Approach to atypical genitalia: Clinical sciences

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 DSD 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. The 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 antiseizure medications.

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 DSD 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 DSD and 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.s

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 DSD. 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 46,XX/46,XY karyotype, diagnose ovotesticular DSD. 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 DSDs, 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-hydroxyprogesterone, or 17-OHP levels.

With elevated 17-OHP, 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-OHP, 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-OHP 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 DHEAS; and androstenedione. Finally, obtain an ultrasound of the pelvis, abdomen, and adrenal glands.

If the testosterone, DHEAS, and androstenedione levels are elevated and the ultrasound demonstrates a pelvic, abdominal, or adrenal mass, diagnose a maternal androgen-producing tumor. 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 DHEAS and androstenedione levels and a normal ultrasound are suggestive of placental aromatase deficiency.