Idiopathic Precocious Pubarche Research Articles

Role of Body Weight in the Onset and the Progression of Idiopathic Premature Pubarche

Background: The term premature pubarche (PP) refers to the appearance of pubic hair before age 8 in girls and before age 9 in boys. Although idiopathic PP (often associated with premature adrenarche) is considered an extreme variation from the norm, it may be an initial sign of persistent hyperandrogenism. Factors contributing to PP onset and progression have not been identified to date. Aims: The objectives of this study are to describe a group of Italian children with PP, to identify potential factors for its onset, and to define its clinical and biochemical progression. Methods: We retrospectively enrolled all infants born between 2001 and 2014 with PP. Children with advanced bone age (BA) underwent functional tests to determine the cause of PP. Hormonal analysis and BA determination were performed annually during a 4-year follow-up period. Results: A total of 334 children with PP were identified: idiopathic PP (92.5%, associated with premature adrenarche in some cases); related to precocious puberty (6.6%); late-onset 21-hydroxylase deficiency (0.9%). Low birth weight was associated with premature adrenal activation. Body mass index (BMI) was the only factor that influenced the progression of BA during follow-up. Conclusions: Low birth weight is a predisposing factor for premature adrenal activation. The increase in BMI in patients with idiopathic PP during the 4-years of follow-up was responsible for BA acceleration. We recommend prevention of excessive weight gain in children with PP and strict adherence to follow-up in order to prevent serious metabolic consequences.

P.Gln318X and p.Val281Leu as the Major Variants of CYP21A2 Gene in Children with Idiopathic Premature Pubarche.

Premature pubarche (PP) is the appearance of sexual hair in children before puberty. The PP phenotype may attribute to nonclassic congenital adrenal hyperplasia (NC-CAH). In this study, we investigated the role of CYP21A2 gene variants in patients with PP in the Iranian population. Forty patients (13 males and 27 females), clinically diagnosed with PP, were analyzed for molecular testing of CYP21A2 gene variants. Direct sequencing was performed for the samples. Also, gene dosage analysis was performed for the cases. Fourteen patients (35%) had a mutation of p.Gln318X and p.Val281Leu, out of which 10% had regulatory variants. Approximately 10% of the patients were homozygous (NC-CAH). 78.5% (11/14) of patients had trimodular RCCX of which 5 patients had two copies of CYP21A1P pseudogene. The prevalence of p.Val281Leu was higher than p.Gln318X in PP patients. In conclusion, CYP21A2 variant detection has implications in the genetic diagnosis of PP phenotype. The genetic characterization of the CYP21A2 gene is important for characterizing the variable phenotype of carriers and genetic counseling of PP and NC-CAH patients.

Basal 17-hydroxyprogesterone cannot accurately predict nonclassical congenital adrenal hyperplasia in children and adolescents.

This study explored whether using the suggested diagnostic serum basal level of 17-hydroxyprogesterone (6.0 nmol/L) would lead to underdiagnosis of nonclassical congenital adrenal hyperplasia. We retrospectively studied 123 patients with nonclassical congenital adrenal hyperplasia, defined as an adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level of more than 45 nmol/L. Of these 13 had basal 17-hydroxyprogesterone levels of less than 6.0 nmol/L and 110 exceeded that level. The 42 controls had idiopathic premature pubarche. Clinical and laboratory data were reviewed and compared. There were no differences between patients with 17-hydroxyprogesterone levels of <6.0 nmol/L or ≥6.0 nmol/L based on age at presentation, gender, anthropometric measurements, bone age advancement, age at glucocorticoid initiation and hydrocortisone dosage. Patients with basal 17-hydroxyprogesterone <6.0 nmol/L had significantly lower stimulated 17-hydroxyprogesterone levels (p = 0.02) and higher stimulated serum cortisol levels (p < 0.008). Children with nonclassical congenital adrenal hyperplasia and premature pubarche were clinically indistinguishable from controls with idiopathic premature pubarche. Androgen levels were significantly higher in the nonclassical congenital adrenal hyperplasia group. A basal 17-hydroxyprogesterone threshold of 6.0 nmol/L was not a sensitive predictive marker for diagnosing nonclassical congenital adrenal hyperplasia. Children whose clinical presentation suggests nonclassical congenital adrenal hyperplasia should undergo diagnostic adrenocorticotropic hormone stimulation testing.

