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Summary Table

Category	Details
Risk Factors	Female sex (idiopathic central form), African American or Hispanic ethnicity, obesity, history of CNS pathology (tumor, trauma, radiation, hydrocephalus), prior international adoption, exogenous hormone exposure, family history (familial male-limited form)
Etiology	Central (GnRH-dependent): premature activation of the hypothalamic-pituitary-gonadal axis; idiopathic in 80 to 90% of girls. Peripheral (GnRH-independent): sex steroid production from gonads, adrenals, ectopic tumors, or exogenous sources independent of the HPG axis
Patient Presentation	Girl under 8 with breast budding, pubic hair, growth spurt, or menses; boy under 9 with testicular enlargement, pubic hair, voice changes, or rapid linear growth
Classic Physical Exam	Tanner stage advancement inappropriate for age, accelerated linear growth crossing percentiles upward, café-au-lait macules with irregular "coast of Maine" borders (McCune-Albright), bilateral testicular enlargement (central) versus unilateral testicular enlargement (gonadal tumor) versus small prepubertal testes with virilization (adrenal source)
Key Diagnostic Results	Advanced bone age greater than 2 standard deviations above chronological age, basal LH greater than 0.3 IU/L, pubertal LH response on GnRH stimulation test (LH greater than 5 IU/L) confirms central form, elevated estradiol or testosterone, MRI brain abnormality in pathological central form
Management	Central form: GnRH agonist (leuprolide depot or histrelin implant) to suppress the HPG axis. Peripheral form: treat the underlying cause (resect tumor, glucocorticoids for CAH, aromatase inhibitors or antiestrogens for McCune-Albright)
Keywords	"Breast development at age 6," "café-au-lait with irregular borders," "polyostotic fibrous dysplasia," "advanced bone age," "rapid linear growth crossing percentiles," "hypothalamic hamartoma," "testotoxicosis," "GnRH stimulation test"

1. Pathophysiology

Normal puberty begins when pulsatile GnRH secretion from the hypothalamus resumes after childhood quiescence, driving LH and FSH release, which in turn stimulates gonadal sex steroid production. Precocious puberty represents secondary sexual development before age 8 in girls and age 9 in boys, and it is mechanistically split into two pathways that the examiner expects you to differentiate confidently.

In central precocious puberty, the HPG axis is prematurely switched on. The pulse generator in the hypothalamus activates early, producing a normal but mistimed cascade: GnRH triggers LH and FSH, gonads enlarge and secrete estradiol or testosterone, and Tanner stages progress in the normal physiological sequence. This is why girls with central form develop breast tissue first (thelarche), then pubic hair (pubarche), then menarche, while boys show testicular enlargement greater than 4 mL as the earliest sign. The accelerated sex steroid exposure pushes the growth plate, producing the classic early growth spurt followed by premature epiphyseal fusion and short adult stature if untreated.

In peripheral precocious puberty, sex steroids appear without HPG activation. The source is the gonad itself (autonomous ovarian cyst, Leydig cell tumor), the adrenal gland (congenital adrenal hyperplasia, adrenal carcinoma), an ectopic hCG-producing tumor, or an exogenous hormone exposure. Because LH and FSH are suppressed by negative feedback, the testes remain prepubertal in size despite virilization, a finding that should immediately point you toward an adrenal or exogenous source in a boy. The exception is hCG-secreting tumors (hepatoblastoma, germ cell tumors), where hCG mimics LH and causes bilateral testicular growth.

A second key concept is secondary central precocious puberty: prolonged peripheral sex steroid exposure can mature the hypothalamus and trigger true central activation on top of the original peripheral process. This explains why untreated CAH or McCune-Albright syndrome can evolve into a mixed picture and why GnRH agonists may be added later.

