Central Precocious Puberty Girls Research Articles

Peak serum luteinising hormone cut-off during gonadotropin-releasing hormone analogue test for diagnosing central precocious puberty was lower in girls with obesity as compared with girls with normal weight.

Serum luteinising hormone (LH) concentration has been reported to be lower in girls with overweight and obesity (OW/OB) as compared with girls with normal weight (NW). This study aimed to evaluate peak serum LH concentration during gonadotropin-releasing hormone analogue (GnRHa) test in girls with OW/OB and NW who had central precocious puberty (CPP) and to determine peak serum LH cut-off for diagnosing CPP in girls with OW/OB. Medical records of 971 girls with premature breast development who underwent subcutaneous GnRHa (100 µgof triptorelin acetate) test were reviewed. All girls were classified as either CPP or premature thelarche. All of them were further classified into two groups according to their body mass index as NW and OW/OB groups for each Tanner stage. There were 634 and 337 girls in NW and OW/OB groups, respectively. CPP was diagnosed in 600 girls (249 had Tanner stage II and 351 had Tanner stage III). There were no differences in peak serum LH concentrations between CPP girls with NW and OW/OB. Peak serum LH cut-off of 5 IU/L (the current widely used cut-off) had a sensitivity and a specificity of 75% and 90%, respectively in NW group. Peak serum LH cut-off for CPP diagnosis was lower at 4 IU/L in the OW/OB group with greater sensitivity and specificity of 86% and 93%, respectively. The results were reproducible for each Tanner stage of breasts. Lower peak serum LH cut-off to 4 IU/L for diagnosing CPP in girls with OW/OB should be considered to avoid underdiagnosis of the condition.

MKRN3 circulating levels in girls with central precocious puberty caused by MKRN3 gene mutations.

MKNR3 is a paternally expressed gene whose mutations are the main cause of central precocious puberty (CPP). Protein circulating levels can be easily measured, as demonstrated in idiopathic CPP and healthy controls. No data are available for patients harboring an MKRN3 mutation. Our aim was to perform MKRN3 mutation screening and to investigate if circulating protein levels could be a screening tool to identify MKRN3 mutation in CPP patients. We enrolled 140 CPP girls and performed MKRN3 mutation analysis. Patients were stratified into two groups: idiopathic CPP (iCPP) and MKRN3 mutation-related CPP (MKRN3-CPP). Clinical characteristics were collected. Serum MKRN3 values were measured by a commercially available ELISA assay kit in MKRN3-CPP and a subgroup of 15 iCPP patients. We identified 5 patients with MKRN3 mutations: one was a novel mutation (p.Gln352Arg) while the others were previously reported (p.Arg328Cys, p.Arg345Cys, p.Pro160Cysfs*14, p.Cys410Ter). There was a significant difference in circulating MKRN3 values in MKRN3-CPP compared to iCPP (p < 0.001). In MKRN3-CPP, the subject harboring Pro160Cysfs*14 presented undetectable levels. Subjects carrying the missense mutations p.Arg328Cys and p.Gln352Arg showed divergent circulating protein levels, respectively 40.56pg/mL and undetectable. The patient with the non-sense mutation reported low but measurable MKRN3 levels (12.72pg/mL). MKRN3 defect in patients with CPP cannot be predicted by MKRN3 circulating levels, although those patients presented lower protein levels than iCPP. Due to the great inter-individual variability of the assay and the lack of reference values, no precise cut-off can be identified to suspect MKRN3 defect.

Combined training in addition to cortisol reduction can improve the mental health of girls with precocious puberty and obesity.

Obesity and central precocious puberty (CPP) are associated with increased anxiety, depression, and anger in girls. The contribution of exercise as an efficacious component in decreasing anxiety, depression, and anger has been increasingly recognized. This study aims to evaluate the effects of combined training on cortisol, anxiety, depression, and anger in overweight and obese girls with CPP. The study involved 30 girls aged 7-9 years diagnosed with CPP (undergoing triptorelin treatment) and dealing with obesity. In addition, these girls scored higher than the cut-off line for anxiety, depression, and anger. The participants were divided into two groups, with 15 individuals in each group. The exercise group engaged in 60 min of combined aerobic and resistance training three times per week for a duration of 12 weeks. On the other hand, the control group did not receive any training. Throughout the study, the serum cortisol levels were measured in both groups. Anxiety, anger, and depression questionnaires were also completed at three different stages, namely, baseline, 12 weeks, and 16 weeks (after a 4-week period of detraining). In the exercise group, there was a significant decrease (P < 0.05) in cortisol serum levels and anxiety, depression, and anger scores. These changes were observed consistently during detraining (P > 0.05). However, in the control group, only the depression score significantly decreased (P < 0.05). Based on the results, it can be concluded that combined training is a method to improve the mental health of CPP girls. https://en.irct.ir/trial/61990, identifier IRCT20170411033378N10.