Importância da prova de Synacthen no diagnóstico diferencial de pubarca precoce

IntroductionIn patients with precocious pubarche (PP), the gold standard for the differential diagnosis between idiopathic PP (IPP) and nonclassical congenital adrenal hyperplasia (NCCAH) is the ACTH stimulation test (ST); this test also estimates the adrenal cortisol reserve in NCCAH patients. ObjectivesTo compare the clinical characteristics and baseline hormonal profile of patients with PP; to determine the importance of ST in the differential diagnosis between IPP and NCCAH and in the evaluation of the adrenal production of cortisol. MethodsCross‐sectonal study of patients with PP who underwent ST. Results43 patients were included; median age at diagnosis was 7.5 years [range: 3.5‐9.4], 37 (86.0%) were female. After ST, 37 (86.0%) were classified as IPP and 6 (14.0%) as NCCAH. No significant differences could be found in the clinical characteristics and baseline determination of ACTH, cortisol and adrenal androgens between the groups. Both basal and stimulated 17‐OHP levels were significantly higher (p=0.001 and p<0.001, respectively) in NCCAH patients (basal: 4.62±3.70ng/ml [0.80‐10.50]; stimulated: 35.41±24.87ng/ml [12.0–80.2]) than IPP patients (basal: 1.04±0.77ng/ml [0.22–3.80]; stimulated: 4.18±1.71ng/ml [1.0–8.96]). Nevertheless, the proposed basal cut‐off level (<2.0ng/ml) for the distinction between the groups, did not allow for this in 2 NCCAH patients that were only diagnosed after ST. Two NCCAH patients (33.3%) had stimulated cortisol levels <18μg/dl, showing the need for glucocorticoid stress therapy. NCCAH patients with higher initial 17‐OHP value had lower cortisol after stimulation (p=0.004; r=‐0.43). ConclusionThe ST was useful to distinguish between patients with NCCAH and IPP, for no basal 17‐OHP level could allow for a definitive differential diagnosis in the individual patient. In some NCCAH cases, it also showed inappropriate cortisol secretion under stress, contributing to the therapeutic decision.

Precocious pubarche: experience in 173 cases

Precocious pubarche (PP), defined as the development of sexual pubic hair before 8 years of age in females and before 9 years in males, is usually a benign condition but it can also be the first sign of an underlying disease. To analyze the etiology and perform a short term follow up in a cohort of patients with PP. A group of 173 patients (158 females) consulted for PP with a mean age of 7.4+/-0.1 years. These patients were followed between 15 to 60 months. Anthropometric measurements, bone age, serum levels of total testosterone, 17 OH progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHEAS) were evaluated. Mean birth weight and length was 3024.1+/-50.5 g and 48.5+/-0.3 cm, respectively. Ten percent of children were small for gestational age at birth. Bone age was accelerated by 1.1+/-0.01 years. One hundred and twelve patients were classified as having idiopathic PP (64.7%; 105 females), 29 as central precocious puberty (16.8%; only females), 16 as exaggerated adrenarche (EA 9.2%; 13 females) and 16 as non classical adrenal hyperplasia (9.2%; 11 females). PP represents a common and usually benign sign. However, 26% of cases had a pathologic underlying condition. Therefore, all children with PP should be evaluated by a pediatric endocrinologist. Low birth weight was not frequent in this cohort and these patients did not show EA .

