History

The first step of approaching precocious puberty is to elicit a detailed history and conduct a comprehensive physical exam. History taking should begin by inquiring about the age of onset of signs of sexual development. Generally, the threshold for evaluating pubertal signs is eight years in girls and nine years in boys.

• Patients should be asked explicitly about the type of pubertal changes and progression rate as it can help guide evaluation. Signs of androgen excess such as pubic and axillary hair growth, acne, adult-type body odor,  and hirsutism indicate adrenal pathology. On the other hand, breast development and menstrual bleeding indicate estrogen excess.
• Rapid progression of pubertal signs may indicate an underlying testicular, ovarian, or adrenal tumor. Establishing the sequence of pubertal changes is essential as precocious pseudopuberty often presents with an abnormal sequence. For example, in McCune Albright syndrome, menstrual bleeding may precede the onset of breast development.[27]
• Patients should also be inquired about a recent increase in height.  Usually, patients with precocious pseudopuberty have a rapid increase in height velocity, causing them to move up to higher centiles on the growth chart, at least initially.
• A history of neurological symptoms (headache, visual changes, seizures) should be elicited to exclude a central cause for precocious puberty. A history of chronic disease and insults to the central nervous system (head trauma, perinatal asphyxia, neoplasms, radiation) should also be noted.
• Patients should be inquired about the ingestion of sex hormones or exposure to topical agents with estrogenic/androgenic/endocrine disrupting activity.
• Family history should focus on the timing of pubertal onset in parents, history of ambiguous genitalia in siblings (possible congenital adrenal hyperplasia), and history of precocity in male relatives (familial male limited precocious puberty).

Physical Exam

• The initial step in the physical exam is to record the vital signs. The presence of hypertension may indicate congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency; and bradycardia may indicate hypothyroidism.
• Growth parameters, including height, weight, and head circumference, should be plotted for determining the growth velocity.
• The general exam should focus on looking for signs of specific conditions such as thyroid enlargement and café au lait spots. In McCune Albright syndrome, the café-au-lait spots have a "Coast of Maine" appearance and are described as large, hyperpigmented spots with irregular borders and a segmental distribution. These should be differentiated from the café au lait spots of neurofibromatosis, which tend to have regular borders. Other findings seen in McCune Albright syndrome include polyostotic fibrous dysplasia, which presents as bony deformities, pathological fractures, gait abnormalities, and bone pain.
• Neurological exam and visual field testing should be done to detect neurological deficits secondary to a possible intracranial mass. An abdominal exam should be done to identify any palpable masses which could arise due to adrenal or ovarian tumors.
• The most important part of the exam is to grade sexual maturity using the Tanner staging. Sexual maturity rating (SMR) is determined for pubic hair, breast and genitalia development, and graded on a scale of 1 to 5, with one representing prepuberty and 5 representing adult development. While assessing breast development in girls, care should be taken to distinguish between irregular ductal breast tissue from the subcutaneous tissue, which is smooth and soft. Similarly, palpation of the testes, measurement of stretched penile length, and testicular volume with an orchidometer should be done accurately. Penile dimensions disproportionately greater than testicular dimensions indicates peripheral precocious puberty due to adrenal pathology. Moderate symmetric enlargement of testes may indicate familial male limited precocious puberty or an HCG secreting tumor. On the other hand, asymmetric testicular enlargement and a palpable testicular mass may indicate a Leydig cell tumor.

I. Lab Investigations

• Sex Hormones

Baseline measurement of testosterone in boys and estradiol in girls should be obtained. The elevation of baseline sex hormones with suppressed gonadotropins indicates precocious pseudopuberty. A significantly elevated testosterone level indicates testicular neoplasm in boys or an adrenal source in both boys and girls. In girls, estradiol levels are interpreted with reference to the tanner stage of breast development. Estradiol levels of >20 pg/mL indicate puberty. Significantly elevated serum estradiol levels (>100 pg/mL) in a girl indicates either an estrogen secreting ovarian cyst or ovarian tumor.  On the other hand, low baseline estradiol level <10 pg/ml indicates central precocious puberty.

• Luteinizing Hormone (LH), Follicular Stimulating Hormone (FSH) and Human Chorionic gonadotropin (HCG) Levels

In precocious pseudopuberty, the baseline LH and FSH levels are in the prepubertal range. Basal LH levels should be measured early in the morning. Basal LH levels < 0.2 mIU/mL indicate either precocious pseudopuberty or benign pubertal variants. Random measurements of FSH are not very useful in diagnosis. Elevated HCG levels indicate the presence of HCG secreting tumors such as embryonal cell carcinoma, choriocarcinoma, and dysgerminoma. 

