Introduction
Puberty can be a source of much concern for adolescents. As children become more self-aware, they also become more aware of comparisons: Why don’t I have breasts yet? My friend does. When are my periods going to start? The clinician’s role is to educate the young person about their body and to guide them through puberty, being well-versed in potential signs that may herald underlying causes of atypical puberty. Genetic context is important: many forms of earlier or later puberty are heritable. When evaluating pubertal progression, the clinician must consider family history, the child’s medical history, and a careful review of systems that could suggest underlying disease; examine the child thoroughly while explaining findings; and develop a plan for evaluation if pubertal aberrations are suspected.
Timing versus tempo of puberty
Both timing and tempo must be considered in diagnosing puberty occurring outside of two standard deviations of average ( Table 6.1 ). Pubertal concerns frequently arise about the timing of pubertal changes. Normal and abnormal pubertal variants change the timing of puberty’s initiation or its sequence. In general, thelarche is considered normal after the age of 8 years and has been suggested as normal after 7 years old in African American girls. However, scrutiny of ascribing normalcy or abnormality for a physical condition based on race or ethnicity has led to the recognition that this is a source of implicit bias that can prevent or delay the evaluation of someone with a pathologic finding. Thus it is prudent to evaluate children who present with thelarche before the age of 8 years. Similarly, the child who has not had thelarche by the age of 13 years should be evaluated. Menarche, on average, occurs by the age of 12 to 12.5 years. The child who has not achieved menarche by 14 to 15 years should undergo thoughtful evaluation. These are examples of considering the timing of the pubertal event.
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Pubertal tempo is also important to consider when evaluating pubertal development. Menarche typically follows true thelarche in 2.5 to 4 years. The child whose thelarche occurred 5 years ago without subsequent menarche might have an underlying health condition preventing this milestone. Similarly, the child who progresses from thelarche to menarche in 6 months, or who has menarche before thelarche, deserves evaluation.
Central versus peripheral causes of abnormal puberty
When delayed or precocious puberty is identified, the clinician can delineate the cause of the abnormality with a careful history, review of systems and examination, and selective use of imaging and laboratory evaluation. 
Perhaps the most important consideration when sorting out causes is determining whether a pubertal anomaly is central or peripheral . Use of ultrasensitive luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and androgen assays are essential, as routine adult assays cannot detect the very low levels of estradiol in early puberty or the initial rise in LH that heralds puberty. Ultrasensitive estradiol and testosterone levels should be determined using liquid chromatography–tandem mass spectrometry. Ultrasensitive measurements of LH and FSH should use two site electrochemiluminescent assays, which are more sensitive than standard immunoassays. Measuring gonadotropins is key in noting whether a pubertal timing or tempo aberration has arisen in the central nervous system (CNS) or stems from concerns elsewhere.
Precocious puberty
A child with a uterus and ovaries who has precocious puberty may present with (1) advanced bone age because of estrogen secretion, (2) breast development, and (3) even menarche. The uterus may be enlarged to a size commensurate with bone age, as both depend on estrogen secretion. Linear growth acceleration is seen with pubertal-level growth velocity. Adrenarchal signs of puberty arising from the adrenal gland often follow, with resultant acne, oiliness of the skin, apocrine body odor, and axillary and pubic hair.
Precocity can occur in isolation or in a complete fashion. Isolated forms include premature thelarche, premature adrenarche, or premature menarche. Complete forms are delineated into central precocious and peripheral sexual precocity based on the causative etiologies.
Premature thelarche (PT) refers to isolated breast tissue development, which can be seen at an early age in a patient who shows no additional signs of precocious puberty. The typical presentation of PT is the appearance of glandular tissue in girls age 3 years or younger, with little increase over the period of many months. Some authors recommend that PT can be managed without hormonal testing or imaging in most girls without continued breast development and/or rapid growth velocity. However, because a small percentage of these patients do actually have true precocious puberty, especially in females age >2, others feel that an initial hormone workup and imaging for abnormal puberty are warranted (as PT can be hard to distinguish from true precocious puberty). Accordingly, assessing for rapidity of thelarche and other pubertal changes; increased growth velocity; changes in ultrasensitive estradiol, LH, and FSH; and serial bone age radiographs should be undertaken to identify patients who have true precocious puberty.
