Precocious puberty is defined as children entering puberty more than 2.5 to 3 standard deviations (SD) earlier than the median age, or before the age of 8 years in girls and 9 years in boys, the prevalence being 10 times higher in girls. The most common mechanism of progressive precocious puberty is the early activation of pulsatile GnRH secretion (central or gonadotropin-dependent precocious puberty), which may result from hypothalamic tumors or lesions but in most cases (approx 90 %) remain unexplained. In at least 50% of cases of precocious puberty, pubertal manifestations will regress or stop progressing, the gonadotropic axis is not activated and no treatment is necessary. For cases in which precocious puberty progresses, concerns include early menarche in girls and short adult stature due to early epiphyseal fusion and adverse psychosocial outcomes in both sexes. We present a rare case of precocious puberty presenting at a very early age (06 months), with clinical, laboratory and radiological features supporting a central aetiology. We also use this case to illustrate an approach to a case of isosexual precocious puberty in girls.
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A sixteen months old female child, second product of a nonconsangenous marriage, brought by parents with history of bleeding per vaginum since six months of age. Initially she had irregular cycles, which evolved into monthly cycles of 3-4 days for next eight months. Clinically her height and weight were at 80th percentile. She had bilateral breast enlargement (PANEL A) and normal systemic examination. She had normal haematological and biochemical profile, however hormonal analysis revealed pubertal response of gonadotropins with luteinizing hormone (LH) - 2.20 mIU/ml (N<0.6mIU/ml), follicle-stimulating hormone (FSH) - 5.58 mIU/ml (N<0.6mIU/ml) and estradiol (E2) - 10.2 pg/ml (N<5pg/ml) with normal thyroid functions. X-ray of left wrist revealed bone age of 24 months (PANEL B). Uterine volume on pelvic ultrasonography was 2.2 ml with no evidence of ovarian cyst/ tumour and MRI brain plain (PANEL C) and post contrast (PANEL D) was done, which revealed hypothalamic hamartoma measuring 1.44cm x 1.38cm. Patient is being managed as a case of isosexual precocious puberty secondary to hypothalamic hamartoma with monthly gonadotropin-releasing hormone (GnRH) analogues. Patient is under regular follow up for seizures, secondary sexual characters, hormonal assays, bone age and annual MRI brain for changes in hypothalamic hamartoma.
Areas of uncertainty in evaluating cases of precocious puberty include appropriate age threshold for the defining precocious puberty, approach to differentiate progressive from non progressive forms, and causal mechanisms underlying idiopathic precocious puberty. Physicians evaluating patients with suspected precocious puberty should address following questions: Is pubertal development really occurring outside the normal temporal range? What is the underlying mechanism, and is it associated with a risk of an intracranial lesion? Is pubertal development likely to progress, and if so, would this impair the child's normal physical and psychosocial development?
The first step in evaluation is to obtain a complete family history (age at onset of puberty in parents and siblings) and any evidence suggesting possible CNS dysfunction such as headache, increased head circumference, visual impairment, or seizures (in particular gelastic). Patients should be evaluated for high growth velocity which may also precede the onset of pubertal manifestations and pubertal development, classified as per Tanner staging. Our patient had no positive family history and presented with menarche at 6 months of age and thelarche (Tanners stage B3) with no clinical evidence of CNS dysfunction. The development of pubic hair results from the effects of androgens, which may be produced by testes or ovaries in CPP, thus in girls, pubic hair in the absence of breast development is suggestive of adrenal disorders, premature pubarche, or exposure to androgens. The physical examination should include an assessment for signs of specific disorders such as hyperpigmented skin lesions suggesting neurofibromatosis or the McCune-Albright syndrome, which were absent in our case. Additional tests are recommended in either Tanner stage > 3/ stage 2 with increased growth velocity or symptoms/ signs suggestive of CNS dysfunction. We subjected this child to additional testing (assessment of the bone age, hormonal analysis, imaging) due to fulfilling first of these mentioned criteria. The bone age of patients with precocious puberty is generally greater than their chronologic age which can be assessed using reference atlas such as by Greulich and Pyle. Our child had bone age 8 months more