• Serum Adrenal Steroids

Measurement of serum adrenal steroid levels is useful in differentiating premature adrenarche from precocious pseudopuberty. In patients with premature adrenarche, levels of dehydroepiandrosterone sulfate (40-135 mcg/dL), testosterone (1.1-3.7 micromol/L), and 17 hydroxyprogesterone (115- 200 ng/dL) are only mildly elevated. Elevation of DHEAS and testosterone above these ranges indicate adrenal tumors or congenital adrenal hyperplasia.  An elevated early morning 17 hydroxyprogesterone (> 200 ng/dL) indicates non-classical congenital hyperplasia due to 21 hydroxylase deficiency. Elevated 11 deoxy cortisol and deoxy cortisone indicate 11 B hydroxylase deficiency.[28][29][30]

• Thyroid Function Test

Serum thyroid-stimulating hormone (TSH) concentration and free T4 levels should be checked in patients with signs and symptoms of primary hypothyroidism.

II. Radiology

• Bone Age Assessment

Radiographs of hand and wrist should be done in cases of suspected precocious puberty to assess epiphyseal maturation. A normal or slightly delayed bone age  (< 2y over chronological age) suggests benign variants such as premature thelarche or premature adrenarche. On the other hand, significantly advanced bone age (>2 standard deviations above the mean for age) indicates accelerated linear growth and precocious puberty. Rapidly progressive bone age should raise concern for congenital adrenal hyperplasia or tumors originating from the ovaries, adrenal glands, or germ cells.[31]

• Ultrasound/Computer Tomography

In girls with suspected precocious pseudopuberty, a pelvic ultrasound is essential to determine if ovarian cysts or tumors are the underlying etiology. Pelvic ultrasound is also helpful in determining the uterine length and volume, which is a good indicator of the duration of estrogen exposure.[32][33] In boys, testicular ultrasound is helpful in identifying malignancies, such as Leydig cell tumor. In patients with clinical signs or lab evidence of excess adrenal androgens, an abdominal ultrasound or computer tomography of the abdomen is recommended.

III. Other Tests

• Patients who have neurological symptoms or visual changes require brain magnetic resonance imaging to exclude intracranial pathology. Brain imaging is also indicated to identify HCG, producing pineal gland tumors.
• Bone scan and skeletal surveys are required in cases of suspected McCune Albright syndrome to identify fibrous dysplasia.
• Genetic testing may be required to identify mutations and confirm the diagnosis in patients with congenital adrenal hyperplasia, familial male-limited precocious puberty, and McCune Albright syndrome.[34]

Cases of precocious pseudopuberty should be promptly referred to an endocrinologist to prevent complications. The goals of managing precocious pseudopuberty are to treat the underlying cause and block the production or response of excess sex hormones. Specific treatments depend on the cause:

• Tumors of the ovary, testis, or adrenal glands often require surgical excision. HCG secreting tumors may require additional treatment with chemotherapy or radiotherapy.
• Functional follicular ovarian cysts rarely require surgical intervention and may be managed conservatively as they usually regress spontaneously.[35]
• Primary hypothyroidism is treated by providing thyroxine supplementation.
• McCune Albright syndrome: Aromatase inhibitors are the most studied medications to manage precocious puberty in McCune Albright syndrome. Theoretically, aromatase inhibitors suppress estrogen production and help in slowing growth maturation, lead to cessation of menses and reduce ovarian volumes. However, studies have shown mixed results. Testolactone has been shown to be temporarily effective in slowing growth rate and advancement of menses, while fadrozole and anastrozole have not been found to be efficacious.[36][37] On the other hand, letrozole, a 3rd generation aromatase inhibitor, was found to decrease growth rate and advancement in bone age significantly.  Long term safety of letrozole is yet to be established.[38] Tamoxifen, a selective estrogen receptor modulator, is effective in halting pubertal progression but is associated with long term safety concerns due to endometrial stimulation.[39] Many patients with McCune Albright syndrome with advanced bone age develop central precocious puberty. In such patients, treatment with gonadotropin agonists may be helpful.
• Familial male-limited precocious puberty: This disorder is treated with an androgen receptor antagonist and aromatase inhibitor to delay epiphyseal maturation. A GnRH analog is added in cases where central precocious puberty occurs.  A case series of 25 subjects with familial male-limited precocious puberty showed that spironolactone with testolactone or anastrozole and a GnRH agonist was effective in increasing adult height.[40] Other drugs used to manage this condition include ketoconazole, which is a steroid synthesis inhibitor, and bicalutamide, which is an anti-androgen and letrozole.

Benign or Non-progressive Pubertal Variants

Benign pubertal variants represent cases of early secondary sexual development that are not progressive, have normal height velocity, and are not associated with an underlying pathological process. Most of these variants require no treatment apart from reassurance and close monitoring for signs of pubertal progression, bone age, and acceleration in height velocity.

