NORD gratefully acknowledges Jerrold S. Olshan, MD, Director, Division of Pediatric and Adolescent Endocrinology/Diabetes, The Barbara Bush Children's Hospital at Maine Medical Center and Associate Professor of Pediatrics, Tufts University School of Medicine, and Emily Sangillo, MS4, Tufts University School of Medicine, for assistance in the preparation of this report.
Precocious puberty means an abnormally early onset of puberty. A sequence of events occurs during which a child develops into a young adult beginning at an unexpectedly early age. Glands that secrete growth and sex hormones begin to function abnormally early in life resulting in this condition. Often, the exact cause of precocious puberty is not known.
Precocious puberty (PP) is a statistical definition; that is, it is the onset of secondary sexual characteristics in children at an age that is two standard deviations younger than the mean age of pubertal onset. The actual age that defines sexual precocity is therefore dependent on the epidemiological data that one uses to define the average age of pubertal onset. Different populations and different time periods will therefore have differing definitions of PP. Classically, in North America, puberty is considered precocious if it begins before age 8 in girls or age 9 in boys. Recently, most likely because of increasing weight in the population, puberty appears to be having an earlier age of onset.
Secondary sexual characteristics include testicular enlargement (>3 ml) and/or pubic hair development in boys, and breast and/or pubic hair development in girls. Other signs suggestive of pubertal onset include acne, growth acceleration, voice changes, vaginal discharge or bleeding, and advanced skeletal maturation. There are many terms used to describe pre-pubertal children who have isolated signs of puberty. These children, however, do not necessarily meet the criteria for true precocious puberty. These terms include premature thelarche, premature adrenarche, premature pubarche and premature menarche. The terminology is often confusing as these are also referred to by some authors as incomplete precocious puberty.
Precocious puberty can occur in several forms. Normally, the hypothalamus initiates puberty by stimulating the pituitary to release gonadotropins (FSH and LH), the hormones which control growth and function of the sex organs. When gonadotropins are released, synthesis and secretion of sex steroids (such as estrogen, progesterone or testosterone) occur, leading to development of secondary sexual characteristics. If this occurs prematurely, a child starts to develop secondary sexual characteristics and proceeds to sexual maturity at an unexpectedly early age. Since the maturing of one’s bones is usually accelerated by this condition, early fusion of the growth plates occurs, resulting in shortening of adult stature. However, during childhood, children with precocious puberty are often taller than their peers.
Central precocious puberty (CPP) can be caused by CNS tumors (craniopharyngioma, glioma, etc.) and other CNS disorders including: hypothalamic hamartoma of the tuber cinereum, encephalitis, brain abscess, static encephalopathy, global delays, sarcoid or tubercular granuloma, head trauma, vascular lesion, cranial irradiation, or neurofibromatosis type 1 (usually associated with optic glioma). A large proportion of CPP is idiopathic, especially in females; however, research is beginning to identify rare genetic causes for some of these cases. For instance, activating mutations of the kisspeptin gene (KISS1) and its receptor (KISS1R), which are known for their stimulatory effect on the hypothalamus ultimately leading to increased gonadotropin secretion, have been identified as precipitating precocious puberty. Additionally, inactivating mutations of a paternally inherited MKRN3 gene, similar to that seen in Prader-Willi syndrome, has been implicated in early puberty. CPP can also follow the treatment of virilizing congenital adrenal hyperplasia or the treatment of other causes of gonadotropin independent precocious puberty (GIPP).
The causes of GIPP include gonadal, adrenal, ectopic, or exogenous sources of hormone production. Hypothyroidism may also cause GIPP, which is felt to be mediated by TSH stimulation of the FSH receptor, but frequently manifests as growth delay in the setting of testicular enlargement or premature menarche; this is also referred to as Van Wyk-Grumbach syndrome. Very rarely, ingestion of birth control pills, or other preparations containing estrogens, or meat containing high estrogen concentrations can cause this disorder. Hormone-secreting tumors of the gonads or adrenal glands are also associated with precocious puberty. Estrogen-secreting ovarian granulosa-thecal cell tumors are probably the most common form of sex steroid-secreting tumors among girls with GIPP. Human chorionic gonadotropin (HCG) tumors of the ovary, such as choriocarcinomas or teratomas may be associated with ovarian sex steroid stimulation and precocious puberty in girls. Benign ovarian cysts may be present in some female patients with PP. HCG-secreting tumors and Leydig cell tumors are causes GIPP in boys.
