Precocious Pseudopuberty

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. ^[4]

The etiologies of precocious pseudopuberty (PPP) can vary between boys and girls and include production of sex steroids by the gonad in an unregulated fashion, such as in McCune-Albright syndrome (MAS) or familial male-limited precocious puberty (FMPP); sex steroid secretion by the adrenal gland as occurs in congenital adrenal hyperplasia (CAH); tumors that secrete human chorionic gonadotropin (HCG); sex steroid–excreting tumors of the adrenal gland, ovary, or testis; or exposure to exogenous sex hormones. ^[6]

Certain aromatic oils, such as lavender and tea tree oil, present in some skin creams, hair care products, and aromatherapy oils and sprays, have estrogenic activity. Transdermal estrogen creams or testosterone gels or ingestion of oral contraceptives are other possible exogenous sources of exposure to sex steroid hormones. ^[2]

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. 21-hydroxylase is the enzyme responsible for the conversion of 17α-hydroxyprogesterone to 11-deoxycortisol, and its deficiency accounts for 95% of cases of CAH. 11β-hydroxylase deficiency is a second enzyme deficiency leading to CAH. Both 21-hydroxylase and 11β-hydroxylase enzyme deficiencies lead to a decrease in cortisol production. This decrease in cortisol production results in chronic stimulation of the adrenal cortex by adrenocorticotropic hormone (ACTH), with an increase in the cortisol precursors. These precursors then are shunted into the androgen pathway, leading to excessive androgen production and, therefore, the signs and symptoms of androgen excess. ^[5]

Potential HCG-secreting tumors may cause Leydig cell stimulation and some testicular enlargement in boys. The locations of HCG-secreting tumors include tumors of the liver (hepatomas, hepatoblastomas) and choriocarcinomas of the gonads, mediastinum, retroperitoneum, or pineal gland.

Adrenocortical tumors are rare in childhood and their etiology is unknown. Adrenocortical tumors may occur at any age from infancy into adolescence, and the clinical manifestations of these tumors depend on the type of the hormones they secrete. The most frequent hormonal effects are secondary to androgen secretion, resulting in virilization of girls and early puberty in boys. The primary hormonal picture is rarely that of estrogen effects, which lead to feminization in males and precocious pseudopuberty in females. ^[9]

Ovarian tumors can be either feminizing or masculinizing. The most common tumor associated with isosexual precocity is the benign ovarian follicular cyst. The cells lining the cysts are luteinized, leading to estrogen production.

Granulosa cell tumor is the next most common feminizing neoplasm of the ovary. Juvenile granulosa cell tumors that develop in premenarchal females produce sexual precocity as a consequence of estrogen secretion. This may present as premature breast development or vaginal bleeding. Virilization may also be present. These tumors may also secrete HCG. Sex-cord tumors may have characteristics of both granulosa and Sertoli cells.

Masculinizing tumors (Leydig-Sertoli cell tumors or arrhenoblastomas) are unusual before adolescence. These tumors are the most common virilizing ovarian tumor. The masculinizing tumors tend to have abnormal differentiation that leads to an unusual pattern of steroid secretion with androstenedione predominating over testosterone secretion.

McCune-Albright syndrome (MAS) involves the overactivity of the cyclic adenosine monophosphate (cAMP) signaling pathway. The G-proteins involved in signal transduction are heterotrimers that consist of alpha, beta, and gamma subunits, each of which is encoded by separate genes. Inactive stimulatory G-protein (Gs) is normally activated by the interaction with a hormone-bound receptor that results in an exchange of guanosine triphosphate (GTP) for guanosine 5'-diphosphate (GDP) and dissociation of the active alpha subunit. In the case of Gs, the GTP-bound alpha subunit interacts with and stimulates adenylate cyclase and specific ion channels. Intrinsic GTPase activity of the alpha subunit inactivates the G-protein. Mutations in the Gs (alpha) gene may result in inhibition of the GTPase activity of Gs, leading to prolonged activation in the absence of a stimulatory hormone.

Familial male precocious puberty (FMPP), also called testotoxicosis, is a dominant mutation in the LH receptor gene that results in the production of a receptor that is capable of spontaneous activation in the absence of either LH or HCG.

Van Wyk-Grumbach syndrome is a rare syndrome characterized by hypothyroidism, precocious puberty with multicystic ovaries, and features of polycystic ovarian disease (PCOD). ^[10] The exact mechanism for the development of sexual precocity secondary to hypothyroidism is unknown. It is believed to be secondary to the structural similarity between thyroid-stimulating hormone (TSH) and LH. This is the only form of sexual precocity in which growth may be arrested rather than stimulated. ^[2]

The 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. ^{[1, 11]}

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. Nonclassical CAH may present with premature development of pubic hair, advanced bone age, and accelerated linear growth velocity. In females, it may be clinically indistinguishable from PCOS because of the development of cystic acne, hirsutism, and secondary amenorrhea.

• 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.

• McCune-Albright syndrome (MAS): This disorder is sporadic, usually attributable to somatic cell mutations, and has been reported in white, black, and Asian populations.

• Familial male precocious puberty: 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.

If precocious puberty is defined on the basis of 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.

• McCune-Albright syndrome (MAS): Ninety-five percent of patients are female.

• 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.

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. ^[12] 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.

• McCune-Albright syndrome (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.

• Familial male precocious puberty: 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 17α-hydroxyprogesterone to diagnose CAH in the routine newborn screen performed on all babies. ^[5]

The prognosis of PP varies with etiology. Note the following:

• McCune-Albright syndrome (MAS): Prognosis varies with the number of endocrinopathies and the extent of the bone disease. Most girls have an excellent prognosis.

• Testotoxicosis: Prognosis is excellent with proper treatment.

• Congenital adrenal hyperplasia (CAH): Prognosis is excellent with proper treatment.

• Ovarian granulosa cell tumors: Early recognition and diagnosis of ovarian granulosa cell tumors leads to improved cure rates and disease-free survival rates.

• Exogenous exposures: The most common etiology in young children has been inadvertent exposure to sex hormones through contact with adult males who use topical androgens such as Androgel or through ingestion of oral contraceptives. Signs of precocious puberty (eg, pubic hair, phallic enlargement) may resolve when such exposure ceases. ^[7]

The morbidity and mortality of precocious pseudopuberty (PPP) also varies with the underlying etiology.

• Short stature: Both central precocious puberty (CPP) and PPP 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, secondary amenorrhea, and infertility).

Complications

In patients with MAS, long-term complications stem from the multiple endocrinopathies that these patients may develop. Patients may also develop extremely deforming and disabling polyostotic bone changes.

Testotoxicosis: Complications of testotoxicosis are related to early sexual and physical maturation. Other complications are psychological and related to the early sexual and physical maturation.

In CAH, complications from overtreatment with hydrocortisone (eg, poor growth, adrenal suppression, features of Cushing syndrome) may be observed. Undertreatment of females may result in irreversible virilization and polycystic ovarian syndrome. Young men with untreated or poorly treated classic CAH may develop testicular adrenal rests, responsive to glucocorticoid suppression. Subfertility may be associated with CAH in both men and women. Adrenal tumors are more common in patients with CAH than in the general population.

Inappropriate societal expectations are often placed on these children based on the appearance of advanced maturity. Reminders of the chronologic age of the child are often necessary for school personnel, caregivers, and parents.

Guidelines for sexuality education for children and adolescents have been established by the American Academy of Pediatrics. ^[13]