THU192 Prevalence Of Brain Abnormalities In Children With Central Precocious Puberty

Abstract Disclosure: A.A. Bastos: None. A.P. Machado Canton: None. L.B. Macena: None. L.F. Pedrosa: None. B.B. Mendonca: None. V.N. Brito: None. A. Latronico: None. Introduction: Brain magnetic resonance imaging (MRI) is the main tool used to investigate the etiology of central precocious puberty (CPP) in children. A systematic review study showed an overall prevalence of 9% of brain lesions in girls with CPP. Aim: To assess the frequency brain lesions in children with CPP. Patients and Methods: In this retrospective study, we recruited data of 163 brain MRI of children with CPP (140 girls,86%; and 23 boys, 14%) followed in a pediatric endocrinology unit from 1990 to 2022. Brain lesions were classified as congenital or acquired, and causative of CPP or incidental. Results: In girls, normal brain MRI was found in 82/140 (59%). Abnormal brain MRI was identified in the remaining 58 girls (41%), with 26 presenting congenital lesions causative of CPP (11 hypothalamic hamartoma, 7 hydrocephalus, 3 optic pathway gliomas, 2 corpus callosum agenesia, 1 pinealoma, 1 tuberous sclerosis, 1 choroid plexus papilloma), and 32 with incidental findings (microadenomas, pituitary stalk deviation, pituitary hyperplasia, rathke cleft cyst, hippocampal alterations). The overall frequency of incidental findings was 20.8%. In addition, the frequency of brain MRI pathological abnormalities in girls older than 6 years without neuro ophthalmological symptoms was 12%(n=7). In boys, normal brain MRI was found in 6/23 (26%). Abnormal brain MRI was identified in the remaining 17 boys, with 14 presenting congenital lesions causative of CPP (9 hypothalamic hamartoma, 4 hydrocephalus, 1 pineal teratoma) and 1 with acquired lesions (1 pilocytic astrocytoma). Incidental findings were detected in only 2 brain MRI (1 pineal cyst and 1 microadenoma). Incidentalomes were more frequent in girls and lesions that can be associated with CPP were more common in boys. Conclusion: The frequency of pathological brain lesions was higher in CPP boys. Hypothalamic hamartoma was the most frequent congenital lesion identified in both sexes. Based on the frequency of pathological brain alterations in girls older than 6 years we recommend to perform brain MRI in all CPP girls. Presentation: Thursday, June 15, 2023

Clinical significance of serum MBD3 detection in girls with central precocious puberty.

Diagnosis of central precocious puberty (CPP) in girls remains a huge challenge. The current study was to measure the serum expression of methyl-DNA bind protein 3 (MBD3) in CPP girls and assess its diagnostic efficacy. To begin with, we enrolled 109 CPP girls and 74 healthy pre-puberty girls. Then, MBD3 expression in their serum samples was measured via reverse transcription-quantitative polymerase chain reaction, and its diagnostic efficacy on CPP was assessed via the receiver operating characteristic (ROC) curve, followed by correlation analysis between serum MBD3 and patient age, gender, bone age, weight, height, body mass index, basal luteinizing hormone (LH), peak LH, basal follicle-stimulating hormone (FSH), peak FSH, and ovarian size using bivariate correlations method. Finally, independent predictors of MBD3 expression were confirmed using multivariate linear regression analysis. MBD3 was highly expressed in sera of CPP patients. The area under the ROC curve of MBD3 diagnosing CCP was 0.9309, with 1.475 cut-off value (92.66% sensitivity and 86.49% specificity). MBD3 expression positively correlated with basal LH, peak LH, basal FSH, and ovarian size, among which basal LH was considered the strongest independent predictor of MBD3, followed by basal FSH and peak LH. In summary, serum MBD3 could act as a biomarker in aiding CPP diagnosis.

