Approach to atypical genitalia: Clinical sciences

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Introduction 0:00–0:50

Atypical genitalia refers to external genitalia that do not appear to be completely male or female and suggests a disorder of sexual development which is also known as differences in sexual development or D SD.
For short. These conditions occur due to complex interactions of genes, proteins and hormones that regulate genital development and can be associated with gonadal malignancy, impaired fertility as well as psychosocial issues such as gender dysphoria and low self esteem based on the underlying cause.
Atypical genitalia can result from chromosomal or genetic abnormalities, excess, circulating androgens, gonadal dysfunction and defects in steroid production or action.
The first step in evaluating a patient who presents with atypical genitalia is to perform a focused history and physical examination history may reveal consanguinity or a family history of infertility, unexplained newborn deaths, as well as a history of steroid based medications or some types of anti seizure medications.

Focused H&P 0:50–3:12

The physical exam reveals atypical genitalia with one or more atypical findings in apparent male newborns. These include bilateral undescended testes, bifid scrotum or hypospadias with coexisting micropenis or an undescended testicle.
In apparent females, you might see clitoromegaly or posterior labial fusion, a single genitourinary opening or an inguinal hernia or mass.
Here are some important clinical pearls. At first glance, some normal findings can give the appearance of atypical genitalia.
For instance, clitoral or labial swelling in newly born biological female infants might be mistaken for clitoromegaly. While an enlarged suprapubic fat pad can make a biological male.
Infant's penis appear smaller than it is some abnormal findings in biological males that require further evaluation but do not suggest D SD include isolated hypospadias or a unilateral undescended testicle.
Now, the identification of atypical genitalia in a newborn can be distressing for parents while there's often a sense of urgency to establish an underlying diagnosis.
Karyotype alone does not dictate gender, gender should not be assigned until a thorough evaluation by an expert is performed.
Additionally, careful discussions with a multidisciplinary team allow parents and providers to consider factors such as the child's anatomy, future fertility risk of gonadal malignancy, probable gender identity and cultural background.
Finally, as patients grow and develop, they should receive ongoing support regarding their diagnosis, gender identity or dysphoria and their self esteem.
With these findings, you should consider D SD in order fluorescence in situ hybridization, also called fish or PCR. For the detection of X and Y chromosomes also obtain a full karyotype to confirm the initial results and detect mosaicism.

Consider DSD 3:12–3:51

Here's a high yield fact, palpable gonads are almost always testes. So a newborn with palpable gonads probably has an xy karyotype.
Historically, this finding was used to guide the evaluation of atypical genitalia. But it has been replaced by more accurate PCR and fish testing if the karyotype is abnormal diagnose sex chromosome D SD.

Sex chromosome DSD 3:51–5:05

Moreover, if there's a 45 x 46 xy karyotype, that's mixed gonadal dysgenesis, which is commonly associated with a streak gonad on one side.
And a dysgenetic fibrotic testicle on the other gonadal biopsy confirms the diagnosis and most patients require early gonadectomy due to a high risk of malignancy.
Alternatively, if there's a 46 xx 46 xy karyotype diagnose ovotesticular D SD. These individuals have ovotestes which are gonads that contain both testicular tissue with seminiferous tubules and ovarian tissue with follicles.
The diagnosis is confirmed with gonadal biopsy. Here's a high yield fact, some sex chromosome D SDS such as Turner Syndrome and Klinefelter syndrome do not present with atypical genitalia at birth and are often diagnosed around puberty when differences in development first become apparent.
Let's go back and take a look at individuals with normal karyotypes. If the karyotype is 46 XX, consider androgen excess and obtain 17 hydroxy progesterone or 17 0 HP levels with elevated 17 0 HP.

46,XX/Congenital adrenal hyperplasia 5:05–6:20

Consider congenital adrenal hyperplasia, also known as 21 hydroxylase deficiency, which is the most common cause of atypical genitalia in individuals with a 46 XX karyotype.
Next, order renin sodium and potassium levels and possibly an ACTH stimulation test finally perform an adrenal ultrasound.
The labs typically demonstrate elevated renin levels, sometimes in combination with low sodium and elevated potassium. The ACTH stimulation test shows an elevated 17 0 HP and the adrenal ultrasound may reveal enlarged adrenal glands.
These findings are suggestive of congenital adrenal hyperplasia. Keep in mind that these individuals can present with a life threatening condition called salt wasting crisis, which typically occurs during the second week of life.
On the other hand, if the 17 0 HP level is normal, your next step is to assess for maternal virilization or hirsutism. If maternal virilization or hirsutism is present, consider fetoplacental causes and proceed with maternal testing by obtaining testosterone, dehydroepiandrosterone sulfate or D hea s and androstenedione finally obtain an ultrasound of the pelvis abdomen and adrenal glands if the testosterone d hea and androstenedione levels are elevated and the ultrasound demonstrates a pelvic abdominal or adrenal mass diagnose a maternal androgen producing tumor.