than the chronological age. Levels of sex steroids should be determined in the morning. In girls, serum E2 levels are highly variable and have a low sensitivity for the diagnosis of precocious puberty. Very high E2 levels (>100 pg/ml or 367 pmol/L) generally indicate an ovarian cyst or tumour. The gold standard is the measurement of gonadotropins after stimulation by GnRH or a GnRH-agonist prior to starting therapy. Peak LH levels of 5-8 mIU/L suggest progressive central precocious puberty, with a specificity of 100% for cut-off figure of 6mIU/L. Unless levels of LH are clearly elevated as in our case (more than 4 times the 95th percentile), caution should be used when interpreting gonadotropin levels in children younger than 2-3 years old (as normally high in this age group) . Random measurements of FSH are not useful, since they vary little throughout pubertal development. In girls, pelvic ultrasonography can reveal ovarian cysts/ tumors and uterine changes (uterine volume > 2.0 ml has 89% sensitivity and specificity) due to E2 exposure. This child had increased volume probably because of increased E2 (twice the normal), but no evidence of any ovarian pathology. In all cases of progressive CPP, MRI - brain should be performed to determine whether a hypothalamic lesion is present. The prevalence of such lesions is higher in boys (40 to 90%) than in girls (8 to 33%) presenting with precocious puberty and is much lower when puberty starts after the age of 6 years in girls (about 2%). Our patient had a hypothalamic hamartoma measuring 1.44cm x 1.38cm which is the commonest cause of CPP at this age.
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Physicians evaluating a case of precocious puberty must take the decision about whether to provide treatment particularly for girls with an onset of puberty < 8 years of age, the most appropriate age for stopping treatment. GnRH agonists are indicated in progressive CPP which continuously stimulate pituitary gonadotrophs, leading to desensitization and decrease in the release of LH and, to a lesser extent, FSH. A suppressed LH response to GnRH or a GnRH agonist or a suppressed response after an injection of the depot preparation (which contains a fraction of free GnRH agonist) indicates that the therapy is having the desired effect. Discontinuation of treatment at the age of 11 years is associated with optimal height outcome and reappearance of pubertal manifestations within months (mean time to menarche - 16 months) after termination of treatment. Consensus statement on the use of GnRH agonists in children is currently being prepared by the European Society for Paediatric Endocrinology and its American counterpart, the Lawson Wilkins Paediatric Endocrine Society. We managed our case with Inj Tryptorelin (GnRH agonist) monthly depot injections with remittance of pubertal changes (clinical and hormonal).
For cases in which precocious puberty is caused by a central lesion (e.g., a mass or malformation), management of the causal lesion generally has no effect on the course of pubertal development. Hypothalamic hamartoma should not be removed surgically for the purpose of managing precocious puberty. When precocious puberty is associated with the presence of a hypothalamic lesion, there may be progression to gonadotropin deficiency.
CONCLUSION AND RECOMMENDATIONS
Evidence of possible causes of precocious puberty should be sought by means of a thorough history taking and careful examination, but this search is often unrevealing. Further evaluation should include assessment of bone age and hormonal evaluation (Levels of E2, LH and TSH). If a randomly measured level of LH is in the pubertal range, an MRI brain should be obtained as was done in our case, and it would be useful to perform a GnRH-agonist stimulation test to confirm progressive CPP before considering treatment with a GnRH agonist. If the randomly measured level of LH is in the prepubertal range, a pelvic ultrasound scan is needed to rule out an ovarian tumour or cyst, particularly if the E2 level is elevated. If randomly measured levels of both E2 and LH are in the prepubertal range, we recommend performing a GnRH or GnRH-agonist stimulation test to further evaluate the activation of the gonadotropic axis and the potential for progression of puberty. If progressive CPP is confirmed, treatment with a depot GnRH agonist is recommended and is generally continued till 11 years, although the optimal duration of therapy is uncertain.
LEGEND FOR FIGURES
PANEL A: Bilateral breast enlargement (Thelarche - Stage B3)
PANEL B: Plain radiograph wrist showing bone age of approximately 24 months.
PANEL C: Plain MRI Brain (T1W image) revealing hypothalamic hamartoma.
PANEL D: MRI Brain post contrast revealing hypothalamic hamartoma measuring 1.44cm x 1.38cm.