eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Precocious Pseudopuberty

Author: Robert J Ferry Jr, MD,, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St. Jude Children's Research Hospital; Brigade Surgeon, 36th Sustainment Brigade, 13th Expeditionary Sustainment Command, U.S. Army
Coauthor(s): Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Contributor Information and Disclosures

Updated: Jun 15, 2009

Introduction

Background

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.

Pathophysiology

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.

Clinical

History

The following may be reported in patients with precocious pseudopuberty:

• Neurologic
  • Document any known CNS risk factors, including infections, perinatal asphyxia, head trauma, neoplasms, or prior radiation therapy.
  • Ask questions regarding the occurrence of personality changes, increased appetite, headaches, and/or visual changes.
• Exposures
  • Obtain a history regarding any exposures to skin or hair products, vitamins, or dietary supplements that may contain estrogenic or androgenic substances, including placental extracts.
  • Excess consumption of soy or other phytoestrogens may also contribute to pseudopuberty.
  • Document any ingestion of medications containing estrogens, such as oral contraceptives.
• Family history
  • In males, testotoxicosis is inherited as an autosomal dominant disorder.
  • Frequently, a strong family history for this disorder is observed.

Physical

The age of onset of pubertal development is determined by the degree of sexual maturation present upon physical examination using the Tanner growth charts.

• Height
  • Measure the individual's height with a stadiometer. The individual should not be wearing shoes.
  • Calculate growth velocity from previous height measurements.
• Weight: A recent study concluded that increasing body mass index (BMI) and excessive weight at age 5 years predicts the advanced stages of puberty.¹ Also, an advanced stage of puberty predicts young adults' BMI and overweight status at age 21 years.
• Abnormal vital signs
  • Bradycardia and low normal temperature may suggest severe hypothyroidism.
  • Elevated blood pressures may be observed in response to an adrenal tumor or in congenital adrenal hyperplasia (CAH) due to 11 β -hydroxylase deficiency.
• Secondary sexual characteristics
  • These are staged using the Tanner growth charts, shown below, for breasts and pubic hair in girls and pubic hair in boys.
    • 
      

      

      Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.

      [ CLOSE WINDOW ]

      

      Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.

    • 
      

      

      Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.

      [ CLOSE WINDOW ]

      

      Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.

  • Accurate measurements of testicular volume and stretched penile length should also be performed and compared with normal measurements for age.
• Testotoxicosis: The penis increases in size, but testicular volume is increased to a size that is less than expected for the degree of sexual maturation.
• Androgenic effects: Perform a careful evaluation looking for the presence of acne, hirsutism, increased muscle mass, and clitoromegaly in females. Looking for these signs helps focus the differential diagnosis toward androgenic causes of precocious puberty.
• Estrogenic effects: Breast development and changes in the vaginal mucosa are signs of estrogen exposure.
  • The vaginal mucosa in prepubertal girls is reddish in hue. Estrogen causes the mucosa to thicken and take on a more pinkish hue. Vaginal maturation index may be helpful. Superficial cells are detected with high estrogen effect, whereas only parabasal cells are observed in the absence of recent estrogen exposure.
  • Increased growth rate and weight gain may also be early signs of sex hormone exposure.
• Skin: Perform a thorough examination of the skin looking for the presence of large irregular café-au-lait pigmentation or multiple smaller café-au-lait spots.
  • Large café-au-lait spots with irregular borders may be a marker of McCune-Albright syndrome (MAS).
  • Multiple café-au-lait spots with smooth borders are characteristic of neurofibromatosis type 1, a syndrome in which precocious puberty is common but usually is gonadotropin-dependent.
• Abdominal: A thorough abdominal examination is critical because adrenal or ovarian tumors may be palpable.²
  • In girls, ultrasonography is a more sensitive technique for examination of the ovaries for mass lesions. Consider the use of pelvic MRI if the clinical presentation is suggestive of a functional ovarian tumor.
  • In boys, physical examination of the testes should reveal a testicular mass, but ultrasonography may be a more sensitive technique.

Causes

The list of potential causes for precocious pseudopuberty is long and varied, but all individuals with this disorder present with early puberty without activation of the HPG axis.

• Environmental exposures: Perform an extensive check for drug exposure because compounds with estrogenic activity may be present in some skin creams, hair care products, and vitamins as well as in oral contraceptives.
• CAH
  • CAH is a group of autosomal recessive disorders of adrenal steroidogenesis.
  • The most frequent cause of CAH is deficiency of the 21-hydroxylase enzyme. 21-hydroxylase is the enzyme responsible for the conversion of 17 α -hydroxyprogesterone to 11-deoxycortisol.
  • 11 β -hydroxylase deficiency is a second enzyme deficiency leading to CAH. 11 β -hydroxylase is the enzyme responsible for the conversion of 11-deoxycortisol to cortisol.
  • Both 21-hydroxylase and 11 β -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.
• Human chorionic gonadotropin (HCG)-secreting tumors: 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.
• Tumors of the adrenal gland: Adrenocortical tumors are rare in childhood. The etiology of these tumors 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.
• Tumors of the ovary
  • 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.
• MAS
  • The molecular basis for 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.
• Testotoxicosis: The human luteinizing hormone (LH) receptor belongs to the family of G-protein coupled receptors. The molecular defect 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.
• Severe hypothyroidism: This disorder also has been called van Wyk-Grumbach syndrome. 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.

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