Approach to precocious puberty: Clinical sciences

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Introduction0:00–0:38

Puberty refers to the transition phase between childhood and adulthood, during which an individual develops secondary sexual characteristics and becomes capable of reproduction.
Precocious puberty is defined as pubertal development before age 8 in biological females and age 9 in biological males. Most isolated signs of early puberty are variants of normal, but an evaluation for precocious puberty is indicated when pubertal development and linear growth proceed rapidly.
Precocious puberty can be divided into two main categories: central and peripheral precocious puberty. Now, let’s talk about what to do if your patient is presenting with chief concerns suggesting precocious puberty.

Focused H&P0:38–1:54

First, perform a focused history and physical examination, including Tanner staging, and measure weight and height. Here’s a high-yield fact!
Puberty begins with activation of the hypothalamic-pituitary-gonadal or HPG axis, which is when the hypothalamus releases gonadotropin-releasing hormone or GnRH that stimulates the anterior pituitary gland to secrete gonadotropin hormones called luteinizing and follicle-stimulating hormones, or LH and FSH for short.
These hormones then travel through the bloodstream to the gonads, where they stimulate the production of sex hormones like estradiol and testosterone!
This process of gonadal activation, growth and maturation is also known as gonadarche. On the other hand, adrenarche is associated with adrenal gland maturation and increased adrenal hormone production, leading to the development of signs like axillary and pubic hair!
In other words, adrenarche is independent of the HPG axis, so to determine the true onset of puberty, you should always look for signs of gonadarche, not adrenarche.Okay, first, let’s focus on benign variants of early puberty, starting with benign isolated premature adrenarche.

Benign isolated premature adrenarche1:54–2:40

These patients can be biological females under age 8 or biological males under age 9. The physical exam reveals normal linear growth velocity with no signs of virilization in combination with apocrine odor and occasionally, acne.
Next, let’s take a look at Tanner staging, also known as the sexual maturity rating, which classifies secondary sex changes that individuals go through in puberty!
These individuals will have stage 1 of breast or testicular development and stage 2 of pubic hair development! With these findings, you can diagnose benign isolated premature adrenarche.Next up is prepubertal vaginal bleeding.

Prepubertal vaginal bleeding2:40–3:32

In this case, your patient will be a biological female under the age of 8 who presents with episodic vaginal bleeding. The physical exam reveals normal linear growth velocity with no evidence of trauma, foreign body, or vaginal mass on the vaginal exam.
Finally, they’ll have stage 1 of breast and pubic hair development. With these findings, diagnose prepubertal vaginal bleeding.
Be sure to thoroughly assess any child who presents with vaginal bleeding for assault or abuse! Here’s a clinical pearl!
There are many other benign variants of early puberty, such as isolated pubic hair of infancy and mini puberty, which is pubertal development that begins during the first few months of life and resolves within a year as the HPG axis matures.

Consider precocious puberty3:32–4:05

Now, let’s take a look at findings that are suggestive of precocious puberty. Keep in mind that the age of normative pubertal development may vary by race and ethnicity.
Generally speaking though, in biological females, the history will reveal breast development before 8 years of age, while in biological males will have testicular enlargement before 9 years of age.
Next, the physical exam might reveal axillary hair and apocrine odor, with stage 2 or higher of breast or testicular development, and stage 2 or higher of pubic hair development.
With these findings, you should consider precocious puberty, so your next step is to order a left-hand X-ray to assess your patient’s bone age.

Bone age4:05–4:31

Once you assess bone age, look for red flags that suggest a pathologic cause of early pubertal development. These include increased height velocity, advanced bone age on X-ray, signs of both gonadarche and adrenarche, and rapid pubertal progression.If you identify no red flags, consider a benign variant of early puberty called benign isolated premature thelarche.

No red flags4:31–5:45

These patients are biologically female and under the age of 8, with early breast development and no symptoms of adrenarche.
If the physical examination confirms Tanner stage 2 or 3 breast development and stage 1 pubic hair development, the diagnosis is benign isolated premature thelarche.
This idiopathic and self-limited condition is especially common in biological females under 2 years of age. Most patients can be monitored every 6 months to ensure that their linear growth rate remains normal and that there’s no evidence of rapid pubertal progression.Here’s a clinical pearl!
When a patient appears to have early breast development, but the exam reveals fatty tissue without underlying firm glandular breast tissue, you can diagnose lipomastia.
This is a benign condition associated with obesity and does not represent true thelarche. On the other hand, the development of glandular breast tissue in a biologically male patient is called gynecomastia.
During puberty, gynecomastia is often normal, but prior to puberty, it requires further investigation. Now, let’s go back and take a look at patients presenting with one or more red flags.

Red flags5:45–6:06

In this case, diagnose true precocious puberty and assess the function of the HPG axis by ordering additional labs, including LH, FSH, as well as estradiol in biological females, and testosterone in biological males.
If the LH, FSH, and estradiol or testosterone results are in the pubertal range, this is consistent with HPG axis activation and central precocious puberty.

Central precocious puberty6:06–6:35

The next step is to assess the patient for indications for an MRI of the brain. These include biological females under the age of 6 years, all biological males under 9 years, and the presence of neurologic signs or symptoms, such as headaches or impaired vision.

