Central precocious puberty (idiopathic)
Pediatric patients that exhibit an onset of puberty that is 2.0 to 2.5 standard deviations earlier than their peers meet the criteria for precocious puberty. While the mean age of pubertal onset is likely to vary slightly in different patient populations, additional work-up for precocious puberty is usually recommended for girls younger than 8 and boys younger than 9 . Initial evaluation typically consists of a thorough physical exam to document the extent of adrenarche and to accurately assign a patient's Tanner stage based on breast development in girls and penile/testicular size in boys. Radiographic evaluation of a patient's bone age can also be valuable for assessing the presence and/or severity of precocious puberty .
Precocious puberty can be central (CPP; i.e. due to premature maturation or inappropriate activation of the hypothalamic-pituitary-gonadal axis) or peripheral (PPP; i.e. driven by a gonadotropin-independent process). Up to 80-90% of CPP cases in girls are idiopathic. In contrast, only 25-60% of CPP cases in boys are deemed idiopathic; many of the remaining cases are associated with CNS lesions, such as hamartomas or glial neoplasms . Additionally, an increasing number of CPP cases have been associated with mutations in specific genes, including KISS1 and MKRN3 [4, 5].
There are a number of potential underlying etiologies for children with peripheral precocious puberty. A thorough clinical history is essential to rule out accidental exposures to medications or supplements containing sex steroids. A number of ovarian/testicular/adrenal neoplasms can also drive excess sex steroid secretion, warranting appropriate imaging if necessary. Less common causes of PPP include congenital adrenal hyperplasia and McCune-Albright syndrome [6, 7].
The major reason for identifying and treating precocious puberty is to prevent premature growth plate fusion, which can significantly reduce terminal adult height. Additionally, precocious puberty may be an indicator of underlying (potentially malignant) pathology. Consequently, timely and accurate diagnosis can help prevent adverse outcomes and influence treatment decisions. In many cases, laboratory quantification of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by immunoassay can help to distinguish central and peripheral causes of precocious puberty. Because the HPG axis is overactive in CPP, baseline LH and FSH levels are expected to be above age-adjusted thresholds in these patients. In contrast, patients with PPP are expected to have an appropriate negative feedback loop that decreases gonadotropin levels in response to elevated sex steroid concentrations. In cases where a central etiology is highly suspected but baseline gonadotropin levels are not severely elevated, HPG axis overactivity can be detected after a single low-dose challenge with leuprolide (a GnRH agonist). Excessive gonadotropin secretion (which typically occurs within 30-60 minutes) after leuprolide challenge is considered acceptable evidence for HPG overactivity .
Interference in immunoassays is an uncommon but well-documented phenomenon that can result in falsely increased or decreased analyte values. In the case of LH detection, heterophile antibodies have been previously implicated in artifactually elevated LH measurements . Immunologically-silent LH variants (i.e. functionally intact hormones that lack the epitope targeted by the immunoassay) have also been described [10, 11]. More recently, the disruptive effects of excessive dietary biotin supplementation on biotin-streptavidin-based immunoassays have been discussed . In this case, treatment of the patient's pre-challenge specimen with a heterophile antibody-blocking reagent and repeating the testing on the same platform corrected the analyte value from below the limit of detection to 5.1 mIU/mL.
Based on the patient's clinical presentation, radiographic evaluation, and laboratory findings, he was diagnosed with idiopathic central precocious puberty. He started receiving high-dose leuprolide depot intramuscularly, which causes pituitary desensitization to GnRH and ultimately reduces gonadotropin secretion . Treatment can be stopped as patients approach expected adult height, with resumption of puberty within 11 months for boys on average .
Contributed by Eric D. Carlsen, MD, PhD; Octavia Peck Palmer, PhD