2. Classification and Clinical Manifestation

Type	Mechanism	LH/FSH Pattern	Typical Causes	Clinical Clues
Central (true, complete, GnRH-dependent)	Premature HPG axis activation	Pubertal levels, pulsatile, rises with GnRH stimulation	Idiopathic (most girls), CNS tumor (hypothalamic hamartoma is pathognomonic), hydrocephalus, trauma, cranial irradiation, neurofibromatosis type 1	Tanner progression in normal sequence, bilateral testicular enlargement in boys, isosexual development
Peripheral (pseudo, GnRH-independent)	Sex steroids from non-HPG source	Suppressed LH and FSH, no rise with GnRH stimulation	McCune-Albright, congenital adrenal hyperplasia, adrenal tumor, ovarian cyst or granulosa cell tumor, Leydig cell tumor, hCG-secreting tumor, exogenous hormone	Out-of-sequence development, virilization in girls (clitoromegaly, deep voice) suggests androgen excess, prepubertal testes with virilization in boys points to adrenal origin
Benign normal variants	Partial or transient activation	Prepubertal	Premature thelarche (isolated breast development, usually under age 2), premature adrenarche (isolated pubic or axillary hair, age 6 to 8), premature menarche (rare)	No advanced bone age, no growth acceleration, no progression through full Tanner sequence
Heterosexual development	Inappropriate-sex hormone exposure	Variable	Virilization in girls (CAH, androgen-secreting tumor), feminization in boys (estrogen-secreting tumor, exogenous estrogen)	Mismatch between phenotypic sex and direction of pubertal change

Two named syndromes appear repeatedly in vignettes.

McCune-Albright syndrome is the triad of peripheral precocious puberty, polyostotic fibrous dysplasia, and café-au-lait macules with irregular borders that respect the midline. The underlying defect is a postzygotic activating mutation of the GNAS1 gene producing constitutive G-protein activation in affected tissues.
Familial male-limited precocious puberty (testotoxicosis) results from an activating mutation of the LH receptor, causing autonomous Leydig cell testosterone production with suppressed LH; boys present at age 2 to 4 with virilization and modestly enlarged testes.

Types of Central Precoccious Puberty

Example	Explanation
Idiopathic central precocious puberty	The most common form, accounting for 80 to 90% of cases in girls and roughly 50% in boys. No identifiable structural, genetic, or metabolic cause is found despite full evaluation. The hypothalamic GnRH pulse generator activates prematurely for unknown reasons, producing normal pubertal sequencing at an early age.
Hypothalamic hamartoma	A congenital, non-neoplastic mass of ectopic neural tissue in the tuber cinereum or floor of the third ventricle. The lesion contains autonomous GnRH-secreting neurons that bypass normal central inhibition. Classic presentation combines very early puberty (often before age 3) with gelastic seizures (uncontrollable laughing spells).
Optic pathway glioma	Low-grade astrocytoma involving the optic nerve, chiasm, or hypothalamus that disrupts inhibitory input to the GnRH pulse generator. Strongly associated with neurofibromatosis type 1, so look for café-au-lait macules with smooth borders, axillary freckling, and Lisch nodules in the vignette.
Craniopharyngioma	Suprasellar tumor arising from Rathke pouch remnants that more often causes pubertal delay, but can trigger central precocious puberty when it irritates rather than destroys hypothalamic tissue. Vignettes typically include headache, bitemporal hemianopsia, and calcifications on imaging.
Post-CNS irradiation	Cranial radiotherapy for childhood leukemia or brain tumors (especially low-dose exposure of 18 to 24 Gy) can disinhibit the hypothalamus and accelerate puberty. Higher doses tend to cause hypogonadism instead, so dose history matters in the vignette.
Post-traumatic or post-infectious	Traumatic brain injury, meningitis, or encephalitis can damage inhibitory pathways that normally restrain GnRH neurons, leading to premature axis activation months to years after the insult.