Premature adrenarche (PA) refers to maturation of the adrenal androgen axis with elevations of dehydroepiandrosterone sulfate (DHEAS) and androstenedione and is associated with the onset of pubic hair, comedones, and/or apocrine body odor. When adrenarche occurs before the age of 8 years in girls but is associated with a normal growth velocity, minimal or no bone age acceleration, and no evidence of clitoromegaly, the diagnosis of premature adrenarche can be made. This diagnosis is more common in girls with eventual polycystic ovary syndrome (PCOS) or those born small for gestational age, and some authors report African American girls. However, a diagnosis of PA should not be overly influenced by ethnicity or race and should be determined carefully.
Typical laboratory findings include a modestly elevated DHEAS for age, commensurate with Tanner hair staging, but prepubertal FSH, LH, and estradiol concentration. Adrenal tumors, late-onset congenital adrenal hyperplasia (CAH; diagnosed with measurement of 17-OH progesterone), exogenous androgen exposure, and true precocious puberty must be eliminated as possible causes before the final diagnosis of PA can be made. Isolated PA has been associated with later hyperandrogenism, decreased ovulatory function, PCOS, hyperinsulinemia, and elevated triglyceride levels in adulthood. Therefore patients with PA should be monitored for these conditions through adolescence into adulthood.
Premature menarche may occur in a child with a uterus who otherwise is experiencing normal puberty or has not even begun puberty. Early bleeding in this situation is likely the result of irregular patterns of hormone secretion seen before puberty is completed. However, other causes of early bleeding must be considered, including infection, foreign body, genitourinary trauma, sexual assault, ovarian mass or cyst, prolapse of the urethra, rectal bleeding mistaken for vaginal bleeding, or vaginal or cervical tumor. Munchausen by proxy (also known as factitious disorder imposed on another ) is also a possible cause in a child who shows no other signs of puberty. McCune-Albright syndrome (MAS) may present with bleeding in a preschool child. Sedation or anesthesia may be needed to adequately examine the vagina and cervix in the younger child. If no etiology can be found, premature menarche is the presumed diagnosis, and the family can be reassured, with follow-up dependent on whether the bleeding recurs ( Table 6.2 ). See Chapter 7 for more information on prepubertal vaginal bleeding.
| Characteristic | Associated Findings |
|---|---|
| Peripheral precocious puberty (gonadotropin-independent precocity) |
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| Unilateral ovarian cysts | Detectable estradiol with prepubertal gonadotropins or enlarged ovary ± cyst visible on ultrasonography |
| Café-au-lait macules | Irregular borders, “coast of Maine” |
| Fibrous dysplasia | Ground-glass appearance and shepherd’s crook deformity on x-ray |
| Other endocrinopathies associated with Guanine nucleotide binding protein, alpha stimulating (GNAS) activation | Thyrotoxicosis, gigantism or acromegaly, Cushing syndrome, hypophosphatemic rickets |
| Other nonendocrinopathies associated with GNAS activation | Cholestasis, hepatitis, intestinal polyps, cardiac arrhythmias, increased risk of malignancy |
Central precocious puberty
Central precocious puberty (CPP), also known as gonadotropin-dependent precocious puberty, is the development of complete isosexual pubertal changes caused by premature reactivation of the hypothalamic-pituitary-ovary axis, which has been quiet since the mini-puberty of infancy resolved ( Table 6.3 ). A child may have central precocious puberty because of a genetic mutation, exogenous exposure to sex steroids, a CNS lesion, or activation of the hypothalamic-pituitary-ovarian (HPO) axis, although often an etiology cannot be determined (idiopathic CPP). As imaging modalities and genetic testing improve, the incidence of the “idiopathic” form of precocity will likely decrease. It is also of note that multiple countries worldwide saw a significant increase in CPP during the COVID-19 pandemic.