CNS tumor6:35–7:09

If any of the indications for MRI are present, your next step is to order imaging of the brain and pituitary gland. The presence of an intracranial mass in the hypothalamic or pituitary region is suggestive of a CNS tumor.
The most common cause of precocious puberty is hypothalamic hamartoma, while other less common causes include glial cell and germ cell tumors.
Keep in mind that subarachnoid cysts, hydrocephalus, cranial irradiation, and severe head trauma could also cause this type of precocious puberty!On the other hand, if brain imaging is normal, or if there’s no indication to perform an MRI, you should consider hypothyroidism as a cause of precocious puberty.

Hypothyroidism7:09–7:39

In this case, be sure to check TSH and free T4 levels. If the TSH is high and the free T4 is low, diagnose hypothyroidism.
Severe, long-standing primary hypothyroidism can present with precocious puberty and is typically associated with a reduced linear growth velocity.
However, if TSH and free T4 levels are normal, you can diagnose idiopathic central precocious puberty, which is the most common cause of central precocious puberty in biological females.Now, let’s move on to peripheral precocious puberty.

Idiopathic precocious puberty7:39–7:52

Peripheral precocious puberty7:52–8:14

In these patients, the HPG axis has not been activated, so lab work will show prepubertal results, meaning low LH and FSH levels, but elevated estradiol and testosterone levels.
With these lab results, you can diagnose peripheral precocious puberty.Your next step is to assess for exogenous steroid exposure.

Exogenous steroid exposure8:14–8:42

History findings associated with ongoing ingestion of oral contraceptives, exposure to transdermal estrogen or testosterone, or exposure to lavender or tea tree oil, are highly suggestive of exogenous steroid exposure as a cause.
On the flip side, if you don’t find any evidence of exogenous steroid exposure, you should consider endogenous causes of peripheral precocious puberty.First, let’s discuss McCune Albright syndrome.

McCune-Albright syndrome8:42–9:52

These patients are usually young children or toddlers, and their caregivers will typically describe the presence of birthmarks or brown skin spots.
Additionally, some caregivers might report that the child has bone pain or a history of fractures. If, on a physical exam, you observe cafe-au-lait spots, consider McCune-Albright syndrome.
Here’s another high-yield fact! In McCune-Albright syndrome, cafe-au-lait spots have borders with an irregular “coast of Maine” appearance, and are often isolated to one side of the body.
On the flip side, in neurofibromatosis, cafe-au-lait spots have smooth borders resembling the “coast of California”. Next, obtain an X-ray or CT scan of the affected bones.
If imaging demonstrates expanded bone with a ground glass appearance, this indicates fibrous dysplasia and confirms the diagnosis of McCune-Albright syndrome.
This is often associated with hyperthyroidism, hyperadrenalism, and acromegaly. Now, let’s discuss the possibility of a hormone-producing tumor, such as ovarian and testicular tumors.

Gonadal tumors9:52–10:49

If history reveals a rapid progression of symptoms, and the physical exam demonstrates an adnexal, abdominal, or testicular mass, consider the possibility of an ovarian or testicular tumor.
In this case, check tumor markers, such as human chorionic gonadotropin, lactate dehydrogenase, and alpha-fetoprotein, and don’t forget to order an abdominal and pelvic ultrasound.
Keep in mind that there are many types of hormone-producing gonadal tumors, including Sertoli Leydig cell tumors, dysgerminomas, and granulosa cell tumors.
Each neoplasm secretes different combinations of tumor markers and hormones. Regardless of tumor markers, if ultrasound reveals abdominal, ovarian, or testicular mass, that’s consistent with ovarian or testicular tumors.

Adrenal pathology10:49–11:34

Finally, let’s consider the possibility of adrenal pathology. Patients usually present with virilization, often in the absence of other signs or symptoms.
In biological females, signs of virilization include hirsutism and clitoromegaly; while in biological males, typical signs include facial hair and penile enlargement.
In both biological females and males, you may notice acne and deepening of the voice. With these signs, consider adrenal pathology, and check levels of testosterone, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate.
Additionally, you could order the adrenocorticotropic hormone stimulation test, and don’t forget to obtain an adrenal ultrasound.If the testosterone, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate are elevated; the ACTH stimulation test demonstrates an elevated 17-hydroxyprogesterone; and the ultrasound is normal, diagnose a non-classical congenital adrenal hyperplasia.

Non-classical congenital adrenal hyperplasia11:34–12:12

This is a mild form of congenital adrenal hyperplasia that presents in late childhood and sometimes in adulthood. On the flip side, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is typically diagnosed in infancy and is associated with virilization of the genitalia and salt wasting.However, if testosterone, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate are normal or elevated, and an adrenal mass is detected on ultrasound, diagnose an adrenal tumor.

Adrenal tumor12:12–12:35

Adrenal carcinomas often produce dehydroepiandrosterone sulfate, while adrenal adenomas commonly produce both androgens and estradiol.

Review12:35–13:26

Alright, as a quick recap… Precocious puberty is generally defined as pubertal development before age 8 in biological females and age 9 in biological males.
Some normal variants of early puberty include isolated thelarche, isolated adrenarche, and prepubertal vaginal bleeding.
If you rule out benign variants of early puberty, diagnose precocious puberty and check LH, FSH, and sex hormone levels to assess the function of the hypothalamic-pituitary-gonadal axis and determine the type.
Central precocious puberty can be associated with a CNS tumor, hypothyroidism, or it can be idiopathic. Peripheral precocious puberty can be caused by exogenous hormone exposure, or conditions like McCune-Albright syndrome, gonadal tumors, nonclassical adrenal hyperplasia, and adrenal tumors.