Precocious Puberty, Pediatric

In most populations, the mean age of onset of puberty is 10.5 years in girls and 11.5 years in boys.

The first sign of puberty in girls is most commonly breast development (thelarche), followed by pubic hair development (pubarche), and then menarche, which generally occurs 2 " “3 years after thelarche; in boys, the first sign is usually testicular enlargement, followed by pubarche and penile growth.

Precocious puberty has traditionally been defined as physical signs of sexual development before age 8 years in girls and age 9 in boys (2.5 " “3 standard deviations below the mean age of onset of puberty).

Recent guidelines propose lowering the age considered to be normal for sexual development in girls to as young as age 6 years in black girls and age 7 years in white girls. These new guidelines have not been universally adopted.

When evaluating precocious puberty, the entire clinical picture, including rate of pubertal progression and the presence of any neurologic symptoms, must be considered.

Epidemiology

Occurs in ¢ ˆ ¼1 in 5,000 children

Precocious puberty is up to 10 times more common in girls than boys.

Racial differences observed in girls: African-American girls may enter puberty 1 year sooner on average than Caucasian girls. Racial difference not present in males.

Increased incidence in internationally adopted children and in children born premature or small for gestational age

In girls: 80 " “90% of central precocious puberty are idiopathic.

In boys: Precocious puberty is more likely to be associated with underlying pathology.

¢ ˆ ¼50% of affected boys have idiopathic central precocious puberty.

Genetics

Genetic causes include the following:

Familial male precocious puberty (testotoxicosis): sex-limited, autosomal dominant inheritance of luteinizing hormone (LH) receptor activating mutation

McCune-Albright syndrome: sporadic, postzygotic, somatic mutation in the stimulatory subunit of G-protein receptor; precocious puberty more common in girls

Pathophysiology

Central precocious puberty can be associated with CNS disorders.

Peripheral precocious puberty

Arises from peripheral sex hormone sources, including gonadal and adrenal disorders, abdominal or pelvic tumors, or exogenous sex steroids

Can progress to central precocious puberty due to maturation of the hypothalamic " “pituitary axis by sex steroids

Etiology

Central precocious puberty (gonadotropin-releasing hormone [GnRH] dependent)

Associated with gonadotropin (LH and/or follicle-stimulating hormone [FSH]) levels that are elevated beyond the normal prepubertal range. Results from activation of hypothalamic " “pituitary " “gonadal axis.

Physical changes are typically those of normal puberty for a child of that sex.

Peripheral sex hormone effects (peripheral precocious puberty or GnRH-independent; less common)

Gonadotropin-independent elevation of sex steroids arising (i) directly from gonads and/or adrenals, (ii) through stimulation of gonads by GnRH-independent mechanism, or (iii) from an exogenous source

Physical changes reflect predominant excess hormones (estrogenic or androgenic) and are often markedly discordant from normal pubertal development.

Diagnosis

Signs & Symptoms

Careful chronology: physical changes, growth spurt, onset of menses

Neurologic, visual, or behavioral changes suggest a CNS lesion.

History

Family history of early puberty (e.g., menarche before age 10 years) or hyperandrogenic disorders (e.g., congenital adrenal hyperplasia)

Presence of exogenous sex steroid medications or creams in the home

Physical Exam

Plot accurate height (using wall-mounted stadiometer), weight, and growth velocity. Growth acceleration within the past year may be strong evidence for puberty.

Careful inventory of early estrogenic and androgenic effects

Estrogenic effects

Girls: careful staging of breasts and color of vaginal mucosa

Boys: gynecomastia in prepubertal child (gynecomastia is common and normal part of puberty in pubescent male.)

Androgenic effects

Girls: careful staging of pubic hair, clitoromegaly

Boys: careful staging of testicular volume (with Prader gonadometer or by measuring testicular length), penile size, and pubic hair

Examine skin for acne and cafe au lait spots.

Perform comprehensive neurologic evaluation to assess for possible CNS pathology.

Diagnostic Tests & Interpretation

Lab

Labs should be selected based on inventory of estrogenic and/or androgenic effects and drawn in early morning.

Estrogenic effects

Girls: FSH and LH (ultrasensitive, pediatric, immunochemiluminometric [ICMA] or electrochemiluminescent [ECL]) (LH is most accurate) and estradiol

Boys: ultrasensitive LH and FSH, estradiol, human chorionic gonadotropin (hCG) level

Androgenic effects

Total testosterone by assay designed to measure low concentrations, adrenal steroids including 17-hydroxyprogesterone (17-OHP) to evaluate for late-onset congenital adrenal hyperplasia and dehydroepiandrosterone sulfate (DHEA-S) to exclude or confirm adrenarche, and ultrasensitive LH to evaluate for central puberty

Other tests

Prolactin: may be elevated with CNS tumors

Thyroid-stimulating hormone (TSH) and free thyroxine (T4)

Avoid lower yield tests, such as total estrogens, nonultrasensitive LH, free testosterone levels (more helpful in adolescent girls with testosterone levels above 30 ng/dL), and other adrenal steroids such as 17-hydroxypregnenolone and DHEA.

Provocative stimulation tests should be done when the aforementioned tests are abnormal or equivocal:

GnRH test (typically leuprolide stimulation) for central precocious puberty; prepubertal GnRH response is predominantly FSH, whereas pubertal response is predominantly LH.

Adrenocorticotropic hormone (ACTH) stimulation test for adrenal abnormalities. Exogenous corticosteroid therapy will interfere with ACTH test but does not interfere with GnRH test of pituitary " “gonadal axis.

Imaging

Bone age x-ray of left hand and wrist: if advanced, further studies, guided by history and physical examination, warranted. If not advanced, or if only early breast or pubic hair development (but not both), premature thelarche or premature adrenarche, respectively, most likely diagnoses.