Association of size for gestational age and dehydroepiandrosterone sulfate with cardiometabolic risk in central precocious puberty girls.

The aim of this study was to assess whether size for gestational age and dehydroepiandrosterone sulfate (DHEAS) are associated with cardiometabolic risk in central precocious puberty (CPP) girls. The retrospective study included 443 patients with newly diagnosed CPP. Subjects were categorized by birth weight for gestational age (appropriate [AGA], small [SGA], and large [LGA] for gestational age) and serum DHEAS concentration (high [≥75th percentile] and normal [<75th percentile] DHEAS). Cardiometabolic parameters were examined. Composite cardiometabolic risk (CMR) score was calculated based on BMI, blood pressure, glucose, insulin, triglyceride, and HDL cholesterol. Non-obesity CMR score was computed, omitting the value from BMI. Logistic regression models, general linear models, and partial correlation analyses were used to evaluate associations. Propensity score matching was performed for sensitivity analyses. Overall, 309 patients (69.8%) were born AGA, 80 (18.1%) were born SGA, and 54 (12.2%) were born LGA. Compared with AGA counterparts, CPP girls born SGA were more prone to have elevated HbA1c (adjusted OR = 4.54; 95% CI, 1.43-14.42) and low HDL cholesterol (adjusted OR = 2.33; 95% CI, 1.18-4.61). In contrast, being born LGA was not associated with increased risk for any glucose or lipid derangements. Despite the fact that elevated CMR score was more common among individuals born LGA than AGA (adjusted OR = 1.84; 95% CI, 1.07-4.35), no significant difference was found on non-obesity CMR score (adjusted OR = 0.75; 95% CI, 0.30-1.88). When controlling for age, birth weight SDS, and current BMI-SDS, individuals with high DHEAS exhibited higher HDL cholesterol and apolipoprotein A-1 concentrations and lower triglyceride level and non-obesity CMR score. Furthermore, DHEAS correlated positively with HDL cholesterol and apolipoprotein A-1 and negatively with triglyceride, prominently in girls born SGA, after adjustments for the three abovementioned confounders. Sensitivity analyses corroborated the findings. Among CPP girls, those born SGA were more likely to possess cardiometabolic risk factors compared to their AGA peers. The difference we observed in cardiometabolic risk between individuals born LGA and AGA was driven by BMI. High DHEAS was associated with favorable lipid profile in CPP girls, even in subjects born SGA.

Analysis of the efficacy of Dabuyin pill combined with gonadotropin-releasing hormone analogue in the treatment of central precocious puberty girls based on network pharmacology.

Traditional Chinese medicine (TCM) believes that central precocious puberty (CPP) is affected by the imbalance of kidney Yin and Yang. Dabuyin pill is a recipe for nourishing Yin and lowering fire. The network pharmacology method was used to analyze the active components, action targets, and molecular pathways of Dabuyin pill in the treatment of CPP. The main chemical components of Dabuyin pill were obtained from the Integrative database of Traditional Chinese Medicine enhanced by Symptom Mapping (SymMap) database and Traditional Chinese Medicine Systems Pharmacology (TCMSP), and compound targets were retrieved from SymMap and the Encyclopedia of Traditional Chinese Medicine (ETCM). Disease targets were retrieved from the DisGeNET and Gene Expression Omnibus (GEO) databases, and the intersection of compound targets and disease targets was performed to obtain the prediction targets of Dabuyin pill acting on CPP. The key targets enriched by Database for Annotation, Visualization, and Integrated Discovery (DAVID) were then used for Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. GO analysis showed that the biological functions of Dabuyin pill in the treatment of key targets of CPP mainly involved apoptosis, nitric oxide synthesis, estradiol response, angiogenesis, inflammation, and so on. KEGG pathway analysis was mainly enriched in the tumor necrosis factor (TNF) signaling pathway, phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling pathway, hypoxia-inducible factor-1 (HIF-1) signaling pathway, and apoptosis. Among them, the regulation effect of Dabuyin pill prescription on apoptosis may both act on TP53 and different signaling pathways of apoptosis, thus playing a synergistic role. Dabuyin pill combined with GnRHa for the prevention and treatment of CPP in girls can effectively intervene CPP, and the effect of Dabuyin pill on sex hormones is one of its protective mechanisms against CPP.