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The most common genetic cause of central precocity is a loss-of-function mutation in the MKRN3 gene. This is the gene on chromosome 15 coding for the makorin RING finger protein 3. MKRN3 protein deficiency disinhibits the hypothalamus, leading to gonadotropin-releasing hormone pulses that activate pituitary secretion of LH and FSH. Rarely, mutations in the genes for kisspeptin (KISS1) or the kisspeptin receptor (KISS1R) may result in CPP. Routine genetic testing for CPP is not currently recommended, as it does not influence outcome.
CNS lesions, whether congenital or acquired, may result in CPP. Among prenatal or congenital causes are hydrocephalus, septo-optic dysplasia (also known as optic nerve hypoplasia sequence ), tuberous sclerosis, and cerebrovascular infarction or bleed. Cerebral palsy, hydrocephalus, and spina bifida are known to sometimes be accompanied by precocious puberty of central origin. Postnatally, CPP can arise with brain tumors, particularly in patients with genetic syndromes such as neurofibromatosis type 1, DICER1 mutation, and Li-Fraumeni syndrome. Russell-Silver syndrome, or temple syndrome, can have central precocity as a finding, which can compromise final height. Acquired causes can include encephalitis, perinatal brain injury, or endocrine disruptor exposures, such as the pesticide dichlorodiphenyltrichloroethane (DDT) or its derivative, dichlorodiphenyldichloroethylene (DDE). Astrocytoma, optic nerve gliomas, and ependymomas are some of the tumors more commonly associated with central precocity. Teratomas, hepatoblastomas, choriocarcinomas, or pineal tumors may produce gonadotropins ectopically. Peripheral precocity related to adrenocortical carcinoma, ovarian virilizing tumors, CAH, or exogenous sex steroids may lead to central precocity by activating the HPO axis.
Evaluation starts with a thorough history and physical examination, including discussion of maternal age of menarche, evaluation for etiologies as noted earlier, and sexual maturity rating. Additional evaluation for CPP includes a bone age radiograph and laboratory testing with FSH, LH, and estradiol. An ultrasensitive random LH level above 0.3 IU/L heralds puberty’s initiation by the CNS. In the absence of this rise in LH, either observed spontaneously or with a luteinizing hormone–releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) analogue stimulation test, evidence points to a peripheral source of precocity. Classically, with stimulation testing, the 20- or 60-minute LH sample should be at or above 5 to 8 IU/L if puberty is underway. If CPP is diagnosed, magnetic resonance imaging (MRI) of the brain is warranted, especially in a child less than 6 years of age at presentation , ( Fig. 6.1 ).
Treatment for CPP
The goals of therapy in CPP include allowing the patient to attain a normal adult height, ideally meeting the genetic potential range, and attaining pubertal completion when the child has the psychosocial and physical mechanisms for dealing with puberty. An additional goal for therapy is to delay menarche until an appropriate developmental age, as early menarche and sexual development can lead to psychosocial stress in the child and family.
CPP in a child with a uterus and ovaries can be temporarily delayed with a GnRH agonist ( Table 6.6 ). GnRH agonists work by providing continuous stimulation of pituitary gonadotrophs, preventing the physiologic pulsatile stimulation by GnRH to the pituitary gland that would lead to FSH and LH secretion. GnRH can be offered for idiopathic CPP and for CPP related to an intracranial pathology. Additionally, if the patient has an identifiable, intracranial lesion, treatment of the underlying lesion may be necessary. This may involve monitoring, as with a hypothalamic hamartoma, or chemotherapy, radiation, and/or surgery in the cases of tumors.
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