Introduction
Precocious puberty (PP) is an uncommon condition (1/5000 to 1/10000 per year) which is difficult to manage ((Brauner, 1992; Mogensen et al., 2011). When the disease is suspected, a diagnostic procedure should be followed to allow an efficient therapeutic indication. In the absence of specific treatment, the abnormal early secretion of sex steroids led to early development of puberty and to an acceleration of linear growth and bone maturation, and consequently to a small final size with all the repercussions that result (Carel and Léger, 2008).

The objective of this study is to report the etiological and evolutionary clinical characteristics of PP in children.

Materials and Methodology
30 children (21 girls and 9 boys) with a PP were hospitalized in Endocrinology department between 2000 and 2014.

The diagnosis of PP was made on a beam of clinical and laboratory arguments: development of secondary sexual characteristics as classified by Tanner, acceleration of the growth rate higher than 6 cm per year, bone age advance and development of genitals objectified on ultrasound (external genitalia in boys, internal genitalia in girls). The diagnostic was confirmed by plasma sex steroid hormone assays: plasma estradiol in girls and testosterone in boys.

The assessment was completed by an etiological exploration guided by clinical examination: measurement of serum gonadotropins (FSH and LH), LHRH test to search for a central origin (positive answer of gonadotropin) or peripheral (no reply) to the PP. On suspicion of congenital adrenal hyperplasia, the balance sheet is completed by an adrenal stimulation test by the common synacthen with plasma cortisol assay, adrenal precursors and measurement of plasma ACTH. When the PP was of central origin, brain magnetic resonance imaging was performed to eliminate an organic cause. In the presence of peripheral origin, abdominopelvic radiological investigation is conducted.

The evolution of the PP is evaluated depending to the importance of sexual impregnation according to Tanner staging, advance in bone age (higher of two years than the chronological age) and paraclinical results: organic causes and hormonal results.

Once the diagnosis (positive and etiologic) is posed and suppressive or/and specific treatment is started, all the children were followed with clinical reassessments, biological and radiological ones.

Results
The PP is twice more common in girls than in boys with a sex ratio (Girl / Boy) of 2.3. The mean age at diagnosis was 4.2 ± 1.4 years (1-8.5) in girls and 5.6 ± 1.4 years (17 months - 9 years) in boys.

The average delay of endocrinology consultation compared to the age detection of signs of early puberty was 2.5 years in boys (6 months - 6 years) and 3.2 years in girls (6 months - 4 years). The PP was evolutive in all the boys (100%) and only half of girls (52.5%) (Table I).

The average of plasma sex steroids was 84.6 pmol / L (60 to 80.4) for estradiol in girls and 4.8 nmol / l (1.4 to 4) for testosterone in boys.

The PP is of central origin (CPP) in 11.6% of girls, whose are of idiopathic causes in 70% of them (Table II).

In boys, the PP is of central origin in 28.5% and of organic causes in all of them. The peripheral origin is noted in 72% of cases and it’s related to a congenital adrenal hyperplasia (Table III).


Congenital adrenal hyperplasia related to a deficiency of the 21-hydroxylase enzyme is the cause of peripheral PP for all the cases in boys (Table III).

The initiation of suppressive treatment of PP by LHRH analogues in the case of central precocious puberty allowed seeing a regression of sexual characters and a stabilization of bone maturation in all cases.
 
At the beginning of treatment, pubertal development was at the stage S3 (S2- S4), with a size at +2.1 ± 0.8 DS / TC) and a bone age of 10.5 ± 0.8 years.

Under treatment, breast development decreased and bone maturation decelerated on the first year. The average of bone age lead after two years of treatment was of 1.4 years (6 months- 2 years) vs. 2.5 ± 1 year at the start of treatment. The mean final height was 158.2 ± 6.6 cm (-1,5 ± 0.1 DS / TS).

A patient with hypothalamic hamartoma presented neurological complications such as gelastic attacks and generalized tonico-clonic epilepsy indicating an urgent neurosurgical care.

The surgical treatment of ovarian tumors has led to the regression of precoce pubertal signs; however the histological study was in favor of malignancy and a complementary therapy with chemotherapy was indicated.

In the case of congenital adrenal hyperplasia, the alternative suppressive therapy with glucocorticoids failed to control the PP. The evolution was marked by the transition to PPC training which required the addition of LHRH analogues. A regression of sexual characters with stabilizing of bone age was recorded.
 
Discussion
The PP is an important reason for consultation in Endocrinology and Pediatrics. Its frequency seems to be increasing in all countries in those 15 to 20 years. Several extrinsic and intrinsic factors are implicated in the hatching of this disease.

This condition is met more often in girls than in boys and occurs at a variable age before 08 years, usually before 06 years (Mogensen et al., 2011) which has been objectified in our study. It is important to distinguish what is only a variant of normal puberty from true precocious puberty (Parent et al., 2003). Premature pubarche and premature thelarche are 2 common, benign, normal variant conditions that can resemble precocious puberty but are non progressive or very slowly progressive. Premature thelarche refers to the isolated appearance of breast development, usually in girls younger than 3 years; premature pubarche refers to appearance of pubic hair without other signs of puberty in girls or boys younger than 7-8 years. A thorough history, physical examination, and growth curve review can help to distinguish these normal variants from true precocious puberty (Aksglaede et al., 2009).