This disorder is classically characterized among females by breast development beginning before the age of eight years in white girls, 6.8 years for Hispanic girls and 6.6 years for Black girls, or the onset of menstruation before the age of approximately ten years (white-10.6 years, Hispanic-10.0 years and black-9.7 years). Among males, precocious puberty can be defined as pubertal development beginning before the age of nine years for white males, 9.5 years for Hispanic males and 8 years for black males. Boys with this disorder will usually have testicular and genital enlargement occur first and then tend to exhibit pubic, underarm (axillary) and facial hair, accelerated growth, and a deepening voice. Puberty may occur even before three years of age in some cases of this disorder.
CPP has an incidence of 1 in 5-10,000 children with a female to male ratio of about 20:1 although this ratio is debated. Eighty to ninety percent of girls with true PP have idiopathic CPP whereas over 50% of boys have an identifiable etiology for true PP.
Normal puberty begins with hypothalamic production of kisspeptin, which stimulates the pulsatile release of GnRH from the hypothalamus. This results in an increase in the frequency and magnitude of gonadotropin release, especially LH. Unfortunately, it is challenging to determine the initial clinical corollary to these biochemical events. It has been suggested that there is a continuum of sexual development in girls from uncomplicated premature thelarche to true precocious puberty; the former being more likely to develop in girls under 2 years of age. This spectrum exists both clinically and biochemically and emphasizes the need for the clinician to distinguish between these conditions in patients when making decisions about treatment. The criteria for diagnosis and treatment of CPP need to be reached through a synthesis of clinical findings as well as laboratory evidence for activation of the hypothalamic-pituitary-gonadal axis. The gold standard for determination of pubertal gonadotropin secretion is the GnRH stimulation test, though many clinicians start with a sensitive measurement of serum LH. Skeletal age determination is frequently obtained early in the work-up, and can be helpful in distinguishing isolated signs of puberty, which do not typically cause advancement in bone age as compared to true PP, which will advance bone maturity. In boys, serum DHEAS, testosterone, 17-OH progesterone and β-HCG levels are useful for the diagnosis of GIPP. In girls, serum DHEAS, estradiol and 17-OH progesterone levels are useful. Diagnostic studies including head MRI and pelvic ultrasound are frequently required in the work-up of children with PP.
The aims of treatment are to arrest physical maturation, prevent early menarche, bring final adult height closer to genetic expectation and allow normal psychosocial development. Treatment with very potent, long acting GnRH analogues have resulted in significant improvement in height in many, although not all, children with PP caused by both organic conditions and idiopathic CPP, with the best treatment outcomes seen in those with onset of puberty before 6 years of age. These can be given as subcutaneous injections, intra-nasally, and as subcutaneous implants. These GnRH superactive agonists work by first stimulating and then, after a few days, suppressing pulsatile LH and FSH release. This leads to suppression of gonadal steroid production. In general, treatment is required for those who progress rapidly through puberty. The degree of bone age advancement is helpful for determining the tempo of pubertal progression. Those who progress more slowly will likely have the unsustained or slowly progressive variety of precocious puberty and will often do well without intervention.
Management of GIPP requires treatment of the underlying disorder. In most cases, this entails removal of the hormone source (i.e. gonadal or adrenal tumor, exogenous hormone etc.); however, for conditions such as McCune-Albright Syndrome (MAS) and familial male-limited precocious puberty, treatment is targeted at blocking the production of and/or the response to sex-steroid hormones. This is primarily achieved through aromatase inhibitors, such as letrozole. The addition of androgen receptor blockers has been helpful in treating FMPP and MAS in boys. Pure estrogen receptor blocker, fulvestrant, is currently being investigated for the treatment of MAS in females with promising results.
Genetic counseling will be of benefit for families of patients with genetic forms of precocious puberty.
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