Links To And Excerpts From Ambiguous Genitalia From PedsCases With An Additional Resource

In this post, I link to and excerpt from PedsCases’ Ambiguous Genitalia, by Terra Morel, Apr 26, 2021.

It is important to remember that Ambiguous Genitalia is a subset of Disorders of Sexual Differentiation.

The following is from‘s Disorders of Sex Development:

Practice Essentials

Key points in the management of disorders of sex development (DSDs) include the following:

  • Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex
  • DSDs, formerly termed intersex conditions, are classified on the basis of genetics and the state of the gonads
  • DSDs may be caused by virilization of a child with 46,XX or undervirilization of a child with 46,XY
  • Some individuals with DSDs have genetic mosaicism and may have abnormal gonads (streak ovary, ovotestis, dysgenetic testis).
  • Karyotype to rule out DSDs should be considered in a male-looking patient with bilateral undescended testes or a unilateral undescended testis and hypospadias, whether the genitalia appear ambiguous or not
  • Congenital adrenal hyperplasia (CAH) is the most common cause of DSD
  • The incidence of CAH is 1 in 15,000
  • The most common cause of CAH is 21-hydroxlase deficiency resulting in virilization of a child with 46,XX
  • Prompt diagnosis of the underlying cause of DSD is essential; 75% of those with 21-hydroxlase deficiency have salt-wasting nephropathy
  • Gender identity is not necessarily the same as phenotypic or chromosomal sex
  • Gender assignment of a child with DSD is best made after parents have been counseled by a gender medicine team


Disorders of sex development (DSDs), formerly termed intersex conditions, are seen in infants who are born with ambiguous or abnormal genitalia and may have indeterminate phenotypic sex. The ability to diagnose these conditions has advanced rapidly. In most cases today, clinicians can promptly make an accurate diagnosis and counsel parents on therapeutic options. However, the paradigm of early gender assignment has been challenged by the results of clinical and basic science research, which show that gender identity development likely begins in utero and may not be the same as chromosomal or phenotypic sex.

Whereas surgical genital reconstruction has been widely applied to infants with DSD in the past, the growing understanding of the psychological and social implications of gender assignment has shifted the paradigm away from early reconstruction in some cases. This article focuses on newborn evaluation and the differential diagnoses in children with DSDs, including children with ambiguous genitalia. [12]

All that follows is from the PedsCases’ Ambiguous Genitalia:

This podcast discusses an approach to the presentation of ambiguous genitalia by describing the typical sequence of sexual determination and differentiation, defining disorder (or difference) of sex development and ambiguous genitalia, generating a differential diagnosis for ambiguous genitalia, and outlining initial approach and management. This podcast was developed by Terra Morel, a third year medical student at the University of Alberta, and was created in collaboration with Dr. Elizabeth Rosolowsky, a pediatric endocrinologist at the University of Alberta.

Related Content

Typical sexual determination and differentiation

Under typical circumstances, an undifferentiated embryo develops into a fetus with gonads, internal genitalia and external genitalia that are either male or female. This process begins at fertilization and continues until around 20 weeks gestational age.

Sex development is a stepwise process. We can think of sex in 4 major ways: chromosomal sex; gonadal sex; hormonal sex; and phenotypic sex.

First, chromosomal sex is established at fertilization and is determined by the chromosomal constitution. The typical male chromosomal sex is 46XY, and female is 46XX (1).

Until 6 weeks gestational age the fetus has undifferentiated gonads that are identical between XY and XX individuals. The gonads at this stage are called “bipotential gonads” because they
have the potential to develop into either testes or ovaries (1).

Then at 6 weeks gestational age things begin to change. The chromosomal constitution drives the bipotential gonads to become either testes or ovaries. The Y-chromosome contains an
important gene called the SRY — the Sex-determining Region of the Y chromosome. If SRY is present, the bipotential gonad is directed to become a testicle. This is a very important step
called sex determination. The Gonadal Sex is determined. Now, it used to be said that the female pathway was the “default” pathway, in other words, if no SRY was present, then the
gonad would develop into an ovary. We now know that this is no longer the case — there are also important genes that regulate ovarian development, but this is beyond the scope of this podcast. Just remember that the bipotential gonad needs SRY on the Y chromosome to become a testicle. If testes are established a male reproductive tract will develop; if testes are not established a female reproductive tract will develop (1).

So as you can see there are four important steps in the process of sex development: first is the establishment of chromosomal sex at fertilization; the chromosomal sex then drives the
bipotential gonad to develop into either testes or ovaries; testes will produce male sex hormones, ovaries will not; male sex hormones will cause a male phenotype to develop, without male sex hormones a female phenotype will develop. In sum, the process goes: chromosomal sex – gonadal sex – hormonal sex – phenotypic sex. Chromosomal sex predicts for gonadal sex, which predicts for hormonal sex, which predicts for phenotypic sex.

