Continuing Education Activity

Precocious puberty is an early onset of puberty and secondary sexual characteristics in children. It is a very challenging diagnosis as the differential varies from benign variants to serious conditions such as malignancy. This activity reviews the early identification, evaluation, and management of precocious puberty and highlights the role of providers in identifying the condition and promptly referring to the pediatric endocrinologist for further management and preventing the complications.

Objectives:

• Identify the etiology of precocious puberty.
• Describe the evaluation of precocious puberty.
• Outline the treatment and management options available for precocious puberty.
• Summarize interprofessional team strategies for improving care coordination and communication to improve outcomes in children with precocious puberty.

Introduction

Puberty is a complex transitional phase in children generally comprising of growth acceleration and development of secondary sexual characteristics. It is a period of physical and psychosocial development. Several genetic, environmental and nutritional factors play an important role in the onset and progression of puberty.[1]

Physiology of puberty

Puberty results from the activation and maturation of the hypothalamic-pituitary-gonadal (HPG) axis. At birth, there is a brief activation of the HPG axis that results in the increased production of steroidal hormones. This activation may result in breast development in females and pubic hair in males. This phenomenon is known as the “mini-puberty of the infancy” usually regresses over the first two years of life. Although it is considered to be benign, there is very little information on its etiology as well as clinical significance.

The HPG axis then becomes dormant until its subsequent activation in adolescence. The pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. FSH and LH initiate spermatogenesis and the release of testosterone in males, and oogenesis and the release of estradiol in the females, respectively. Activation of the gonads is known as gonadarche.

It is important for a clinician to be familiar with the terminology of pubertal progression. Thelarche is the development of breasts, which is a response to estrogen. Pubarche is the development of pubic hair, which is a response to androgens. Adrenarche is the onset of adrenal androgen production, which contributes to pubarche.

Definition

The traditional definition of precocious puberty is the development of secondary sexual characteristics before 8 years of age in girls and 9 years in boys.

Etiology

Precocious puberty classifies into two major categories based on the etiology

• Central precocious puberty (GnRH dependent)
• Peripheral precocious puberty (GnRH independent)

Central Precocious puberty (CPP)

This type of precocious puberty represents true pubertal development due to the earlier maturation and activation of the HPG axis. Most of the time, the common cause in females is idiopathic, and in males, there is usually an underlying pathology. It is attributable to a multitude of conditions.

The most relevant categories include

• CNS tumors – Hypothalamic hamartoma, optic glioma, arachnoid cysts, astrocytoma, ependymoma, hydrocephalus, septo optic dysplasia, pineal tumors
• CNS injury- head trauma,  cranial irradiation, cerebral palsy, infections( Tuberculous meningitis)
• Genetics – Loss of function mutation encoding the MRF3 (Makorin ring finger 3) gene, a gain of function mutation encoding the kisspeptin (KISS1) and its receptor (KISSR) genes
• Syndromes – Neurofibromatosis type 1, Sturge Weber syndrome, Tuberous sclerosis
• Environmental – internationally adopted children, withdrawal from sex steroid therapy.
• Familial precocious puberty

The most common brain lesion causing CPP is hypothalamic hamartoma. The ectopic neural cells in the lesion serve as an accessory GnRH pulse generator.  It presents with precocious puberty in infancy as early as 12 months of age. The most characteristic association is gelastic seizures, which are usually refractory to medications. The other associated features include cognitive, behavioral, and psychiatric symptoms. Increased prevalence is a noted feature in internationally adopted children. The exact mechanism is not known, but suggestions are that better nutrition and exposure to endocrine disrupting chemicals can play a role. There have been some reports of familial forms, but the genetic basis is not well understood. Recent years have seen some interesting associations with mutations of kisspeptin (KISS1) and makorin ring finger (MRF3) genes and their receptors. These genes are responsible for the stimulatory and inhibitory signals to the GnRH release. Loss or gain of function mutations in these genes results in CPP.

Peripheral Precocious Puberty (PPP)

Precocious development of secondary sexual characteristics independent of the GnRH pulsatile secretion constitutes PPP; this is due to the production of sex steroids from endogenous or exogenous sources. It is less frequent compared to the CPP. Some important causes include

• Congenital adrenal hyperplasia
• McCune-Albright syndrome (CAH)
• Gonadal tumors – Sex cord-stromal tumors such as Leydig cell tumors and Sertoli cell tumors, Germ cell tumors such as dysgerminoma, teratoma, and embryonal tumors.
• Adrenal tumors
• Familial male-limited precocious puberty (testitoxicosis)
• Exogenous exposure to sex steroids
• Van Wyk and Grumbach syndrome

Tumors are rare causes of PPP. There is an increased androgen production in CAH, adrenal tumors, and Leydig cell tumors. There is an increased production of human chorionic gonadotropin (hCG) with germ cell tumors, hepatoblastoma, pineal, and mediastinal tumors.