Pubarquia precoz: Experience in 173 cases

Background: Precocious pubarche (PP), defined as the development of sexual pubic hair before 8 years of age in females and before 9 years in males, is usually a benign condition but it can also be the first sign of an underlying disease. Aim: To analyze the etiology and perform a short term follow up in a cohort ofpatients with PP. Material and methods: A group of 173patients (158 females) consulted for PP with a mean age of 7.4+0.1 years. These patients were followed between 15 to 60 months. Anthropometric measurements, bone age, serum levels of total testosterone, 17 OH progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHEAS) were evaluated. Results: Mean birth weight and length was 3024.1+50.5 g and 48.5+0.3 cm, respectively. Ten percent of children were small for gestational age at birth. Bone age was accelerated by 1.1+0.01 years. One hundred and twelve patients were classified as having idiopathic PP (64.7%; 105 females), 29 as central precocious puberty (16.8%; only females), 16 as exaggerated adrenarche (EA 9.2%; 13 females) and 16 as non classical adrenal hyperplasia (9.2%; 11 females). Conclusions: PP represents a common and usually benign sign. However, 26% of cases had a pathologic underlying condition. Therefore, all children with PP should be evaluated by a pediatric endocrinologist. Low birth weight was not frequent in this cohort and these patients did not show EA .

Influencia del peso al nacer sobre el inicio y progresión de la pubertad y la talla final en la pubarquia precoz

Girls born small for gestational age (SGA), with a birth weight < 1.5 SDS, are at increased risk of early onset and rapid progression of puberty, with reduced final height. In contrast, idiopathic precocious pubarche (PP) does not seem have negative effects on the onset of puberty or final height. We evaluated the relationship between birthweight, the onset and progression of puberty and final height in girls with PP. We performed a retrospective study of girls at the onset of puberty with a history of PP (pubic hair before the age of 8 years). A total of 124 girls (37 SGA) were investigated; 61 had presented menarche and 44 had reached final height. The mean ( SD) age was 6.8 0.8 years at pubarche, 9.5 0.9 at the onset of puberty and 11.7 6 0.9 at menarche. No significant differences were found in the correlation between birth weight expressed in SDS and age at presentation of pubarche, bone age at presentation of pubarche, age at telarche or age at menarche. A positive correlation was found between birthweight and height at pubarche, telarche, and menarche and final height. These data suggest that pubertal progression is faster in SGA girls. All patients reached the familial target height but only those with an appropriate birthweight were taller than their mothers. PP does not seem to modify age of onset or progression of puberty or final height in girls with adequate birth weight. In contrast, in SGA girls, PP is associated with faster puberal development and shorter final height. Therefore, SGA girls with PP require periodic monitoring.

Long-term consequences of childhood-onset congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a general term applied to several diseases caused by inherited defects of cortisol synthesis. The most common of these is steroid 21-mono-oxygenase (also termed 21-hydroxylase) deficiency (CAH-21OHD), found in approximately 1:10 000-1:15 000 live births. Potentially lethal adrenal insufficiency is characteristic of about two-thirds to three-quarters of patients with the classic salt-wasting form of CAH-21OHD. Non-salt-wasting forms of CAH-21OHD may be diagnosed based in part on genital ambiguity in affected newborn females, and/or by later evidence of androgen excess in members of either sex. Non-classical CAH-21OHD may be detected in up to 1-3% of certain populations, and is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women. This chapter addresses issues relating to long-term consequences in adult life of CAH-21OHD diagnosed in early childhood or adolescence.

Congenital adrenal hyperplasia: transition from chil dhood to adulthood.

Congenital adrenal hyperplasia (CAH) is a group of disorders caused by inborn errors of steroid metabolism. The most common form owing to 21-hydroxylase deficiency (CAH-21OHD) is present in about 1:10,000- 1:15,000 live births worldwide. In its classic salt-wasting form (-66-75% of cases) patients may suffer potentially lethal adrenal insufficiency. Non-salt-wasting forms of CAH-21 OHD are recognized by genital ambiguity in affected females, and by signs of androgen excess in later childhood in males. Non-classic CAH-21 OHD may be detected in up to 1-3% of certain populations, and is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women. This chapter will address issues relating to transition of CAH care from the pediatric to the adult endocrinologist.