Maternal androgen producing tumor/Placental aromatase deficiency 6:20–8:02

Common examples include benign ovarian luteomas, adrenal adenomas or Krukenberg tumors of the ovary. On the other hand, possible testosterone elevations in combination with elevated D hea and androstenedione levels and a normal ultrasound are suggestive of placental aromatase deficiency because the aromatase enzyme converts androgens to estrogens.
A deficiency in this enzyme prevents the conversion of fetal adrenal androgens to estrogen. So, both fetal and maternal androgens will be elevated.
This can result in atypical genitalia in the newborn as well as maternal hirsutism or virilization during the second half of pregnancy.
Here's a clinical pearl. If you find maternal virilization or hirsutism and the mother reports exposure to exogenous androgens.
Then that is the most probable cause of atypical genitalia. All right, if there's no maternal virilization or hirsutism, consider 46 xx ovotesticular D SD in this case, obtain molecular genetic analysis to look for single gene defects and consider ordering anti mullerian hormone or A H levels, which is a glycoprotein produced by sertoli cells that causes regression of the mullerian ducts during early genital development.

Ovotesticular DSD 8:02–8:52

If the genetic analysis shows a translocation in the sex determining region Y gene or S ry or a duplication in sox three or sox nine genes and amh levels are in the male range indicating the presence of functional testicular tissue, diagnose ovotesticular D SD.
Now that we've discussed patients with a 46 xx karyotype, let's switch our focus to individuals with a 46 xy karyotype. In this case, begin the evaluation with an amh level and an ultrasound of the pelvis abdomen and adrenal glands if amh levels are normal and the ultrasound reveals absent mullerian structures with or without enlarged adrenal glands.

46,XY 8:52–9:41

Your next step is to assess steroid production. In other words, check LH FSH and testosterone levels if the LH and FSH are elevated and the testosterone is low, consider abnormal steroid production.
So be sure to assess adrenal function using the ACTH stimulation test ACTH stimulation test. Demonstrating an adrenal profile suggests adrenal hyperplasia.

Congenital adrenal hyperplasia 9:41–10:25

So you can diagnose congenital adrenal hyperplasia or cah keep in mind that there are several different enzyme deficiencies that can cause ch in xy individuals.
So don't forget to determine the type using genetic testing. Here's a clinical pearl.
Some types of ch do not cause atypical genitalia in newborns with an xy genotype. For example, lipoid cah presents with a female phenotype with ultrasound, demonstrating absent mullerian structures and enlarged adrenal glands.
On the other hand, a normal adrenal profile is strongly suggestive of a defect in testosterone synthesis along the steroidogenesis pathway.

Testosterone synthesis defect 10:25–10:53

Various enzyme defects can cause decreased testosterone synthesis. One example is 17 beta hydroxysteroid dehydrogenase type three deficiency which impairs the conversion of androstenedione to testosterone in the testes.
Now that we've discussed abnormal steroid production, let's consider cases in which the LH FSH and testosterone levels are normal.

Partial androgen insensitivity syndrome 10:53–12:00

Here, you should consider abnormal steroid action and obtain levels of dihydrotestosterone or DHT, which is a more potent metabolite of testosterone.
If DHT levels are normal, consider the possibility of partial androgen insensitivity syndrome and obtain molecular genetic analysis.
If the analysis demonstrates a substitution in the androgen receptor gene, there's partial androgen insensitivity syndrome or AIS.
Here's a high yield fact in AIS, a defect in the androgen receptor causes impaired androgen activity depending on the severity of the mutation.
Affected individuals could have partial or complete AIS. The partial type presents with atypical genitalia while the complete A I typically results in apparently female genitalia at birth.
Patients with complete AIS are often diagnosed at a later age during an evaluation for an inguinal hernia or primary amenorrhea.
Alternatively, if the D HT level is low or absent, consider five alpha reductase deficiency and obtain molecular genetic analysis.

5-Alpha reductase deficiency 12:00–12:19

The mutation of the SRD five A two gene confirms the diagnosis of five alpha reductase deficiency. Finally, let's go back to our amh level and ultrasound and take a look at gonadal dysgenesis.

XY Gonadal dysgenesis 12:19–13:24

In this case, the amh level will be low or absent while the ultrasound may or may not demonstrate the presence of mullerian structures.
Additionally, the adrenal glands will appear normal with these findings, consider gonadal dysgenesis and obtain LH FSH testosterone D hea s and androstenedione levels as well as molecular genetic analysis.
If the LH and FS H are high, but the testosterone D hea s and androstenedione are low and you detect a mutation of the Sr yw T one gene diagnose xy gonadal dysgenesis.
In contrast to mixed gonadal dysgenesis, individuals with xy karyotype can have partial gonadal dysgenesis and atypical genitalia or pure gonadal dysgenesis.
Also known as Swyer syndrome, which is associated with phenotypically female external genitalia. All right.
It's a quick recap, atypical genitalia refers to external genitalia that do not appear to be completely male or female. Causes include chromosomal abnormalities such as mixed gonadal dysgenesis and ovotesticular D SD in 46 xx individuals.

Review 13:24–14:12

Congenital adrenal hyperplasia is the most common cause of atypical genitalia. Others include maternal androgen producing tumors, placental aromatase deficiency and ovotesticular D SD individuals with a 46 xy karyotype could have congenital adrenal hyperplasia, defects and testosterone synthesis, partial androgen insensitivity syndrome, as well as five alpha reductase deficiency or xy gonadal