Types of peripheral precoccious puberty

Example	Short Explanation
McCune-Albright syndrome	Postzygotic activating mutation of the GNAS1 gene producing constitutive G-protein signaling in affected tissues. Classic triad of peripheral precocious puberty, polyostotic fibrous dysplasia, and café-au-lait macules with irregular "coast of Maine" borders. Girls present with recurrent autonomous ovarian cysts and episodic estrogen surges causing breast development and vaginal bleeding. Treated with aromatase inhibitors (letrozole) or tamoxifen.
Familial male-limited precocious puberty (testotoxicosis)	Activating mutation of the LH receptor causing autonomous Leydig cell testosterone production independent of LH stimulation. Boys present at age 2 to 4 with virilization and modestly enlarged testes, suppressed LH, and elevated testosterone. Treated with combined antiandrogen (spironolactone or bicalutamide) plus aromatase inhibitor.
Congenital adrenal hyperplasia (21-hydroxylase deficiency)	Enzymatic block in cortisol synthesis shunts precursors into the androgen pathway, producing excess adrenal androgens. Boys show virilization with prepubertal-sized testes, a key discriminator pointing away from gonadal sources. Diagnosed by markedly elevated 17-hydroxyprogesterone. Treated with hydrocortisone replacement to suppress ACTH drive.
Non-classic congenital adrenal hyperplasia	Milder enzymatic deficiency presenting later in childhood with premature pubarche, accelerated bone age, and mild virilization. Often confused with simple premature adrenarche, but bone age advancement and elevated 17-hydroxyprogesterone after ACTH stimulation distinguish it.
Granulosa cell tumor of the ovary	Estrogen-secreting ovarian neoplasm, the most common cause of isosexual peripheral precocious puberty in girls aside from McCune-Albright. Pelvic ultrasound reveals a unilateral ovarian mass with markedly elevated estradiol and suppressed gonadotropins. Treated by surgical resection.
Leydig cell tumor of the testis	Unilateral testosterone-secreting testicular tumor. Vignette gives asymmetric testicular enlargement with a palpable mass and virilization, while the contralateral testis remains prepubertal because LH is suppressed. Diagnosis confirmed by scrotal ultrasound and surgical pathology.
Sertoli cell tumor of the testis	Rare estrogen-producing testicular tumor that can cause feminization (gynecomastia) in boys. Often associated with Peutz-Jeghers syndrome (mucocutaneous pigmentation and hamartomatous GI polyps) or Carney complex, which are favorite syndromic associations on exams.
hCG-secreting tumor	Ectopic hCG mimics LH at the testicular LH receptor, producing testosterone. Causes bilateral testicular enlargement in boys with virilization, mimicking central precocious puberty, but with suppressed LH and elevated beta-hCG. Common sources include hepatoblastoma, mediastinal or intracranial germ cell tumors, and choriocarcinoma. Notably, this mechanism does not produce precocious puberty in girls because ovarian estrogen synthesis requires both FSH and LH.

3. Diagnostic Workup

Test	Purpose	Expected Finding
Bone age radiograph (left hand and wrist)	Initial screening for advanced skeletal maturation	Bone age advanced more than 2 SD above chronological age
Basal LH, FSH, estradiol or testosterone	Initial hormonal screen	Elevated basal LH greater than 0.3 IU/L favors central form; suppressed gonadotropins with elevated sex steroids favors peripheral form
GnRH (or GnRH analog) stimulation test	Gold standard to differentiate central from peripheral	Pubertal LH peak greater than 5 IU/L confirms central form; flat response confirms peripheral form
Pelvic ultrasound (girls)	Confirm pubertal uterine and ovarian development; identify ovarian cyst or tumor	Uterine length greater than 3.5 cm, endometrial stripe, ovarian volume greater than 1 to 2 mL indicates estrogen exposure
MRI brain with pituitary protocol	Identify intracranial pathology in central form	Hypothalamic hamartoma, optic glioma, other CNS lesion
17-hydroxyprogesterone, DHEA-S, androstenedione	Evaluate for CAH or adrenal tumor	Markedly elevated 17-OHP suggests 21-hydroxylase deficiency; very high DHEA-S suggests adrenal carcinoma
Beta-hCG	Identify hCG-secreting tumor in boys with bilateral testicular enlargement and suppressed LH	Elevated beta-hCG
TSH, free T4	Rule out severe primary hypothyroidism (Van Wyk-Grumbach syndrome)	Markedly elevated TSH with low T4

The workup follows a logical sequence built around one question: is the HPG axis the driver, or is the sex steroid coming from somewhere else?

Begin with bone age as the first practical step. A bone age that matches chronological age in a child with apparent pubertal signs argues against true precocious puberty and favors a benign normal variant such as premature thelarche or premature adrenarche. An advanced bone age more than 2 SD above chronological age confirms that meaningful sex steroid exposure has occurred and justifies further evaluation.

Next obtain basal LH, FSH, and the dominant sex steroid (estradiol in girls, total testosterone in boys). Modern ultrasensitive assays detect a basal LH greater than 0.3 IU/L, which alone may confirm central activation. When basal levels are equivocal, proceed to the GnRH stimulation test, which is the gold standard. Synthetic GnRH (or a GnRH analog such as leuprolide) is administered, and LH is measured at intervals. A peak LH greater than 5 IU/L indicates a pubertal HPG axis and confirms central form; a blunted response with continued sex steroid elevation confirms peripheral form.