Effect of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty.

We examined the effects of aerobic exercise and detraining on adiponectin, resistin, tumor necrosis factor alpha (TNF-α), white blood cell, and pubertal signs (uterine length, ovarian volume, luteinizing hormone [LH], and follicle-stimulating hormone [FSH]) in girls with central precocious puberty (CPP). Thirty girls with CPP (7-9 yr old) were randomly divided into CPP and CPP + Exercise (EX) groups. Fifteen healthy age-matched girls without precocious puberty participated for comparison with CPP. Subjects in the CPP + EX group attended 12 wk of aerobic exercise protocol three sessions a week. In the baseline, after completing the exercise protocol and after 4 wk of detraining, all the parameters were measured. In the CPP and healthy groups, all the parameters were measured in all three stages. To measure adiponectin, resistin, and TNF-α, the ELISA method was used. LH and FSH were measured by electrochemiluminescence immunoassay. White blood cell counts were analyzed by an automated blood cell counter. Repeated-measures ANOVA was used to analyze the results. CPP girls have lower adiponectin ( P = 0.01) and higher TNF-α levels ( P = 0.001) than healthy girls. In the CPP + EX group, after 12 wk, body weight and fat mass decreased, and adiponectin increased significantly ( P = 0.02). Resistin ( P = 0.02), TNF-α ( P = 0.02), neutrophils ( P = 0.01), and signs of puberty significantly ( P < 0.05) decreased. After detraining, no significant change was observed except TNF-α, which increased significantly ( P = 0.03). In the CPP group, no significant change was observed in any of the parameters; only LH ( P = 0.0001) and uterine length and ovarian volume ( P = 0.003, P = 0.001) decreased after 12 and 16 wk, respectively. Aerobic exercise can have a positive effect on the state of inflammation and pubertal signs. Positive effects remain after 4 wk of detraining.

Development and validation of a model for predicting the adult height of girls with idiopathic central precocious puberty.

A model for predicting the AH of girls with ICPP was developed incorporating the variables of height SDS, height SDS for bone age, and target height. The internal and external validation ensures an appropriate degree of discrimination and calibration of the prediction model. •Uncertainty prevails as how to predict the adult height of patients with central precocious puberty following gonadotropin-releasing hormone analog treatment. • Previous models for predicting adult height of girls with idiopathic central precocious puberty have not been proven translational to the Chinese population. •This study develops a new model for predicting the adult height of idiopathic central precocious puberty girls who underwent gonadotropin-releasing hormone analog treatment. • The internal and external validation assures a good degree of discrimination and calibration of the prediction model in this study.

Serum irisin levels increase in girls with central precocious puberty not dependent on BMI: a pilot study.

ObjectiveThe objective of this study is to investigate the role of serum irisin level in diagnosis of central precocious puberty (CPP) in girls and its major determinants.MethodsThis study was conducted in 67 girls with CPP, 19 girls with premature thelarche (PT) and 59 normal controls. The major determinants of irisin were assessed by multivariate linear regression (MLR) analysis. Propensity score matching (PSM) analysis was performed to minimize the bias that can result from BMI. A receiver operating characteristic curve was used to obtain the optimal threshold value of irisin.ResultsThe girls with CPP and PT had higher irisin levels than controls (P < 0.05). The optimal cutoff value of irisin levels for predicting CPP was 91.88 ng/mL, with a sensitivity of 70.1% and a specificity of 72.9%. MLR analysis showed that BMI was a predictor of irisin (P < 0.05). Serum irisin levels remained higher in the CPP girls than the controls with adjustment for BMI (P < 0.05).ConclusionsIncreased serum irisin levels with CPP suggest that irisin is involved in puberty. However, due to low sensitivity and specificity, irisin level can only be used as an auxiliary indicator rather than a single diagnostic indicator of CPP.

The Assessment of Brain Volume Differences in Idiopathic Central Precocious Puberty Girls; Comparison of Age-Matched Girls and Normal Puberty Girls.

