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All the children attaining 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, with prevalence being 10 times higher in girls is said by precocious puberty. Early activation of pulsatile GnRH secretion (central or gonadotropin-dependent precocious puberty), that result from hypothalamic tumors or lesions but in most cases (approx 90 %) remain unexplained, is the most common mechanism for progressive precocious puberty. Pubertal manifestations will regress or stop progressing, the gonadotropic axis is not activated and no treatment is necessary in at least 50% of cases of precocious puberty. In cases with progressive precocious puberty, they present with adverse psychosocial outcomes, early menarche and short adult stature due to early epiphyseal fusion. 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.
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. To evaluate patients with suspected precocious puberty internists should consider following questions: The pubertal development occurring is it outside the normal temporal range? Is any risk of an intracranial lesion associated with it and what could be the underlying mechanism? Is there any impairment in the child's normal physical and psychosocial development associated with progression of pubertal development?
To take a complete family history (age at which onset of puberty in parents and siblings) and any signs and symptoms such as headache, increased head circumference, visual impairment, or seizures (in particular gelastic) suggesting possible CNS abnormality should be the first step in evaluating the case. 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. In precocious puberty bone age is generally greater than chronological 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. Early in the mornings are preferred to determine the levels of sex steroids. Due to high variability of serum E2 levels in girls, they have low sensitivity in the diagnosis of precocious puberty. Very high levels of E2 (>100 pg/ml or 367 pmol/L) generally indicate an ovarian cyst or tumour. The gold standard for determining precocious puberty is to the measure 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), it is important to be careful when interpreting gonadotropin levels in children younger than 2-3 years old (as generally in this age group it is high). FSH levels taken randomly are not useful, since they vary little throughout pubertal development. In girls, ovarian cysts/ tumors and uterine changes (uterine volume > 2.0 ml has 89% sensitivity and specificity) can be noticed in pelvic ultrasonography. This child had increased volume probably because of increased E2 (twice the normal), but no evidence of any ovarian pathology. To confirm whether a hypothalamic lesion is present, MRI - brain should be performed in all cases of progressive CPP. The prevalence of these hypothalamic lesions is low in girls (8 to 33%) who present with precocious puberty and is more lower if puberty starts after the age of 6 years (about 2%) when compared to boys (40 to 90%). Our patient had a hypothalamic hamartoma measuring 1.44cm x 1.38cm which is the commonest cause of CPP at this age.
Internists evaluating a case of precocious puberty must take the decision about whether to provide treatment for girls in particular, if onset of puberty < 8 years of age as it is the most appropriate age for stopping treatment. The use of GnRH agonists in progressive CPP is to continuously stimulate pituitary gonadotrophs which help in decreasing and desensitizing the release of LH and, to a lesser extent, FSH. To determine the desired effect of the therapy, a suppressed response of LH to GnRH is visualised by administering GnRH, its agonist or an injection of the depot preparation (which contains a fraction of free GnRH agonist). To obtain an optimal height and for pubertal manifestations to reappear within months (mean time to menarche - 16 months) after termination of treatment, the treatment should be discontinued at the age of 11 years. The European Society for Paediatric Endocrinology and its American counterpart, the Lawson Wilkins Paediatric Endocrine Society is now preparing the consensus statement in relation to the use of GnRH agonists in children. We managed our case with Inj Tryptorelin (GnRH agonist) monthly depot injections with remittance of pubertal changes (clinical and hormonal).
Any central lesion causing precocious puberty (e.g., a mass or malformation), if managed, show no effect on the course of pubertal development. Generally hypothalamic lesions in association with precocious puberty may lead gonadotropin deficiency and one should remember not to surgically remove hypothalamic hamartoma to manage precocious puberty.
CONCLUSION AND RECOMMENDATIONS
A thorough history taking and careful examination is required to determine the possible causes of precocious puberty, however it is often vague. Assessment of bone age and hormonal evaluation (Levels of E2, LH and TSH) should also be added for further evaluation. If a randomly measured level of LH is in the pubertal range, an MRI brain should be obtained as was done in our case, any time as it would be useful in confirming progressive CCP by performing GnRH-agonist stimulation test before the treatment with GnRH agonist is started. A pelvic ultrasound scan is required to rule out an ovarian tumour or cyst, mainly if the E2 level is elevated, if the random levels of LH are in prepubertal range. A GnRH or GnRH-agonist stimulation test is recommended to further evaluate the activation of the gonadotropic axis and the potential for development of puberty if both the levels of E2 and LH are in prepubertal age. In a case progressive CPP, treatment with a depot GnRH agonist is suggested and is generally continued till 11 years, even though the best duration of therapy is undecided.
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.