Once you have classified the process, target the source. For central form, obtain an MRI of the brain and pituitary to look for hypothalamic hamartoma, optic pathway glioma, or other lesion. MRI is mandatory in all boys with central form and in girls under age 6, since pathological causes are more common at younger ages. For peripheral form, the source determines the next test: pelvic ultrasound for ovarian pathology, adrenal CT or MRI for suspected adrenal tumor, 17-OHP for CAH, beta-hCG for hepatic or germ cell tumors, and a careful history for exogenous hormone exposure (creams, supplements, contaminated medications).

4. Management and Treatment

Diagnosis	First-Line Treatment	Dose and Frequency	Goals
Central precocious puberty	Long-acting GnRH agonist	Leuprolide acetate depot 7.5 mg IM every 4 weeks, or 11.25 mg or 30 mg IM every 12 weeks; histrelin subcutaneous implant once yearly; triptorelin depot every 12 weeks	Halt pubertal progression, preserve adult height, address psychosocial concerns; continue until age 11 (girls) or 12 (boys)
Hypothalamic hamartoma with refractory seizures	GnRH agonist plus consider surgical or stereotactic intervention	Per neurosurgery	Seizure control plus pubertal suppression
McCune-Albright syndrome	Aromatase inhibitor (letrozole) or selective estrogen receptor modulator (tamoxifen)	Letrozole 2.5 mg daily; tamoxifen 20 mg daily	Block estrogen synthesis or action; bisphosphonates for bone disease
Familial male-limited precocious puberty	Antiandrogen plus aromatase inhibitor	Spironolactone or bicalutamide combined with letrozole or anastrozole; ketoconazole is an alternative	Block androgen action and prevent estrogen-driven bone maturation
Congenital adrenal hyperplasia	Glucocorticoid replacement	Hydrocortisone 10 to 15 mg/m²/day divided three times daily; add fludrocortisone if salt-wasting	Suppress ACTH, normalize androgen production
Gonadal or adrenal tumor	Surgical resection	Per oncology and surgery	Source control
Severe primary hypothyroidism	Levothyroxine	Weight-based dosing	Pubertal signs typically regress with thyroid replacement
Premature thelarche or adrenarche	Reassurance and observation	Annual monitoring of growth and Tanner staging	No pharmacologic therapy needed

The management framework hinges on the type. Central form is treated with GnRH agonists, which produce paradoxical suppression of the HPG axis after an initial flare. Continuous (rather than pulsatile) GnRH receptor stimulation downregulates pituitary GnRH receptors, shutting off LH and FSH and halting gonadal steroid production. Leuprolide depot is the workhorse: 7.5 mg intramuscularly every 4 weeks, or longer-acting formulations every 12 weeks. The histrelin implant placed subcutaneously delivers continuous drug for at least one year and is a practical option for adherence. Treatment is monitored by suppression of basal and stimulated LH, slowing of growth velocity, regression or stabilization of Tanner stage, and deceleration of bone age advancement. Therapy continues until a developmentally appropriate age, generally around 11 in girls and 12 in boys, after which puberty is allowed to resume.

Peripheral form demands treatment of the cause. In McCune-Albright syndrome, aromatase inhibitors (letrozole, anastrozole) block estrogen synthesis at the ovary, while tamoxifen blocks estrogen action at the receptor. Familial male-limited precocious puberty requires combined blockade: an antiandrogen (spironolactone, bicalutamide) plus an aromatase inhibitor to prevent androgen-driven bone maturation. Congenital adrenal hyperplasia is treated with hydrocortisone replacement to suppress ACTH and reduce androgen overproduction; fludrocortisone is added when there is salt-wasting. Tumors are resected. Once a peripheral process has been suppressed, watch for secondary central activation that may then require a GnRH agonist on top of the original therapy.