DSDs and Ambiguous Genitalia

What happens when this process goes awry?

The result is a disorder of sex development. Again, a DSD is defined as any atypical development of chromosomal, gonadal or phenotypic sex. Depending on the root cause of the DSD, it can present in many ways, including atypical external genitalia, delayed puberty, amenorrhea, or infertility. As such, a DSD can present across the lifespan, from birth to adulthood (9).

The objective of the podcast today is to give you an approach to a very specific DSD presentation: ambiguous genitalia. Ambiguous genitalia is defined as an infant that presents
with two or more of cryptorchidism, hypospadias, a microphallus <2.5cm, or clitoralmegaly >1cm (9).

Let’s break this definition down:

● Cryptorchidism is where one or both testicles are absent from the scrotum.
● Hypospadias is where the urethral meatus — the opening of the urethra — is not at the tip of the penis. The opening might be on the underside of the penis or scrotum.
● A microphallus is defined as a stretched penis length < 2.5cm. A typical penis length for a full term male infant is between 3 and 4cm.
● Finally, clitoralmegaly is defined as clitoral length > 1cm. A typical clitoral length for a full term female infant is between 2.5 to 4mm. (12).

To meet the definition of ambiguous genitalia, an infant must present with two or more of cryptorchidism, hypospadias, microphallus or clitoralmegaly. Any one in isolation is not
considered to be ambiguous. A baby with descended testicles and typical penis length with mild hypospadias might be described as having atypical genitalia, but the trained pediatrician wouldnot likely have difficulty in naming the sex. Some patient advocates prefer not to use the term ambiguous genitalia, because to the patient, there’s nothing ambiguous about their genitals…they are what they are. For the purposes of this podcast, we will use the term “ambiguous
genitalia” to refer to those rare cases where the presence of cryptorchidism, hypospadias,
and/or microphallus/clitoralmegaly can make assignment of sex of rearing challenging.

Atypical sex determination and development

Now that we have a better understanding of what ambiguous genitalia is, let’s review when and why it might happen, versus a different DSD.

As you know, the first step in sexual development is the establishment of chromosomal sex at fertilization, where a baby typically possesses either a 46XX or 46XY complement. Any variation here will cause a sex chromosome DSD. Sex chromosome DSDs occur when the baby has one too little or one too many X or Y chromosomes. They also include mosaicism and chimerism. Turner syndrome and Klinefelter syndrome are the most common presentations of sex chromosome DSDs (7). Let’s discuss these in greater detail.

In Turner syndrome the chromosomal complement is 45,X. With only one X chromosome the ovaries do not develop fully and instead remain as streak ovaries. There is no Y chromosome,
and in its absence no testes grow, and the hormonal milieu is not male. Instead, the hormonal sex is female, and so female internal and external genitalia develop including the uterus,
fallopian tubes, vagina, labia majora, labia minora, and clitoris. Therefore, newborns with Turner syndrome do not have ambiguous genitalia. Instead, this DSD presents with short stature, neck webbing, and delayed puberty (10).

Let’s compare this to Klinefelter syndrome, where the chromosomal complement is 47,XXY. Because of the Y chromosome, testicles form. However, because of the extra X chromosome, testicles do not develop completely and they do not function well. As a result, there is some testosterone, but less than normal. Levels are usually sufficient for normal male internal and external genitalia to develop, although sometimes an infant may present with isolated microphallus or hypospadias. As such, newborns with Klinefelter syndrome also do not have ambiguous genitalia. This DSD manifests with testicular insufficiency, so instead individuals often present later in life with signs of androgen deficiency or infertility (11).

We will now talk about the mechanisms that can cause these to happen. The differential diagnosis for each mechanism is complex and is beyond the scope of our discussion today.

In a 46 XY embryo, a DSD can occur from one of three mechanisms:

  1. “First there can be a failure of testicular generation” due to a genetic mutation and is called gonadal dysgenesis. “Without the testicles there, the hormonal and phenotypic sex are female.
  2. The second mechanism is insufficient hormone levels. “Depending on the hormonal milieu, this mechanism can present in different ways, including as ambiguous genitalia.
  3. “The last mechanism in an 46 XY individual is androgen insensitivity.

See the show notes for the details of above.

“In the 46 XX embryo there are two main mechanism that cause DSD.

See the show notes for the details of the above.

To summarize, a DSD may occur as a result of a sex chromosomal abnormality or due to one of many different mechanisms. In a 46XY individual, the testicle may not have formed; there might be a block in making androgens; or there might be androgen insensitivity. In a 46XX individual,
the ovaries might not have formed, or there might be androgen excess. As you can see, a DSD may occur as a result of an abnormality at any stage in early sexual
determination and differentiation. Depending on the etiology, the individual may present at birth with ambiguous genitalia, or may present later with other concerns.


Review pages 7 through 14.

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