The management of the PP is done in three steps: affirm the reality of pathological puberty, search the central or peripheral origin also idiopathic or organic etiology and finally pose an indication of a suppression therapy of puberty.

The central PP (CPP) is 4-5 times more common in girls than in boys. The clinical picture is more or less rich depending on the speed and duration of the evolution. The combination of breast development in girls, testes in boys and pubic hair reorients etiological exploration to a central origin of iso sexual precocity (Figure 1; 2) (Herman-Giddens et al., 1997). However, an authentic CPP may present initially as an isolated development of a secondary sexual characteristic or even an isolated accelerated of linear growth which may precede by several months or years the appearance of secondary sexual characteristics posing an etiologic diagnosis problem (Brauner et al., 1987).

When the diagnosis of PP is affirmed, the study of plasma gonadotropins can guide the etiologic diagnosis to a central cause and appreciate the scalability of puberty while studying the hormonal response after stimulation with GnRH analogues (Boepple et al., 1992). The progressive forms are predominant both in girls and in boys and account for 60-70% of cases (Kaplowitz, 2004). In our study, they were present at all the boys (100%) and in half of girls (52.5%).

The organic forms are more frequent than other etiologies. In boys, they represent 65% of etiologies (VS 78% in our study). In girls, they are found in 30% of cases VS 17% in our series (Bridges et al., 1994).

The frequency of intracranial tumors responsible for CPP is variable and it’s between 7 and 12% in girls (Ng et al., 2003); and are responsible for 50-80% of boys CPP (Styne, 1991). In our patients, they were present in half of the cases represented by hypothalamic hamartoma (Figure 3). Indeed, the optic chiasm glioma and hypothalamic hamartoma are the most conventional tumors; more rarely other tumors arising from the posterior hypothalamus can be found such as astrocytoma, ependymoma and rarely craniopharyngioma. Also a CPP can be secondary to other causes such as hydrocephalus, malformation syndromes and after irradiation (Bridges et al., 1994).

The idiopathic forms predominate in girls. They have no clinical or hormonal characteristics. The evolution is variable, generally fast as it was noted in patients of this study (Brauner et al., 1987). Idiopathic character of the pathology can only be retained after elimination of the classic causes of CPP systematically sought.
 
Precocious pseudopuberty is much less common and refers to conditions in which increased production of sex steroids is gonadotropin-independent. Correct diagnosis of the etiology of sexual precocity is critical, because evaluation and treatment of patients with precocious pseudopuberty is quite different than that for patients with central precocious puberty.

Congenital adrenal hyperplasia is a common etiology of iso-sexual precocious puberty in boys (Bridges et al., 1994; Agboola-Abu et al., 1999). In our series, it represents the exclusive cause (Figure 4).

Precocious puberty is observed in case of significant delay in the diagnosis of the congenital adrenal hyperplasia and delay in the initiation of substitute and suppressive therapy with hydrocortisone. It can be observed in case of treatment inobservance and if under-dosing patient. The androgen excess upstream of the enzymatic block is responsible (after aromatization to an estrogen) of the development of secondary sexual characters. In some cases a true central precocious puberty can be constitute.

The PPP can be secondary to adrenocortical tumor, ovarian tumor or more rarely a testicular tumor most often of interstitial tissue or of Leydig cells (Holland et al., 1987; De Sousa et al., 2008; Bajpai and Menon, 2011).

The McCune Albright syndrome is a rare cause of PPPs. More common in girls, it’s diagnosed very early before 4 years. It is based on the presence of skin latte tasks, a fibrous dysplasia of bone, and sometimes an autonomous hypersecretion of endocrine glands particularly thyroid and ovarian ones (Cavanah and   Dons,1993; Haddad and Eugster, 2007).

These characteristics have been objectified in our patient, clinically the PP was dominated by metrorrhagia occurred at the age of one year which was relevant to with a large ovarian cyst. The initial endocrine exploration had not found other endocrinopathies, but the checks carried out revealed the appearance of a pre toxic thyroid nodule requiring radical treatment.

Treatment of CPP relies on suppression therapy with GnRH analogues. The study of the different factors influencing the adult size shows the importance of advanced bone age for the size and the age in the beginning of symptoms. It should however be noted that patients who have non-progressive or slowly progressive puberty have a good prognosis without treatment on the size, due to the absence of major bone age advance (Kaplowitz and Oberfield, 1999).

Aromatase inhibitors indicated in ovarian or testicular PPP lead a regression of secondary characters but give partial results on bone maturation. The specific treatment of organic causes can control endocrine disorders (Isguven et al., 2003; Kalfa et al., 2005).

Conclusion
The PP is an important condition to recognize and treat. Its frequency seems to be increasing in all countries in girls. It should be known the characterization of the etiological and evolutionarily of this pathology. The decision of treatment should be reflected in every individual case. The identification of children at risk can prevent the complications related to this disease.
 
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