The "next best step" logic that recurs in vignettes is: confirm advanced bone age, classify the form with basal gonadotropins or a GnRH stimulation test, image the brain when central form is found, and start a GnRH agonist when central form is confirmed and progressive. Do not start a GnRH agonist before classification. Do not image the brain in a child with isolated premature thelarche and no advanced bone age.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It's Similar	Key Discriminator
Premature thelarche	Breast development in a young girl mimics central precocious puberty	Isolated breast tissue, no pubic hair, no growth acceleration, bone age matches chronological age, prepubertal LH and estradiol; usually presents under age 2
Premature adrenarche	Pubic or axillary hair and adult body odor in a child suggest puberty	Isolated androgenic signs without breast or testicular development, mild or absent bone age advance, mildly elevated DHEA-S, no estrogen effect on uterus or ovaries
Congenital adrenal hyperplasia (non-classic)	Causes virilization with advanced bone age	Markedly elevated 17-hydroxyprogesterone, prepubertal testes in affected boys, suppressed LH and FSH; treated with hydrocortisone, not GnRH agonist
McCune-Albright syndrome	Peripheral form with breast development resembles central form	Café-au-lait macules with irregular borders, polyostotic fibrous dysplasia, recurrent ovarian cysts, suppressed gonadotropins, GNAS1 mutation
Exogenous hormone exposure	Pubertal changes mimic endogenous causes	History of contact with topical estrogen or testosterone products, herbal supplements, or contaminated foods; pubertal signs regress after exposure removal
hCG-secreting tumor (in boys)	Bilateral testicular enlargement looks like central form	Elevated beta-hCG, suppressed LH and FSH (hCG mimics LH); look for hepatoblastoma, mediastinal germ cell tumor, intracranial germ cell tumor
Severe primary hypothyroidism (Van Wyk-Grumbach)	Causes breast development and even galactorrhea with delayed bone age	Bone age is delayed, not advanced; markedly elevated TSH; mechanism is TSH cross-reactivity at the FSH receptor; treat with levothyroxine
Leydig cell tumor (boys)	Virilization with testicular enlargement	Asymmetric, unilateral testicular enlargement with palpable mass, suppressed LH, elevated testosterone
Granulosa cell tumor (girls)	Estrogen excess with breast development	Pelvic ultrasound shows ovarian mass, suppressed LH and FSH, very high estradiol
Idiopathic central precocious puberty	Looks like McCune-Albright when only breast development is present	Pubertal LH on GnRH stimulation, no skin or bone findings, no GNAS1 mutation, MRI may be normal

6. Traps and High-Yield Pearls

The most common error is failing to distinguish central from peripheral form before reaching for treatment. Vignettes will hand you a child with breast budding and advanced bone age and tempt you to choose a GnRH agonist. If basal LH is suppressed, GnRH agonists will not work; the source is elsewhere. Always anchor your reasoning on the gonadotropin pattern: pubertal LH points central, suppressed LH points peripheral.

The classic boys' trap centers on testicular size. Bilateral enlargement greater than 4 mL implies LH stimulation, which means either central form or an hCG-secreting tumor. Prepubertal testes with virilization implies adrenal androgens (CAH or adrenal tumor) because the gonad is not being stimulated. Asymmetric or unilateral enlargement with virilization implies a Leydig cell tumor. Sorting boys by testicular findings cuts the differential cleanly.

The hypothyroidism trap is favored by exam writers because it inverts the usual pattern: bone age is delayed, not advanced. A child with breast development, short stature, weight gain, and constipation, found to have profound primary hypothyroidism, has Van Wyk-Grumbach syndrome. Treating with levothyroxine resolves the precocious changes. Picking a GnRH agonist here is wrong.

McCune-Albright is a high-yield distractor that can be solved by reading the skin description carefully. Café-au-lait macules with irregular "coast of Maine" borders that respect the midline, combined with bone pain or fractures from polyostotic fibrous dysplasia, points away from idiopathic central form and toward peripheral form requiring an aromatase inhibitor or tamoxifen rather than a GnRH agonist.

For benign normal variants, the rescue cue is usually the bone age. Premature thelarche and premature adrenarche have bone ages within one year of chronological age, no progressive Tanner advancement, and normal growth velocity. Choosing extensive imaging or hormonal therapy in these children is an exam trap; the correct next step is reassurance and observation.

The core competency being tested is mechanistic classification followed by directed therapy: recognize the age-based threshold (under 8 in girls, under 9 in boys), confirm the process is real with bone age and basal gonadotropins, distinguish central from peripheral with a GnRH stimulation test, image the brain when central form is confirmed (always in boys), and treat the cause rather than the surface phenotype.

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