AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 are variable 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• 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.
• 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 CAH due to 11β-hydroxylase deficiency.
• Secondary sexual characteristics: These are staged using the Tanner growth charts for breasts and pubic hair in girls and pubic hair in boys. 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 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.
• • 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 17α-hydroxyprogesterone to 11-deoxycortisol.
  • 11β-hydroxylase deficiency is a second enzyme deficiency leading to CAH. 11β-hydroxylase is the enzyme responsible for the conversion of 11-deoxycortisol to cortisol.
  • 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.
• 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 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Virilizing adrenal tumor
Feminizing adrenal tumor
Testotoxicosis
Ovarian cyst
Leydig cell adenoma
Granulosa cell tumor
Theca cell tumor
Choriocarcinoma
Germ cell tumors
LH-secreting pituitary adenoma
Exposure to exogenous estrogen or androgen
Syndrome of glucocorticoid resistance
Aromatase excess syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Sex steroids: The common laboratory finding for all causes of precocious pseudopuberty consists of pubertal levels of sex steroids (ie, substances with either androgenic or estrogenic effects in the presence of low-basal LH and FSH with the lack of a pubertal increase in LH and FSH concentrations in response to exogenous GnRH stimulation).
• LH and FSH levels
• • LH and FSH levels are in the prepubertal range.
  • LH and FSH levels are not increased in response to exogenous gonadotropin-releasing hormone.
• Adrenal steroid precursors: Enzyme deficiencies in the pathway for cortisol synthesis lead to elevated cortisol precursors. The exact elevated precursor depends on the enzymatic deficiency.
• • 17α-hydroxyprogesterone: This steroid precursor is elevated in 21-hydroxylase deficiency and also in 11β-hydroxylase deficiency.
  • 11-deoxycortisol and deoxycorticosterone: These steroid precursors are elevated in 11β-hydroxylase deficiency but should be either low or low-normal in patients with 21-hydroxylase deficiency.
  • Androstenedione: This precursor of testosterone is more stable and is not an acute phase reactant. Therefore, androstenedione may provide a more reliable marker of 21-hydroxylase deficiency than does the 17α-hydroxyprogesterone. An elevated androstenedione is not a specific cause of precocious puberty because androstenedione may be elevated in individuals with tumors and CAH.
• HCG: This is elevated in patients with HCG-secreting tumors.
• Urinary 17-ketosteroids: The level of 17-ketosteroids in a 24-hour urine collection provides a means of quantifying the amount of adrenal androgens being produced. 17-ketosteroids tend to be markedly elevated in patients with tumors of the adrenal glands. Dehydroepiandrosterone (DHEA) and DHEA-sulfate and metabolites (eg, androstenedione) are the major constituents of this assay. Testosterone and dihydrotestosterone contribute less than 1% of total urinary 17-ketosteroids.
• Estradiol: A random measurement of estradiol may not be elevated because secretion may be cyclic in individuals with MAS.
• Testosterone: In males with testotoxicosis, the levels of testosterone are pubertal with low-basal LH and FSH.
• Thyroid function test: Serum TSH should be elevated markedly and the serum free thyroxine (T4) should be markedly decreased if the patient's sexual precocity is secondary to severe primary hypothyroidism.

Imaging Studies

• The number of imaging studies that a clinician should obtain depends on the suspected diagnosis.
• Ultrasonography is a sensitive test that aids in the evaluation of the ovaries, testes, and adrenal glands.
• • Ultrasonography of the ovaries and uterus can aid in determining the etiology of precocity. The uterus is sensitive to estrogen and is a good bioassay to determine the length of time and magnitude of estrogen exposure. In girls with MAS, the ovaries are frequently asymmetric secondary to the presence of large unilateral cysts. Ovarian tumors are also visible using ovarian ultrasonography.
  • Testicular ultrasonography may detect Leydig cell tumors that are not palpable on testicular examination.
  • Ultrasonography of the adrenal glands may help to establish the diagnosis of an adrenal tumor; however, abdominal CT scanning and MRI are more sensitive techniques for imaging the adrenal gland.
• Many clinicians perform bone scanning in young girls suspected of having MAS.
• • Areas of fibrous dysplasia are positive on bone scan.
  • A skeletal survey may identify the presence of polyostotic fibrous dysplasia, which is observed in patients with MAS.
• Brain MRI is indicated in males (and in select females at the discretion of the clinician) with sexual precocity and in any patient with neurologic signs or symptoms.
• Pelvic MRI can be useful in the diagnosis and evaluation of females with precocious puberty. Uterine volume and evaluation of the different uterine layers can be well visualized on MRI. In premenarchal girls, the uterine corpus is small, and the cervical length is greater than that of the uterine body until about age 13 years. The ovarian tumors have characteristic MRI findings and may assist in the diagnosis of ovarian neoplasms.