Objective: Although there have been several studies on the neuroanatomical changes in idiopathic central precocious puberty (ICPP), the association between each brain region and ICPP has not yet been clearly elucidated. This study aimed to evaluate the difference in brain structure in ICPP compared with age-matched healthy controls and normal puberty controls, and additionally the correlation between brain volume difference and the luteinizing hormone (LH). Materials and Methods: The study enrolled fifteen girls with ICPP, as well as 15 age-matched healthy girls and 15 normal puberty girls as controls. The subjects underwent a 1.5 Tesla Avanto MR Scanner. Anatomical T1-weighted images were acquired with a T1 spin-echo sequence. The volumes of total and regional brain were compared with each of the two control groups and analyzed through the paired T-test, and the brain region related to the peak LH level was also analyzed through a simple correlation test. Results: The mean age of the ICPP group, age-matched group, and puberty group were 8.0 ± 0.9 years, 7.8 ± 0.9 years, and 11.9 ± 0.9 years, respectively. In our findings, the regional cerebral volumes in ICPP were different from age-matched controls. Compared with controls, ICPP showed a significant increase in gray matter (GM) volumes (the medial prefrontal cortex, superior parietal gyrus, supramarginal gyrus, angular gyrus, postcentral gyrus, superior occipital gyrus, cuneus, hippocampus, parahippocampal gyrus, posterior cingulate gyrus (PCgG), cerebellar cortex (Cb)) and in white matter (WM) volumes (the insular, caudate, splenium of corpus callosum (p < 0.001)). Especially, the GM volumes of the PCgG (r = 0.57, p = 0.03) and Cb (r = 0.53, p = 0.04) were correlated positively with LH concentrations stimulated by the gonadotropin-releasing hormone agonist. Compared to the normal puberty control, no significant difference in GM volume was found. Conclusions: This study showed the overall brain volumetric differences between ICPP girls and age-matched controls using voxel-based morphometric analysis, and further showed the correlation between brain volume and the sex hormone in ICPP. Through a comparison between the two groups, the cerebral development pattern of ICPP is similar to that of normal puberty, and these local differences in cerebral volume may affect social and congenital changes. These findings will be useful for understanding the neuroanatomical mechanisms on the specific morphological variations associated with ICPP.

Short-term effects of gonadotropin-releasing hormone analogue treatment on leptin, ghrelin and peptide YY in girls with central precocious puberty.

To determine appetite-regulating hormone levels in girls with central precocious puberty (CPP) before and after 20weeks of gonadotropin-releasing hormone analogue (GnRH-A) treatment. Eighteen newly diagnosed CPP girls were enrolled. Body composition measured by bioelectrical impedance analysis and GnRH-A test were performed with fasting serum leptin, ghrelin and peptide YY (PYY) measurements at baseline (before) and after 20 weeks of GnRH-A treatment. Following GnRH-A treatment, all patients had prepubertal gonadotropin and estradiol levels. Mean (SD) fat mass index (FMI) was significantly increased from 4.5 (1.7) to 5.0 (1.8) kg/m2 after treatment. Also, median (IQR) serum leptin level was significantly increased from 6.9 (4.2-8.6) to 7.4 (5.3-13.1) ng/mL. FMI had a positive correlation with serum leptin level (r=0.64, p=0.004). In contrast, no significant changes of serum ghrelin and PYY levels were observed. Decreased estrogen following short-term GnRH-A treatment in CPP girls may cause an increase in appetite and consequently an elevation of FMI. Increased serum leptin may be a result of having increased FMI secondary to an increase in appetite.

Sedentary lifestyle and precocious puberty in girls during the COVID-19 pandemic: an Italian experience.

ObjectiveThis retrospective study aimed to evaluate children observed for suspected precocious puberty in five Italian centers of Pediatric Endocrinology during the first wave of coronavirus disease 2019 pandemic (March–September 2020), compared to subjects observed in the same period of the previous year.DesignThe study population (490 children) was divided according to the year of observation and final diagnosis: transient thelarche, non-progressive precocious puberty, central precocious puberty (CPP), or early puberty.ResultsBetween March and September 2020, 338 subjects were referred for suspected precocious puberty, compared to 152 subjects in the same period of 2019 (+122%). The increase was observed in girls (328 subjects in 2020 vs 140 in 2019, P < 0.05), especially during the second half of the period considered (92 girls from March to May vs 236 girls from June to September); while no difference was observed in boys (10 subjects in 2020 vs 12 in 2019). The percentage of girls with confirmed CPP was higher in 2020, compared to 2019 (135/328 girls (41%) vs 37/140 (26%), P < 0.01). Anthropometric and hormonal parameters in 2019 and 2020 CPP girls were not different; 2020 CPP girls showed more prolonged use of electronic devices and a more sedentary lifestyle both before and during the pandemic, compared to the rest of the 2020 population.ConclusionsThe present findings corroborate the recently reported association between the complex lifestyle changes related to the lockdown and a higher incidence of CPP in Italian girls.