Testitoxicosis is a rare autosomal dominant disorder with the clinical phenotype limited to males. It is caused by a germline activating mutation of the LH receptor gene, resulting in the activation of the Leydig cells and high testosterone levels. Van Wyk and Grumbach syndrome are characterized by primary hypothyroidism, ovarian cysts, and precocious puberty. Researchers speculate that untreated primary hypothyroidism results in pituitary hyperstimulation and the production of multiple pituitary hormones resulting in precocious puberty. McCune-Albright syndrome is a sporadic condition caused by activating mutation of the GNAS 1 gene, which encodes the alpha subunit of the G protein. This gene activation increases the cAMP formation, and all its dependent receptors become hyper-functional.  It usually presents as a triad of precocious puberty, fibrous dysplasia of the skeletal system and café au lait pigmentation.  The other likely endocrine manifestations are hyperthyroidism, Cushing syndrome, and growth hormone excess.

Epidemiology

There are very limited studies describing the trends and prevalence of precocious puberty. The first epidemiologic study from a Danish national registry estimated that 0.2 % of females had some form of precocious puberty (CPP, PPP or benign variants) while it was less than 0.05% in males. There was female predominance about 20 to 23 per 10000 girls compared to boys, which were less than 5 per 10000 boys.[2] Another observational study in Spain estimated the annual incidence of central precocious puberty to be between 0.02 and 1.07 cases per 100000 persons.[3] A study looking into the Korean population estimated the prevalence of CPP to be 55.9 per 100000 girls and 1.7 per 100000 boys. The reported overall incidence of CPP in Koreans was 15.3 per 100000 girls, and 0.6 per 100000 boys.[4] The prevalence and incidence vary significantly among different populations making it difficult to estimate definitive numbers.

History and Physical

The presentation is usually consistent with premature development of pubertal signs. The initial clinical signs are breast development in females and increased testicular volume (greater than 4 ml) in males. The other signs and symptoms include increased linear growth, acne, muscular changes, body odor, and pubic and axillary hair development.

The initial step is to verify whether pubertal development is occurring before the normal age of onset or not. Rapid progression of puberty, although started at a normal age, is also considered abnormal. The clinician should inquire about neurological symptoms such as headache, increased head circumference, seizures, visual and cognitive changes along with symptoms of anterior and posterior pituitary deficiency (polyuria, polydipsia, and decreased growth velocity). Ovarian pathology might present with abdominal pain. Any relevant history of head trauma, brain infections, or use of unusual creams, pills, or diet that might expose them to estrogen or testosterone should be explored.   It is also essential to take a complete family history about the onset of puberty in parents and siblings, which may point to the possibility of a familial condition.[5]

Linear growth acceleration is one of the important features of early puberty. So the exact height, weight, growth velocity (cm/year) and BMI should be documented.  In females, accurate Tanner staging of the breast should take place, which is particularly challenging in obese or overweight girls to differentiate between adipose tissue and the glandular breast tissue. In males, an orchidometer should be used to determine the testicular volume. Volumes of more than 4 ml confirm pubertal development.  In males and females with pubic hair and body odor, the absence of increased testicular volume and breast development should prompt investigation of peripheral causes. Unilateral testicular enlargement is likely due to testicular tumors.

A thorough examination should be done to look for acanthosis nigricans, café au lait macules, neurofibromas which might indicate specific causes such as neurofibromatosis type 1 and McCune-Albright syndrome.

Evaluation

Initial screening tests usually include bone age, measurement of LH, FSH Testosterone, Dehydroepiandrosterone sulfate (DHEA-S), 17 OH progesterone levels, and thyroid function tests.

Bone age is an initial screening test. If the bone age is advanced (greater than two standard deviations) than the chronologic age, further testing should follow.  Hormonal testing differentiates peripheral and central causes.  A baseline prepubertal LH level of greater than 0.3 IU/L is suggestive of CPP.  Levels under 0.3 are indicative of peripheral causes or benign variants. If there is a high suspicion for central causes, a GnRH stimulation test, which is considered to be the gold standard, should be done. This test is not available in the United States so that the GnRH agonist is an alternative.  FSH levels are of limited utility.  Very high levels of estradiol in females or testosterone in males associated with suppressed LH and FSH are indicative of peripheral precocity. Measurement of adrenal androgens such as dehydroepiandrosterone sulfate (DHEA S) differentiates between testicular and adrenal sources of androgens.

Human chorionic gonadotropin (hCG) levels should be a consideration in boys. Some germ cell tumors secrete hCG, which activates the LH receptors and increases testosterone production.

In cases of PPP, pelvic ultrasonography detects ovarian tumors or cysts in females while testicular ultrasonography in males reveals nonpalpable Leydig cell tumors.

