Precocious Pseudopuberty Clinical Presentation

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.

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.^[2] 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. 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.^[3]

  • 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.

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.