CONGENITAL ADRENAL HYPERPLASIA OWING TO 21-HYDROXYLASE DEFICIENCY

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is the most common cause of genital ambiguity in the newborn and is present in about 1 in 15,000 live births worldwide. The disease is further characterized in its classic salt-wasting form (approximately 75% of cases) by potentially lethal adrenal insufficiency. A non-salt-wasting form of classic CAH with 21-hydroxylase deficiency is also recognized by genital ambiguity in affected females and by signs of androgen excess in later childhood in males. Nonclassic CAH with 21-hydroxylase deficiency may be detected in 1% to 3% of populations and is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women. This article presents an overview of clinical and genetic aspects of the various forms of CAH with 21-hydroxylase deficiency.

Gas chromatography-mass spectrometry determination of plasma 5 alpha-androstane-3 alpha,17 beta-diol and 5 alpha-androstane-3 alpha,17 beta-diol glucuronide in children with premature and normal puberty

Using stable isotope dilution/gas chromatography-mass spectrometry, we determined the plasma concentrations of 5 alpha-androstane-3 alpha,17 beta-diol (AD) and 5 alpha-androstane-3 alpha,17 beta-diol-glucuronide (ADG) in 20 patients with premature pubarche (16 patients with idiopathic premature pubarche, 4 patients with late onset 21-hydroxylase deficiency) and in 55 healthy children with Tanner stages P1 to P4. No differences between sexes were found in healthy children with Tanner stages P1 and P2. Patients with idiopathic premature pubarche (median, range, nmol/1: 0.22; 0.12-0.31) or late onset 21-hydroxylase deficiency (0.27; 0.23-0.29) had higher plasma AD concentrations than healthy prepubertal children (0.09; 0.00-0.17). Regarding ADG, patients with idiopathic precocious puberty (1.35; 0.25-4.74) or late onset 21-hydroxylase deficiency (4.01; 3.50-4.58) had also higher plasma concentrations than healthy prepubertal children (0.35; 0.00-0.75). Thus, AD and ADG, which both represent end metabolites of peripheral androgen metabolism, can be regarded as markers of androgenicity. Steroid analysis by mass spectrometry is recommended, whenever uncertainties of immunological determinations are to be avoided.

PRECOCIOUS PUBARCHE: DIFFERENTIAL DIAGNOSIS

59 patients (49 females and 10 males; aged 7 months - 9 years) were studied in the last 13 years for precocious isolated pubarche. We evaluated clinical signs, bone age (B.A.), hormonal findings (ACTH-test, LHRH-test), ultrasound examination of adrenal and gonads. We devided ipatients in four groups:A) 81.3% Idiopathic precocious pubarche (HPP): with normal steroids plasma levels, high DHEAs plasma levels (47.3%), advanced B.A. (29%), advanced statural age (S.A.)(22.9%), normal pelvic ultrasonography.B) 10.1% Late Onset CAH (LOCAH): elevated basal and after ACTH stimulus 17 OH Progesteron plasma levels in all patients, advanced B.A. (83%), advanced S.A. (50%), normal pelvic ultrasonography.C) 6.9% Central Precocious Puberty (CPP): elevated LH plasma levels, advanced B.A. and advanced S.A. in 100%. In all patients large size of gonads were found with pelvic ultrasonography.D) 1 female (1.7%) had adrenal adenomas demonstred by hormonal data and adrenal ultrasound and tomography.In conclusion: HPP is the most frequent cause of premature pubarche, a differential ethiological diagnosis can be easily performed by hormonal and ultrasound investigations.

Adrenal steroidogenic defects in children with precocious pubarche.