MRI of head: In the absence of specific clues to CNS disease, the probability of an intracranial abnormality depends primarily on age of onset of puberty, rate of progression, and the sex of the child. MRI is almost always done in boys because they are less likely than girls to have idiopathic precocious puberty.

Ultrasound of gonads/adrenals: as indicated by examination and studies. Evaluates for tumors in both sexes; in girls, ultrasound can also evaluate ovarian/uterine maturity.

Alert

Obese children often have advanced bone ages.

Palpation of breast tissue (buds) can be difficult due to adiposity.

Differential Diagnosis

Causes of central precocious puberty:

Often idiopathic (girls >> boys)

Any cause of peripheral precocious puberty

CNS tumors

Hypothalamic hamartoma: most common CNS mass causing precocious puberty; benign (nonprogressive) congenital malformation of GnRH-secreting neurons

Hypothalamic " “chiasmatic glioma: often associated with neurofibromatosis

Astrocytoma

Ependymoma

Post-CNS trauma or damage

Surgery

Radiation: may occur after 18-Gy exposure

Hydrocephalus/other CNS malformations

Infections: brain abscess, meningitis, encephalitis, granuloma. Lesions may result in stimulation or lack of inhibition of GnRH-secreting area of the hypothalamus, resulting in early pituitary activation.

Environmental: exogenous estrogens (creams and oral forms) and/or exogenous androgens (anabolic steroids or testosterone formulations)

Congenital adrenal hyperplasia: Poorly controlled congenital adrenal hyperplasia can activate the hypothalamic " “pituitary " “gonadal axis in either gender.

McCune-Albright syndrome: triad of precocious puberty, cafe au lait spots, and polyostotic fibrous dysplasia

Familial male precocious puberty (testotoxicosis)

Refeeding after severe malnutrition during early development (such as adopted children who had kwashiorkor)

Incomplete pubertal development

Premature thelarche

Premature adrenarche

Premature menarche

Treatment

Medication

Central precocious puberty: GnRH agonists are the treatment of choice. Adjunctive therapy with growth hormone may be needed to optimize final adult height.

Calcium supplementation may assist bone mass accretion during GnRH agonist therapy.

Peripheral sex hormone effects: aromatase inhibitors and antiandrogens (spironolactone or ketoconazole), glucocorticoids for congenital adrenal hyperplasia

Ongoing Care

When to expect improvement:

Depends on cause. For example, sexual changes of McCune-Albright syndrome are due to autonomously functioning ovarian cysts, which regress variably over time.

Treatment of central precocious puberty with a GnRH agonist usually results in cessation of menses within 2 months, slowing or nonprogression of pubertal changes over 4 " “6 months, and decreased rate of bone age acceleration within 12 months.

Typically, GnRH agonists such as leuprolide (Lupron) are administered in a depot form every 28 days. Some children require shortening of the interval, often prompted by incomplete pubertal suppression. A longer acting formulation of leuprolide is sometimes used as an every 3-month injection. A 12-month duration implantable formulation (histrelin) is also available.

The length of treatment is highly individualized but typically continues until the age of normal pubertal onset.

Prognosis

With treatment, improvement in predicted height may be achieved. Earlier treatment results in improved final height, but most children do not reach target height predicted by mid-parental height measurements.

Treatment may decrease psychosocial distress.

Long-term effects of central precocious puberty and GnRH agonists on fertility have not been fully elucidated.

Complications

Short stature

Psychosocial stresses of early puberty

Additional Reading

Carel ‚ JC, Eugster ‚ EA, Rogol ‚ A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123(4):e752 " “e762. ‚ [View Abstract]

Carel ‚ JC, Leger ‚ J. Clinical practice. Precocious puberty. N Engl J Med. 2008;358(22):2366 " “2377. ‚ [View Abstract]

Herman-Giddens ‚ ME, Slora ‚ EJ, Wasserman ‚ RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research Office in Settings network. Pediatrics. 1997;99(4):505 " “512. ‚ [View Abstract]

Kaplowitz ‚ PB. Treatment of central precocious puberty. Curr Opin Endocrinol Diabetes Obes. 2009;16(1):31 " “36. ‚ [View Abstract]

Kaplowitz ‚ P, Oberfield ‚ SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 1999;104(4, Pt 1):936 " “941. ‚ [View Abstract]

Nathan ‚ BM, Palmert ‚ MR. Regulation and disorders of pubertal timing. Endocrinol Metab Clin North Am. 2005;34(3):617 " “641. ‚ [View Abstract]

Oostdijk ‚ W, Rikken ‚ B, Schreuder ‚ S, et al. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child. 1996;75(4):292 " “297. ‚ [View Abstract]

Codes

ICD09

259.1 Precocious sexual development and puberty, not elsewhere classified

253.1 Other and unspecified anterior pituitary hyperfunction

ICD10

E30.1 Precocious puberty

E22.8 Other hyperfunction of pituitary gland

E30.8 Other disorders of puberty

SNOMED

400179000 Precocious puberty (disorder)

237816004 Central precocious puberty (disorder)

19911007 Precocious female puberty (disorder)

190291004 Premature puberty due to hypothyroidism (disorder)

102889008 Premature development of the breasts (finding)

FAQ

Q: If my child is treated with a GnRH agonist, will he or she go through puberty when we stop the medication?

A: Yes. Children on GnRH agonist treatment proceed through normal puberty when the medication is stopped. Effects on fertility have not been fully studied long-term.

Q: If my child already has some pubertal changes, can they be reversed?

A: If GnRH agonists are used, menses will cease and breast tissue and pubic hair will often partially or completely regress.