Other Tests

• GnRH stimulation test: Administer a standardized dose of GnRH (3.5 mcg/kg intravenously; not to exceed 100 mcg) after obtaining baseline LH/FSH levels. Then, obtain FSH and LH levels at 30, 60, and 90 minutes (or an abbreviated test may be performed with sampling at 30 min only). In the case of gonadotropin-independent precocious puberty, no increase over basal levels is observed. FSH and LH response is termed flat.
• Leuprolide acetate stimulation test: GnRH has been difficult to obtain; an alternative to the GnRH stimulation test is a Leuprolide acetate stimulation test. Administer leuprolide acetate [20 µg/kg²] Obtain a baseline LH, estradiol and testosterone are optional. Measure the LH level at 3 hours after injection. Measure estradiol or testosterone 24 hours after injection. An LH level of more than 8 IU/L is consistent with central precocious puberty (CPP). If the estradiol stimulates to 50 pg/mL or greater this is consistent with CPP. If the estradiol levels are 25-50 pg/mL this is consistent with early CPP.
• Bone age
• • Perform a bone age assessment for any patient who presents with clinical signs of early puberty.
  • Bone age is advanced (>2 standard deviations above the mean for age) in children who have had significant sex steroid exposure over an extended time, regardless of etiology.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Available treatment options depend on the underlying etiology of the precocious pseudopuberty.

• The initial evaluation can usually be performed on an outpatient basis. However, inpatient studies and surgical treatment may be required.
• Medical and surgical therapies are directed at treatment of the underlying cause of precocious puberty. The therapies are designed to minimize both the short-term and the long-term morbidity and mortality of precocious puberty.

Surgical Care

If the patient has a tumor that is causing the precocious puberty, consult the appropriate surgeon.

Consultations

• Pediatric endocrinologist: Pediatric endocrinologists may be invaluable in the diagnosis of precocious puberty, as well as in the treatment and follow-up care for the patient.
• Pediatric hematologist and oncologist (if supported by the diagnosis): In the case of malignancy leading to the sexual precocity, the oncologist needs to be involved for possible chemotherapy.
• Surgeon: In the case of malignancy, surgical subspecialists need to be consulted. Recommendation for clitoral reduction in virilized females is controversial at the present time.
• Pediatric urologist: A urologist may be needed for patients with testicular tumors.

Diet

No special diet is required.

Activity

No restrictions on activity are necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The underlying pathophysiology of gonadotropin-independent precocious puberty is autonomous function of the gonadal axis; thus, the use of GnRH analogs does not appear to be effective in the management of these disorders. No medications are routinely used in young children with a US Food and Drug Administration (FDA)-approved indication for the treatment of gonadotropin-independent precocious puberty. Therefore, a physician with expertise in the area should closely monitor the use of medications.

Drug Category: Steroid synthesis inhibitors

Ketoconazole blocks enzymes in the steroid biosynthetic pathway. It primarily inhibits C-17,29-desmolase, the enzyme responsible for androstenedione biosynthesis.

Drug Category: Antiandrogens

These drugs block the effect of testosterone and dihydrotestosterone at the androgen receptor.

Drug Category: Aromatase inhibitors

This category of drugs is usually used in conjunction with an antiandrogen. Aromatase inhibitors prevent the conversion of androstenedione to estrone and testosterone to estrogen. Because estrogens play a major role in epiphyseal maturation (besides their obvious role in generating female secondary sexual effects), inhibiting estrogen production has salutary effects on slowing the progress of precocious pseudopuberty.

Drug Category: Antiestrogens

Estrogen receptor blockade (eg, with tamoxifen) may be an alternative to aromatase inhibitors and progestins in the treatment of MAS in girls. The predominant problem in childhood is precocious pseudopuberty associated with excess estrogen secretion from ovarian cysts.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• No further inpatient care should be required.

Further Outpatient Care

After the initial diagnosis of peripheral precocious puberty and the determination of its etiology, most patients require continued monitoring.

• MAS: Closely follow the cases of patients with MAS for the occurrence of other endocrinopathies or associated pathology.
• Testotoxicosis: Treatment decisions of these patients are complex. The most extensive report followed 10 boys during 6 years of treatment, but none had reached final height.¹ Thus, no firm recommendations for one particular form of therapy are currently available. Offer genetic counseling for families affected with this condition.
• CAH: Classic simple virilizing CAH requires lifelong therapy with glucocorticoids in both males and females. Most males with late-onset nonclassic CAH do not require glucocorticoid treatment. Treat symptomatic girls with nonclassic CAH with low-dose glucocorticoids throughout their reproductive years.
• Testicular, ovarian, and adrenal tumors: These tumors are typically unilateral and should be surgically removed. Once removed, the remaining contralateral testis, ovary, or adrenal gland should recover from suppression and be adequate for normal function.