Serum Kisspeptin and AMH Levels Are Good References for Precocious Puberty Progression.

Aim The aim of this study was to evaluate the levels of kisspeptin and AMH in children with PT or CPP or controls to provide a reference for diagnosis and prognosis. Methods 38 Chinese children with central precocious puberty (CPP), 38 Chinese children with premature thelarche (PT), and 75 controls were recruited. Results In CPP girls, AMH levels decreased significantly compared to control girls at T2 stage. Compared with the PT and control groups, AMH is the lowest in girls in the CPP group at T3 stage. Kisspeptin decreased significantly in girls in the PT group and increased significantly in girls in the control group from T2 stage to T3 stage. At T3 stage, kisspeptin was significantly higher in girls in the CPP and control groups than in the PT group. In the control group, kisspeptin was significantly higher in boys than in girls at T2 stage. AMH and height were negatively correlated in the girls group. Conclusions Kisspeptin and AMH have a unique significance in the auxiliary diagnosis, the differential diagnosis, the treatment, and prognosis of sexual puberty disorder.

Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty.

Makorin ring finger protein 3 (MKRN3) is associated with the initiation of puberty, and loss of function mutation of MKRN3 is the most common genetic cause of central precocious puberty (CPP). A recent study reported that MKRN3 interacts with and suppresses neural pentraxin-1 precursor (NPTX1) activity via polyubiquitination during early puberty in the mouse hypothalamus. This study investigated the correlation between serum NPTX1 and MKRN3 in CPP girls and predicted the potential role of NPTX1 in pubertal progression. In this case-control study, we examined 34 girls diagnosed with CPP and 34 healthy prepubertal girls. Anthropometric and hormonal parameters were measured and serum levels of NPTX1 and MKRN3 were evaluated with commercial enzyme-linked immunosorbent assay kits. Serum MKRN3 level decreased significantly in CPPpatients compared to controls (344.48±333.77 and 1295.21±780.80pg/mL, respectively, p<0.001). Serum MKRN3 tended to decrease as Tanner breast stage increased. However, no significant difference was observed in serum NPTX1 levels between patients and controls (20.14±31.75ng/mL and 12.93±8.28ng/mL, respectively, p=0.248). The serum level of NPTX1 did not change significantly with the Tanner breast stage. Serum NPTX1 was correlated with the height standard deviation score (r=0.255; p<0.05), but was not correlated with serum MKRN3 level or the others. Conclusion: Although serum NPTX1 level was independent of serum MKRN3 level, the possibility they might be involvedin the progression of puberty or CPP remains. Further research is needed to determine their role in the hypothalamus.

Relationship between growth velocity and change of levels of insulin-like growth factor-1, insulin-like growth factor binding protein-3 and, IGFBP-3 promoter polymorphism during GnRH agonist treatment.

Purpose This study aims to investigate the effect of gonadotropin-releasing hormone agonist (GnRHa) on the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis and to evaluate whether -202 A/C IGF binding protein-3 (IGFBP-3) promoter polymorphism affects growth velocity in females with central precocious puberty (CPP) during treatment.Methods Data was collected from 97 females younger than 9 years, diagnosed with precocious puberty and treated with GnRHa for at least 1 year at Kangdong Sacred Heart Hospital from 2014 to 2015. Their body height, weight, change in height standard deviation score (∆SDS), serum IGF-1, serum IGFBP-3, bone age, and -202 A/C IGFBP-3 promoter polymorphism were measured before and after GnRHa treatment. The interrelationships between the variables were calculated.Results During treatment, height SDS, IGF-1 SDS, IGFBP-3 SDS, and IGF-1/IGFBP-3 ratio significantly decreased. A significant correlation was observed between ∆IGF-1 SDS and ∆height SDS (r=0.405, P<0.001). The presence of the C allele was significantly correlated with IGF-1 SDS after treatment (P=0.049) and with IGFBP-3 SDS before and after treatment (P=0.012 and P=0.001), but not with ∆IGF-1 SDS, ∆IGFBP-3 SDS, ∆IGF-1/IGFBP-3 ratio, or ∆height SDS.Conclusions Growth velocity during GnRHa treatment is related to ∆IGF-1 SDS, indicating the apparent impact of GnRHa on the GH-IGF-1 axis. The -202 A/C IGFBP-3 promoter polymorphism does not affect the growth velocity of GnRHa in CPP girls.