Magnetic resonance imaging is to be performed in all cases of CPP, especially in males, to rule out a hypothalamic lesion. It is also to be considered in females who present with early pubertal changes (less than 6 years of age).

Treatment / Management

Central precocious puberty

 The decision to treat depends on the age of the child and the progression of puberty. If the child has rapidly progressing symptoms or if bone age is significantly advanced, consider treatment. The main goals of treatment are to preserve the adult height and to alleviate the associated psychosocial stress. GnRH agonists are the standard of care.[6] Many different formulations (intranasal, intramuscular and subcutaneous) of long and short-acting GnRH agonists exist. The choice of the formulation depends on the patient and clinician preference.  In the United States, leuprolide acetate is the most common. It is a depot injection administered every 3 months.

GnRH agonist therapy is generally considered safe, with no reported significant adverse events. The most common adverse events include local skin reactions (intramuscular pain, sterile abscesses) and post-menopausal symptoms (hot flushes).

While on treatment, periodic monitoring of pubertal progression, growth velocity, and skeletal maturation are necessary.

Peripheral Precocious puberty

Treatment is directed towards eliminating the source of sex steroids. Surgery is indicated in gonadal and adrenal tumors.  If exogenous sources of sex steroids are identified, they should be eliminated. Classic congenital CAH is treated with glucocorticoids. In McCune-Albright syndrome, some benefit occurs with blocking the estrogen synthesis using aromatase inhibitors (anastrozole, letrozole) and selective estrogen selective receptor modulator (tamoxifen).  The optimal treatment for familial male-limited precocious puberty is not well established, but the preferred treatment is a combination of an androgen antagonist (spironolactone) and an aromatase inhibitor (anastrozole, testolactone).[7]

Differential Diagnosis

Precocious puberty requires differentiation from the benign forms of puberty.[8] These include

• Premature Thelarche: It is the premature unilateral or bilateral development of the breast tissue in girls between the age of 12 to 24 months. There are no other associated pubertal changes. Bone age, growth velocity, and biochemical testing are normal. It is usually a diagnosis of exclusion. Frequent clinical follow up to monitor growth, and pubertal progression is required.

• Premature Adrenarche: The early production of adrenal androgens characterizes this benign condition. It presents with pubic or axillary hair, body odor, or acne before the age of 8 years.  There is no breast development in females and no testicular enlargement in males. Bone age is usually not advanced. It is essential to rule out exposure to androgen sources such as creams or gels, adrenal tumors, and late-onset CAH.

• Premature Menarche: Isolated premature menarche is the onset of vaginal bleeding in girls less than 7 years of age. They may present with either a single episode or few cycles (less than 3) of bleeding and have normal progression to puberty. Recent studies have suggested no effect on adult height. Sexual abuse, vaginal foreign body, and infections of the vulva and vagina need to be ruled out.

Prognosis

Early onset of treatment is usually associated with greater success in preserving final adult height.  The outcomes depend on factors; such as advancement of bone change, age at which precocious puberty initiated, the timing of initiation, and duration of treatment.[9]  The HPG axis returns to normal after the cessation of the therapy, and these children usually have a normal progression of puberty after stopping treatment. There is very little information on the long term endocrine, metabolic, reproductive, and psychological consequences.[10] The prognosis of PPP varies depending on the cause.

Complications

Untreated precocious puberty usually leads to short stature and can also cause significant emotional and behavioral issues. Few studies have shown that children experiencing precocious puberty are at high risk of engaging in high-risk behaviors such as substance abuse, conduct issues, social isolation, truancy, and multiple sexual partners. They also have a lot of peer pressure and self-image concerns. However, most of these problems resolved by early adulthood.[11] More studies are needed to validate the psychological consequences.

Deterrence and Patient Education

The primary care providers and the pediatric endocrinologists should have a detailed conversation explaining the early pubertal changes even if it's a benign variant. If treatment is required, duration and the adverse effects require discussion and consideration. Apart from this, the parents should receive education on how to explain the condition to their children and families.[12]

Educational materials for the parents are available in the Section on Endocrinology Patient Education Committee by the Pediatric Endocrine Society/American Academy of Pediatrics.

Enhancing Healthcare Team Outcomes

Precocious puberty is becoming increasingly common owing to a multitude of factors such as genetics, lifestyle changes, and exposure to endocrine disrupting chemicals. It is one of the common conditions encountered in pediatric endocrinology practice. It raises a lot of concerns and uncertainties in parents and children. This condition is best managed by an interprofessional team that includes an endocrinologist, pediatrician, nurse, surgeon (if involving masses or tumors) and a mental health counselor.

Precocious puberty, in its various forms, requires an interprofessional team approach, including physicians, specialists, counseling professionals, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]