A 4-year-old Caucasian girl presents to her pediatrician because of early development of breast buds, pubic hair, and body odor. On exam, the girl is noted to have Tanner stage 3 breast buds and pubic hair. She is also noted to have clitoromegaly (Figure 200-1). The pediatrician refers the girl to a pediatric endocrinologist, who orders a bone age, estradiol levels, and an MRI of the brain. The girl is found to have an advanced bone age of 7 years, and levels of estradiol consistent with her stage of sexual development. An MRI of the brain is normal. She is diagnosed with idiopathic central precocious puberty. The options for management are discussed with the family.

The age at which puberty begins in normal children varies among the different ethnic groups. Early, or precocious puberty, is defined as the onset of sexual development occurring before the age of 7 years in Caucasian girls, 6 years in African American girls, and 9 years for all boys. Central precocious puberty refers to gonadotropin-releasing hormone (GnRH)-dependent activation from the hypothalamic-pituitary-gonadal axis leading to secondary sexual characteristics. Peripheral precocious puberty refers to GnRH-independent activation.

Early puberty.

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  The incidence is estimated to be 15 to 30 per 100,000 girls and is 1- to 15-fold less common on boys.^1,2

  
  
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  Idiopathic precocious puberty is more common in girls than boys.

  
  
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  African American girls develop secondary sexual characteristics at an earlier age than Caucasian girls. Thus, age of evaluation of precocious puberty in girls depends on ethnicity and race.

  
  
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  Boys mature at comparable ages regardless of ethnicity and race.

  
  
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  Age of onset of precocious puberty varies depending on the etiology; it can present as early as the first month of life.

Central or GnRH-dependent precocious puberty may be idiopathic or may be caused by a central nervous system (CNS) abnormality.^3,4

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  Precocious puberty is idiopathic in more than 90 percent of girls. This diagnosis is one of exclusion, in that no clinical, biochemical, or radiologic abnormalities are present other than those of precocious puberty.

  
  
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  Boys with precocious puberty have an idiopathic cause much less commonly than girls; CNS abnormalities are found in 25 to 75 percent of boys with precocious puberty.

  
  
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  The most common CNS abnormality causing precocious puberty is a hypothalamic hamartoma. This is a GnRH-producing nonmalignant congenital mass that causes pulsatile secretion of gonadotropins leading to stimulation of the gonads during childhood.⁵

  
  
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  Other structural CNS abnormalities include tumors such as pinealoma, astrocytoma, ganglioneuroma, ependymoma, and optic glioma, or congenital malformations such as ventricular and arachnoid cysts.

  
  
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  Neurofibromatosis and tuberous sclerosis, as well as CNS insults such as acute head injury, hydrocephalus, CNS infection, or cranial radiation therapy can cause central precocious puberty.

Causes of GnRH-independent precocious puberty include:⁶

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  McCune Albright syndrome—More common in girls. Caused by constitutive somatic activation mutations in the GNAS1 gene encoding the α-subunit of the stimulatory G-protein resulting in autonomous hypersecretion of hormones. It may be associated with other endocrine abnormalities including hyperthyroidism, hypercortisolism, hypersomatotropism, and hypophosphatemia.

  
  
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  Ovarian tumors and cysts may cause isosexual (changes appropriate for same sex) or heterosexual (changes appropriate for opposite sex) pubertal changes.

  
  
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  Testicular tumors, such as a testosterone secreting Leydig cell tumor, may manifest as isosexual precocious puberty in young boys.

  
  
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  Familial male-limited GnRH-independent pseudoprecocious puberty—Otherwise known as testotoxicosis. Caused by a luteinizing hormone receptor-activating mutation resulting in significant enlargement of penis without enlargement of testes.

  
  
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  Congenital adrenal hyperplasia—Occurs in both boys and girls is caused by a deficiency of either CYP21A2 (21-hydroxylase), CYP11B1 (11β-hydroxylase), or 3β-HSD enzyme. Can presents in early childhood with bone age advancement; usually isosexual in boys and manifests as pubic hair development, acne, body odor, and increased penis size without testicular enlargement; usually heterosexual (virilizing features) in girls.

  
  
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  Adrenocortical tumors—Occurs in both boys and girls; usually isosexual in boys and heterosexual (virilizing) in girls.

  
  
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  Ectopic human chorionic gonadotropin (hCG)—Secreting tumors such as chorioblastoma, hepatoblastoma, germinoma of the pineal gland. Mainly occur in boys and result in testosterone production in the testes.

  
  
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  Exogenous estrogen—Can result from oral (contraceptive pills or anabolic steroids) or topical agents. Estrogens are readily absorbed through the skin, so estrogens in cosmetics, hair creams, and breast-augmentation creams can cause breast development in girls and gynecomastia in boys.

  
  
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  Severe long standing hypothyroidism can cause early puberty in boys and girls.

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  CNS insults.

  
  
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  Positive family history.

  
  
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  Obesity.

  
  
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  Adopted child status from a developing country—Maybe due to early malnutrition followed by normal or excessive nutrition with resultant advancement of pubertal age.

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  A careful history and physical examination should provide helpful clues as to the etiology and guide the evaluation. Tanner (sexual maturation rating) charts should be used to stage pubertal development.