Precocious Pseudopuberty 

Puberty is the process of physical maturation manifested by an increase in growth rate and the appearance of secondary sexual characteristics. Precocious puberty is typically defined as the appearance of any sign of secondary sexual maturation in boys younger than 9 years, in white girls younger than 7 years, and in black girls younger than 6 years.

Precocious puberty can be divided into 2 distinct categories. The first category is gonadotropin-dependent precocious puberty, which involves the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. The second category is gonadotropin-independent precocious puberty, in which the presence of sex steroids is independent of pituitary gonadotropin release.

Causes of precocious pseudopuberty include congenital adrenal hyperplasia (CAH); tumors that secrete human chorionic gonadotropin (HCG); tumors of the adrenal gland, ovary, or testis; male-limited precocious puberty; McCune-Albright syndrome (MAS); aromatase excess syndromes; and exposure to exogenous sex steroid hormones.

The diagnosis is made with the help of a careful history and physical examination in conjunction with the use of radiologic and laboratory evaluations.

In gonadotropin-independent precocious puberty, the presence of testosterone in boys or estrogen in girls is not secondary to activation of the HPG axis. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations are low, and response to exogenous gonadotropin-releasing hormone (GnRH) is suppressed (prepubertal).

Circulating sex steroids (testosterone or estrogen) cause secondary sexual development. The sex steroids (estrogen or testosterone) come from either the adrenal gland or the gonad, independent of the hypothalamic-pituitary portion of the pubertal axis. In aromatase excess syndromes, an apparent increase in the extraglandular aromatization of androgens leads to an increase in the circulating estrogen levels. This is associated with isosexual precocious puberty in girls and prepubertal gynecomastia in boys. Sex steroids may also be ingested or absorbed from exogenous sources. Thus, the exact pathophysiology varies with the underlying cause of precocious puberty.

Frequency

United States

Incidence of precocious puberty is estimated to be 1 per 5000-10,000 individuals. Gonadotropin-independent precocious puberty is about one fifth as common as gonadotropin-dependent precocious puberty.

Mortality/Morbidity

The morbidity and mortality of gonadotropin-independent precocious puberty varies with the underlying etiology.

• Short stature: Both true precocious puberty and precocious pseudopuberty are characterized by an accelerated rate of growth and bone maturation. This early growth manifests as early tall stature; however, as the puberty progresses and the bones are continually exposed to the sex steroids, the growth plates mature and fuse at an early age. This can lead to an overall decrease in adult height.
• Multiple endocrinopathies: Children with MAS are at risk for various endocrinopathies. These individuals have an increased incidence of thyrotoxicosis, Cushing syndrome, acromegaly, hyperprolactinemia, ovarian cysts, and hyperparathyroidism as part of their primary disease process. Although the exact incidence of other nonendocrine manifestations of the disease is unclear, other potential problems include bone cysts (polyostotic fibrous dysplasia), hepatobiliary dysfunction, pancreatitis, gastrointestinal polyps, abnormal cardiac muscle cells, and even sudden or premature death.
• Contrasexual physical development: In some cases, secondary sexual characteristics of the opposite sex can develop (eg, girls with CAH or girls with an androgen-secreting adrenal or ovarian tumor may have clitoral enlargement).

Race

The overall ethnic predilections depend on the etiology of the precocious puberty.

• Nonclassic CAH due to 21-hydroxylase deficiency: In a heterogeneous US population, the carrier frequency is approximately 1 in 6 individuals, and the disease frequency is 1 in 100 individuals. However, in Ashkenazi Jews, the carrier frequency is 1 in 3 individuals, and the disease frequency is as high as 1 in 27 individuals. Importantly, note that not all individuals affected with this mild inborn error of steroid hormone metabolism are symptomatic.
• Classic CAH due to 21-hydroxylase deficiency: Worldwide, the incidence is about 1 in 10,000-15,000 live births. Approximately 75% of cases are of the salt-wasting type, which usually is diagnosed in infancy because girls have ambiguous genitalia and both sexes have potentially life-threatening salt-wasting adrenal crises. The other 25% of cases, known as simple virilizers, may be missed in infancy and may present in early childhood with signs of inappropriate somatic growth, epiphyseal maturation, pubic hair, acne, and progressive clitoromegaly in girls. If bone age advances sufficiently, true central precocious puberty may be triggered.
• MAS: This disorder is sporadic, usually attributable to somatic cell mutations, and has been reported in white, black, and Asian populations.
• Testotoxicosis: This disorder is inherited in an autosomal dominant pattern expressed only in males and has been reported in individuals who are white, black, and Asian. De novo mutations may arise; therefore, consider diagnosis even in cases without a clear family history of precocious puberty.

Sex

If precocious puberty is defined based on the mean age of pubertal development plus or minus 2 standard deviations from the mean, the frequency of precocious puberty should be the same for both genders. However, girls present more often for evaluation of precocity than boys. Most cases of precocious puberty in girls are secondary to idiopathic central precocious puberty.

Some causes of gonadotropin-independent precocious puberty are more common in one gender than the other.

• MAS: Ninety-five percent of patients are female.
• Testotoxicosis: This condition is also known as familial male precocious puberty (FMPP). The pattern of inheritance is autosomal dominant with greater than 90% penetrance. Female carriers are unaffected by early sexual development or endocrine abnormalities.
• Ectopic HCG-secreting tumors: These tumors are rare and are associated with sexual precocity in males. This precocity is thought to be secondary to the stimulatory effect of HCG on the Leydig cells leading to increased testosterone secretion.

Age

By definition, males who have precocious puberty must develop secondary sexual characteristics when younger than 9 years. In black girls, puberty when younger than 6 years is considered precocious, whereas in white girls, puberty when younger than 7 years is considered precocious.

The classic definition of sexual precocity for girls is the onset of secondary sexual characteristics prior to age 8 years. The current guidelines recommend the evaluation of any girl younger than 8 years who has an advanced bone age or a rapid progression through puberty.

• MAS: Girls with MAS may present at any age. The average age of pubertal onset is 3 years; however, vaginal bleeding has been reported in females as young as 4 months.
• Testotoxicosis: Male patients develop progressive secondary sexual characteristics with rapid physical growth and skeletal maturation often accompanied by sexually aggressive behavior within the first 2-3 years of life.
• CAH: Clinical symptoms of nonclassic 21-hydroxylase deficiency vary and may present at any age. After the newborn period, nonclassic 21-hydroxylase deficiency may present as various hyperandrogenic symptoms, including precocious pubarche, advanced bone age, and accelerated growth in childhood. In women, irregular periods, polycystic ovarian disease, acne, hirsutism, and infertility are common manifestations. As noted above, classic CAH is usually detected in infancy with ambiguous genitalia in girls and salt-wasting adrenal crisis in boys. In addition, some clinics and hospitals include testing for increased blood concentration of 17 α -hydroxyprogesterone to diagnose CAH in the routine newborn screen performed on all babies.