synthetic ACTH. An inadequate response indicates adrenal insufficiency and the likely need for hydrocortisone replacement, as seen in conditions such as CAH or panhypopituitarism. Results are usually available quickly and can guide safe and timely management.
Important note: All investigations related to steroidogenesis should be completed before starting hydrocortisone, as the medication can interfere with test results.
Lastly, if an underlying issue with the pituitary is suspected, there may be issues with the synthesis of other pituitary hormones, such as TSH. Therefore, it may be beneficial to check TSH and free T4.
Management
Ultimately, the management of a baby with atypical genitalia is entirely dependent on the underlying condition, and how the baby presents. A detailed discussion is beyond the scope of this article.
The most important aspect of management is the involvement of the multidisciplinary team (MDT). There should be a local DSD service with regular meetings of the team members. The team should include members from paediatric endocrinology, paediatric surgery/urology, specialist nurses, and psychologists. The expertise and advice of radiologists, geneticists, and laboratory team members may also be required.
Communication with the parents
This is an incredibly important area—and one that hasn’t always been handled well in the past. Poor communication can cause significant distress and trauma for families during an already challenging time.
First and foremost, congratulate the parents on the arrival of their beautiful baby. Be mindful of the language used when discussing sex and gender—these are distinct concepts. Sex refers to biological characteristics, while gender relates to personal identity.
The investigations we carry out are intended to help determine the most appropriate sex of rearing—that is, whether the baby will be raised as male or female. These tests do not predict the gender the child may identify with as they grow up.
Explain to the family that when it’s not possible to determine whether a baby is male or female based on examination alone, there is a clear and structured pathway we follow. Our first priority is always the baby’s safety, which usually involves regular blood tests over the first few days.
As part of this pathway, we consult with specialists and carry out a series of investigations, including blood tests and ultrasound scans (often described as “jelly scans” for families). Some results come back quickly, while others may take one to two weeks—or occasionally longer.
Once all the results are available, we review them carefully and discuss the findings with the family. This helps guide the decision about the baby’s sex of rearing—that is, whether they will be raised as male or female.
The family should be updated regularly. The family should be signposted to further resources – ideally support from psychology services, but when this isn’t feasible, the website ‘DSD families’ has some excellent resources.
It’s important to manage expectations from the outset. All team members should avoid speculating about the baby’s sex, as this can cause confusion and distress. No promises should be made about timelines—while some results return quickly, others may take longer. Clinicians should be open and honest about this uncertainty, reassuring families that they will be kept informed throughout the process.
Take home points
Sometimes atypical genitalia is the only clinical sign of a significant underlying condition
Safety first – check U&Es and blood sugars regularly, then progress other investigations in a stepwise manner
Communication is key – do not speculate about the sex of the baby, do not promise time frames, be open and honest, and keep parents informed throughout
References
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