In/Out Patient Meds

The treatment of peripheral precocious puberty depends on its etiology. Although therapy is rarely carried out by anyone other than a pediatric endocrinologist, the following list is included for completeness:

• MAS may be mild and slowly progressive; thus, no outpatient medical management is required. If the puberty is rapidly progressive or adult height is severely compromised, treatment may be indicated. Testolactone, an aromatase inhibitor, is the most commonly used medication for the treatment of MAS. Other drugs have included medroxyprogesterone acetate and, more recently, tamoxifen. A gonadotropin agonist may have an additional benefit but only if the bone age is so advanced that central precocious puberty has begun.
• The management of testotoxicosis is difficult and controversial. Testotoxicosis is often treated with ketoconazole, a nonspecific inhibitor of steroidogenesis. An alternative regimen has included spironolactone and testolactone. Gonadotropin agonists may be added as noted in the management of MAS.
• Treatment of CAH with near-physiologic replacement doses of hydrocortisone is used to suppress adrenal androgen production.

Transfer

• If an experienced pediatric endocrinologist or appropriate surgical subspecialty support is not available, transferring the patient to another facility with experienced staff is highly encouraged.

Complications

• 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 are related to early sexual and physical maturation. Other complications are psychological and related to the early sexual and physical maturation.
• 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.

Prognosis

Prognosis varies with etiology.

• 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.
• 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.

Patient Education

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

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

Because these diseases are rare, involving medical subspecialists with experience in the evaluation, treatment, and follow-up of these diseases probably is always advisable. Legal retribution is possible should the medical care provider fail to recognize precocious pseudopuberty and fail to refer the patient to the appropriate subspecialist. For example, if a patient presents with rapid virilization and the medical care provider fails to diagnose the adrenal tumor and tells the parents that this is a normal process, the provider opens the door for legal recourse.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Leschek EW, Jones J, Barnes KM, et al. Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset. J Clin Endocrinol Metab. Jan 1999;84(1):175-8. [Medline].
2. Acerini CL, Tasker RC. Traumatic brain injury induced hypothalamic-pituitary dysfunction: a paediatric perspective. Pituitary. Jun 15 2007;[Medline].
3. Agboola-Abu CF, Aligwekwe PK, Olowu AO, Kuku SF. Congenital adrenal hyperplasia due to 11-hydroxylase enzyme deficiency in three siblings. A brief report. West Afr J Med. Apr-Jun 1999;18(2):80-6. [Medline].
4. Cavanah SF, Dons RF. McCune-Albright syndrome: how many endocrinopathies can one patient have?. South Med J. Mar 1993;86(3):364-7. [Medline].
5. DiMeglio LA, Pescovitz OH. Disorders of puberty: inactivating and activating molecular mutations. J Pediatr. Jul 1997;131(1 Pt 2):S8-12. [Medline].
6. Garibaldi LR, Aceto T Jr, Weber C, Pang S. The relationship between luteinizing hormone and estradiol secretion in female precocious puberty: evaluation by sensitive gonadotropin assays and the leuprolide stimulation test. J Clin Endocrinol Metab. Apr 1993;76(4):851-6. [Medline].
7. Haddad N, Eugster E. An update on the treatment of precocious puberty in McCune-Albright syndrome and testotoxicosis. J Pediatr Endocrinol Metab. Jun 2007;20:653-661. [Medline].
8. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. Apr 1997;99(4):505-12. [Medline].
9. Holland FJ, Kirsch SE, Selby R. Gonadotropin-independent precocious puberty ("testotoxicosis"): influence of maturational status on response to ketoconazole. J Clin Endocrinol Metab. Feb 1987;64(2):328-33. [Medline].
10. Ibanez L, Potau N, Zampolli M, et al. Use of leuprolide acetate response patterns in the early diagnosis of pubertal disorders: comparison with the gonadotropin-releasing hormone test. J Clin Endocrinol Metab. Jan 1994;78(1):30-5. [Medline].
11. Isguven P, Yoruk A, Adal E, et al. Adult type granulosa cell tumor causing precocious pseudopuberty in a 6year-old girl. J Pediatr Endocrinol Metab. Apr-May 2003;16(4):571-3. [Medline].
12. Josan VA, Timms CD, Rickert C, Wallace D. Cerebellar astrocytoma presenting with precocious puberty in a girl. Case report. J Neurosurg. Jul 2007;107(1 Suppl):66-8. [Medline].
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Article Last Updated: Nov 30, 2007