Association study of DLK1 in girls with idiopathic central precocious puberty.

Objective Mutations in the delta-like 1 homolog (DLK1) gene have recently been reported in patients with idiopathic central precocious puberty (CPP). We aimed to investigate DLK1 mutations or polymorphisms in girls with CPP. Methods A total of 100 girls diagnosed with idiopathic CPP were enrolled. DLK1 coding regions were sequenced in girls with idiopathic CPP and healthy girls (controls). The relationship between identified sequence variations and CPP was evaluated via comparison of allele frequencies between patients with CPP and normal healthy controls. Results We identified five polymorphisms in DLK1. There was no significant difference with regard to allele frequency between patients with CPP and controls. Polymorphism c.549C>T (p.G183G) in DLK1 gene was identified in only one patient with CPP. In silico analysis with human splicing finder suggested that the variant (c.549C>T) leads to splicing defect. Conclusions The sequencing of DLK1 gene has uncovered only one potentially meaningful variant. However, our results demonstrate that DLK1 mutations are a relatively rare cause of idiopathic CPP.

Prevalence of idiopathic scoliosis in girls with central precocious puberty: effect of a gonadotropin-releasing hormone agonist.

PurposeAdolescent idiopathic scoliosis (AIS) is the most common form of scoliosis and occurs in children between 10 to 18 years old, during periods of growth spurts and puberty changes. In patients with central precocious puberty (CPP), due to early growth spurt, AIS is expected to develop before 10 years of age. Both AIS and CPP are more common in girls than in boys. The aim of this study was to determine the prevalence of AIS in girls with CPP and to evaluate the effect of treatment with gonadotropin-releasing hormone (GnRH) agonists on progression of scoliosis in these patients.MethodsWe retrospectively reviewed medical records of 553 girls, 338 with CPP and 215 without CPP. Scoliosis angle was measured on the standing frontal radiograph of each patient according to the Cobb method. Patients with a Cobb angle of 10° or more were diagnosed with scoliosis. For girls with CPP, follow-up spine radiographs were collected 1 year after treatment with GnRH agonists. Progression of scoliosis before and after treatment was compared in terms of Cobb angle changes.ResultsAIS was more prevalent in girls that were affected by CPP compared tocontrols without CPP (11.5% vs. 6.0%, CPP girls vs. non-CPP girls, respectively, P=0.031). The peak serum luteinizing hormone level positively correlated with Cobb angle (R2=0.015, P=0.023) in the CPP group. No progression of scoliosis was observed in CPP girls after one year of GnRH agonist treatment. Additionally, the prevalence of scoliosis decreased in CPP girls after 1 year of the treatment.ConclusionsWe report that the prevalence of AIS is higher in girls with CPP than in non-CPP patients. A regular follow-up schedule for spine radiographs should be considered to reduce the risk of progression. Furthermore, GnRH agonist treatment for CPP may have a suppressive effect on progression of AIS.

SUN-LB18 Serum 25-Hydroxyvitamin D Is Not Associated With the Type of Central Precocious Puberty in Girls