Variants under this category include:

• Premature thelarche is isolated breast development in young girls without the development of other secondary sexual characteristics. This condition is usually seen in girls younger than six to eight years. Breast development in premature thelarche often does not progress beyond tanner stage 3. The presence of normal height velocity, normal bone age, and absence of other secondary sexual characteristics differentiate this condition from precocious pseudopuberty.
• Premature pubarche is the isolated development of pubic and axillary hair before the ages of eight years in girls and nine years in boys. This condition may be associated with a mild elevation in dehydroepiandrosterone sulfate and mild advancement in bone age. Patients with premature pubarche require close monitoring as it may be the initial sign of precocious pseudopuberty. Signs of virilization, growth acceleration, and significant advancement in bone age in these patients should prompt a workup for congenital adrenal hyperplasia or virilizing adrenal tumors.
• Benign prepubertal vaginal bleeding is the presence of isolated prepubertal vaginal bleeding that resolves spontaneously. The diagnosis of this condition requires the exclusion of other causes of vaginal bleeding, such as sexual abuse, foreign body, or local trauma. The absence of other secondary sexual characteristics, a normal pelvic ultrasound, and prepubertal gonadotropin levels differentiate this condition from precocious puberty.

Central Precocious Puberty

Central precocious puberty occurs due to premature activation of the hypothalamic-pituitary-gonadal axis and can be idiopathic, genetic, or due to central nervous system lesions. Unlike peripheral precocious puberty, patients with central precocious puberty tend to follow the normal sequence of secondary sexual development. They may also have neurological signs or visual changes. Central precocious puberty is gonadotropin independent and is associated with elevated levels of the follicular stimulating hormone (FSH) and luteinizing hormone (LH). Central precocious puberty can be confirmed by a basal LH concentration of > 0.3 IU/L or an elevation of LH in response to GnRH stimulation test.[41][42]

Prognosis of McCune Albright syndrome varies depending on the severity of bone disease and the number of endocrinopathies. The outcome of non-classical congenital adrenal hyperplasia is generally favorable if glucocorticoids are administered early. However, despite treatment, many patients go on to develop short stature in adulthood. The prognosis of ovarian granulosa cell tumors depends on the stage of the disease and the presence of residual disease.[43] Similarly, Leydig tumors have an excellent prognosis and high disease-free survival rates if the condition is localized. However, metastatic disease is associated with poor outcome.[44] Cases of precocious pseudopuberty caused by exogenous hormones or endocrine-disrupting chemicals resolve spontaneously upon discontinuing exposure.

Patients with precocious puberty may encounter different complications, depending on the primary diagnosis:

• Short stature patients with precocious puberty initially have a growth spurt in adolescence due to rapid linear growth. However, if left untreated, this is followed by premature fusion of the epiphyseal plates, which leads to short stature in adulthood.
• Early development of breasts in girls and increased libido in boys can cause significant emotional distress.
• The changes associated with puberty may lead to long term psychosocial stress, behavioral issues, and psychiatric problems such as depression.
• Contrasexual precocious puberty in girls caused by excess androgens can lead to virilization in the form of clitoromegaly, which may require genital reconstructive surgery.
• Patients with McCune Albright syndrome can develop musculoskeletal complications (bone pain, deformities, pathological fractures, gait abnormalities) and endocrinopathies (acromegaly, hyperthyroidism, Cushing syndrome). They are also at risk of developing arrhythmias, intestinal polyps, and malignancies.
• Patients with congenital adrenal hyperplasia may suffer from suboptimal fertility. They can also develop complications due to chronic glucocorticoid therapy, e.g., cushingoid features, poor growth, osteoporosis, secondary diabetes, and adrenal suppression. Women with congenital adrenal hyperplasia have a higher risk of requiring cesarian delivery due to underlying cephalopelvic disproportion.

Patients with precocious pseudopuberty should be offered psychological and emotional support as the physical changes of puberty may lead to emotional distress. Affected patients are often subjected to higher societal expectations based on their physical maturity rather than their age. Parents and teachers, therefore, need to be counseled and reminded to maintain age-appropriate expectations. Patients who experience early puberty may start engaging in risk-taking behavior (drugs, alcohol use, ad sexual activity) at an earlier age and require age-appropriate sex education.

Patients with precocious pseudopuberty are usually seen initially by a primary care physician or pediatrician. All physicians should be aware of the physiological pubertal changes, their normal sequence, and the age cutoff for considering pubertal changes as precocious. The onset of puberty before the age of six years in African American girls, seven years in caucasian girls, and nine years in boys should be evaluated thoroughly for precocious puberty.[45] [Level 5] Cases of precocious pseudopuberty should be promptly identified and referred to a pediatric endocrinologist for further management to prevent the development of short stature in adulthood.

Although primarily managed by an endocrinologist, patients often require interprofessional care. Consultations with oncology are required in cases of precocious puberty due to malignancy. Referral to surgery may be required for surgical excision of an underlying adrenal, ovarian, or testicular tumor. A referral to urology may be required due to the proximity of the gonads to the genitourinary system. Patients with McCune Albright syndrome may require referral to orthopedics to correct bone deformities due to fibrous dysplasia. Patients with precocious pseudopuberty can develop depression or behavioral disorders, which may require consultation with a psychiatrist and a child psychologist. Interdisciplinary collaboration is important for optimal patient outcomes in precocious pseudopuberty.