The occurrence of nonclassical congenital adrenal hyperplasia among children with precocious pubarche is still a matter of debate. We studied the adrenal steroid response to ACTH stimulus (Synacthen, 0.25 mg i.v. bolus) in 26 Italian children (5 boys, 21 girls) who had presented pubic hair, without other signs of virilization, at ages ranging between 0.45 and 8.8 years. The control groups comprised 8 prepubertal children (5 boys, 3 girls) and 12 children at Tanner stage 2 for pubic hair development (1 boy, 11 girls). Two patients were diagnosed as having nonclassical congenital adrenal hyperplasia: 1 due to 21-hydroxylase deficiency, the other due to 3 beta-hydroxysteroid-dehydrogenase deficiency. The remainder, classified as having idiopathic precocious pubarche (PP), had adrenal androgens higher than normal prepubertal children and similar levels to those observed in early pubertal controls. In contrast to a recent report, we confirmed that mild adrenal enzymatic defects can occur in PP, and, consequently, the use of ACTH testing in children with PP seems to be recommended.

Identification of nonclassical 21-hydroxylase deficiency in girls with precocious pubarche.

Recent studies have described mild adrenal enzymatic defects in patients presenting with precocious pubarche. In order to identify these defects we have evaluated basal and ACTH- (25 IU iv) stimulated serum adrenal steroid levels in 19 girls, 2- to 8.3-year-old, with precocius pubarche (pubic hair Tanner II-III). Two patients had clitorial enlargement. Bone age was moderatly advanced in 10 patients and 2 to 3.7 yr in four others. Four patients had high basal serum levels of 17-hydroxyprogesterone (17OHP) (525 + 202 ng/dl, mean +SD), compatible with the diagnosis of nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH-21OH), which was confirmed by an increased response of 17OHP to ACTH (3425 +/- 953 ng/dl). Fifteen patients had moderately elevated basal 17OHP levels (56 + 38 ng/dl) but a normal 170HP response (191 +/- 71 ng/dl) to ACTH, compatible with the diagnosis of idiopathic precocious pubarche (IPP). The cortisol response to ACTH was normal in both groups. Basal values of DHEA-S were 651 +/- 256 and 506 + 462 ng/ml and of DHEA 380 +/- 24 ng/dl and 205 +/- 102 ng/dl, in NCCAH-210H and IPP, respectively. We conclude that: i) clinical findings and baseline levels of DHEA-S and DHEA in IPP can be indistinguishable from the late onset 21 hydroxylase deficiency; ii) baseline levels of 17OHP are sufficient for the diagnosis of NCCAH-21OH; iii) the ACTH stimulation test is indicated only when baseline levels of 17OHP are moderately elevated (100-300 ng/dl).

Adrenarche as a cause of benign pseudopuberty in boys

We found elevations of plasma dehydroepiandrosterone-sulfate (DHAS) in five boys, 5.5 to 10.3 years of age (group A), with premature pubarche (pubic hair development) or acne as an isolated phenomenon. Four boys (group B) with seemingly idiopathic premature pubarche (DHAS normal for age) were discovered to have above-average dehydroepiandrosterone levels. All of these boys with premature pubarche had some evidence of cerebral dysfunction or were obese. Plasma testosterone values and bone age were not markedly increased in either group. In each case studied, the patterns of plasma steroid intermediates before and after administration of adenocorticotropin were typical of adrenarche rather than of congenital adrenal hyperplasia or Cushing syndrome. In addition, DHAS was dexamethasone suppressible, and in those patients in whom nocturnal testosterone sampling or gonadotropin-releasing hormone testing was performed, no evidence of true puberty could be found. Fifteen percent of our normal male volunteers over 10 years of age developed pubarche with plasma DHAS levels over 120 micrograms/dl without evidence of true puberty. Thus pubarche as an isolated phenomenon does not necessarily indicate a virilizing disorder or true puberty. In the majority of cases, isolated pubarche appears to be the result of isolated adrenarche, the maturational increase in adrenal production of 17-ketosteroids.