[Objective] To evaluate the clinical value of serum 25-hydroxyvitamin D (25OHD) in girls with different types of central precocious puberty (CPP), in order to provide basis for the clinical diagnosis and treatment. [Methods] 340 CPP girls diagnosed in our hospital from January 2016 to January 2018 were enrolled and retrospectively studied. According to the progression of Tanner stage ≥1 during 6 months, bone age(BA) levels were higher than chronological age of more than 1 year. 226 patients were included in the rapidly progressive CPP group (RP-CPP), while 114 patients were included in the slowly progressive CPP group (SP-CPP) as a control. We analyzed the correlation between serum 25OHD levels and the different puberty characteristics (BA, disease course, body mass index (BMI), bone mineral density (BMD), serum LH peak to FSH peak ratio (LHP/FSHP), insulin-like growth factor 1(IGF1)) of two groups. According to sunshine duration, the sampling season was divided into two groups (December to May, June to November), then we compare the correlation between different serum 25OHD levels and season of sampling as well as the different puberty characteristics respectively. [Results] (1) The mean serum 25OHD levels of CPP girls were 15.89±6.87ng/ml. The 25OHD levels of 68 (20.0%), 95 (27.9%) and 167 (49.1%) patients were <10, 10-15 and 16-29 ng/mL, respectively. Only 10 (2.9%) patients had normal 25OHD (>30 ng/mL). (2) No significant difference in serum 25OHD levels between RP-CPP group and SP-CPP group (F =0.809, p=0.369) was found. There is no correlation of BMD and disease course between the two groups (p>0.1). Bone age, BMI, LHP/FSHP and IGF1 levels in RP-CPP group were higher than SP-CPP group (P<0.05). Logistic regression analysis showed that BMI, LHP/FSHP and IGF1 were the independent risk factors for CPP (OR 2.690, 1.005, 3.288, respectively). (3) There were significant differences among different serum 25OHD levels as for season, disease course and IGF1 (p<0.05). The correlation with the season was the highest (r=0.402, p<0.001). [Conclusions] (1) Vitamin D levels are generally insufficient in CPP girls and are not related to different types of CPP. (2) The higher BMI, IGF1, LHP/FSHP levels are, the easier CPP girls will transfer to RP-CPP, but not associated with vitamin D levels. (3) CPP girls suffer from vitamin D deficiency in seasons of winter and spring easilier.

SUN-085 Clinical and Hormonal Features of 37 Families with Central Precocious Puberty Due to MKRN3 Loss-Of -Function Mutations

Context: Loss-of-function mutations in the maternally imprinted Makorin RING-finger 3 (MKRN3) gene (15q11.2) are the most prevalent cause of familial central precocious puberty (CPP). Objectives: To analyze the phenotypes of a large cohort of children with CPP due to MKRN3 mutations and to compare them with the phenotypes of idiopathic CPP. Setting and Participants: We studied 73 individuals from 37 families with mutations in MKRN3 originating from nine different countries. The phenotypes of these patients at initial diagnosis were compared to a cohort of 124 patients with idiopathic CPP. Additionally, expression of nine different genes implicated with pubertal timing, including MKRN3, was performed in the hypothalamus of female mice in different phases of sexual maturation. Results: Nineteen different heterozygous, paternally inherited mutations in MKRN3 were identified in 73 patients with CPP (48 girls and 25 boys). Six MKRN3 mutations were frameshifts, one introduced a premature stop codon, 11 were missense mutations predicted to be pathogenic, and one was a deletion in the promoter region. A frameshift mutation affecting codon 161 in the amino terminal region of the protein was the most frequent MKRN3 defect (46%), representing a hotspot region. Among the cohort with MKRN3 mutations, first pubertal signs occurred at 6·2 ± 1·2 years in girls and 7·6 ± 1·4 years in boys. Patients harboring severe frameshift/nonsense mutations did not differ significantly in any clinical or hormonal parameters compared to the 20 patients with missense variants. However, when the 48 girls with MKRN3 mutations were compared with 124 idiopathic CPP girls, some parameters could be considered as possible predictors of the genetic cause: a lower age at first medical appointment (7·1 ± 1·1 in the MKRN3 group vs. 8·0 ± 2 years in the idiopathic group; p< 0.001) and a shorter time interval between puberty onset and medical assistance (0·8 ± 0·8 vs 2·2 ± 2·1 years; p< 0.001). Interestingly, the other predictor of MKRN3 mutations was a higher basal FSH level (5·1 ± 2·3 vs 3·9 ± 2·7 IU/L; p = 0.017) at first evaluation, although no cutoff value yielded good accuracy. Patients originating from European/Mediterranean countries were more likely to have missense variants (56% of all mutations) than North American and South American (23%) counterparts (p <0.001). Mouse Mkrn3 mRNA levels in the arcuate nucleus were highest in the prepubertal phase when compared with expression of other genes and Mkrn3 decreased progressively through puberty and adult ages. Conclusions: Different types of loss-of-function MKRN3 mutations were associated with premature sexual development in both sexes. Their phenotypes were relatively uniform, regardless of the mutation type. Clinical features of children with MKRN3 mutations were similar to the idiopathic CPP group.