Makorin RING finger protein 3 (MKRN3) is a key inhibitor of the hypothalamic-pituitary-gonadal (HPG) axis. The association between MKRN3 gene variants and central precocious puberty (CPP) has been repeatedly examined. In a recent study, MKRN3 has been assigned a role of tumor suppressor in lung carcinogenesis. Therefore, it is hypothesized that MKRN3 may be the link between CPP and lung cancer (LC), and certain MKRN3 gene variants may affect individuals\' susceptibility to CPP and LC. The rs12441287, rs6576457 and rs2239669 in the MKRN3 gene were selected as the target variants. Sanger sequencing was applied to genotype them in two sets of case-control cohorts, namely 384 CPP girls and 422 healthy girls, 550 LC patients and 800 healthy controls. The results showed that rs6576457 but not rs12441287 or rs2239669 was significantly associated with the risk of CPP and LC. Their association with CPP risk was further confirmed in the following meta-analysis. Subsequent functional assays revealed that the rs6576457 genotypes were correlated with differentially expressed MKRN3, and the rs6576457 alleles affected the transcription repressor Oct-1 binding affinity to the MKRN3 promoter. Collectively, the MKRN3 gene rs6576457 may participate in the CPP pathology and LC tumorigenesis in the Hubei Chinese population. However, the present findings should be validated in additional investigations with larger samples from different ethnic populations.

Sotos syndrome is a rare overgrowth condition characterized by tall stature, distinctive facial features, and learning disabilities. It is primarily caused by a microdeletion of the nuclear receptor-binding set domain protein 1 (NSD1) gene on chromosome 5q35. Patients often present with various clinical manifestations, including tall stature, precocious puberty, cardiac anomalies, and mild intellectual disability. Management of Sotos syndrome involves a multidisciplinary approach due to its complex nature and potential comorbidities. This case discusses the management of a 10-year-old female with a known gene mutation consistent with Sotos syndrome that presented to the clinic with behavioral changes, and highlights the importance of integrated care models when addressing complex clinical scenarios.

OBJECTIVE: To evaluate the suitability of serum osteocalcin (OC) as a marker to distinguish between rapidly and non-rapidly progressive central precocious puberty (RP-CPP and NRP-CPP), as well as its potential to assess growth rates following treatment with gonadotropin-releasing hormone agonist (GnRHa).
METHODS: Serum levels of OC were measured using enzyme-linked immunosorbent assays in girls diagnosed with either RP-CPP or NRP-CPP as well as in normal control subjects. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value for OC. Multivariate linear regression analysis was used to analyse the main influencing factors associated with OC.
RESULTS: Serum OC levels were higher in the CPP girls when compared to normal controls (110.76 ± 43.69 vs 55.97 ± 20.96 ng/mL, P < 0.001). The level in the RP-CPP group was higher than the NRP-CPP group (153.28 ± 33.89 vs 88.33 ± 29.26 ng/mL, P < 0.001). The cut-off value of OC levels for distinguishing between RP-CPP and NRP-CPP was 107.05 ng/mL, the sensitivity was 94.7% and the specificity was 77.8%, which was superior to using the basal luteinising hormone (B-LH) levels, and the area under ROC curve (AUC) were 0.933 versus 0.695, respectively. Following 1-2 years of treatment with GnRHa for girls with CPP, both OC levels and the growth rates decreased to pre-pubertal values. B-LH levels, bone age and body weight were also significant factors, which affected OC levels.
CONCLUSIONS: Serum OC levels may be a useful marker for distinguishing RP-CPP from NRP-CPP. In addition, it was also found to be a useful predictor for growth rate during GnRHa treatment.

OBJECTIVE: Gonadotropin-releasing hormone (GnRH) test is the gold standard test to evaluate the hypothalamus-pituitary-gonadal (HPG) axis for the diagnosis of central precocious puberty (CPP). However, the diagnosis of cases with clinical features of CPP whilst have borderline peak luteinizing hormone (LH) remain challenges. We aimed to evaluate diagnostic performance of the average of LH levels measured during GnRH stimulation test.
METHODS: Cases with diagnosis of CPP and premature thelarche (PT) who had a GnRH stimulation test results were retrospectively reviewed. Anthropometric measurements (weight, height, and body mass index), age and sex-specific standard deviation scores, growth velocity, puberty stages, bone ages, serum FSH, LH, and estradiol levels were measured by electrochemiluminescence immunological method (ECLIA), and the GnRH stimulation test results, which performed by obtaining venous blood samples at basal, 20th, and 40th minutes for FSH and LH measurement, were recorded.
RESULTS: A total of 76 girls (38 CPP, 38 PT) were included. We detected an average peak LH cut-off value of 4.25 IU/L with 94.7 % sensitivity and 97.4 % specificity, a 97.3 % positive predictive value, and a 94.9 % negative predictive value in GnRH test to differentiate cases with CPP from PT.
CONCLUSIONS: This is the first study evaluating the diagnostic utility of the average of LH levels measured during GnRH stimulation test. We showed that the average of two LH measurements has a high diagnostic performance. Therefore, it can be used as a valid and reliable diagnostic tool for assessment of HPG axis activation, particularly for cases with a borderline peak LH level.

OBJECTIVE: This study aimed to analyze the height growth pattern and the incidence of significant growth deceleration in girls with CPP and EFP on GnRHa treatment, and thereby identify relevant predictors of growth deceleration.
METHODS: The data of 99 girls diagnosed with CPP and 47 girls with EFP were included in this retrospective analysis. The incidence of growth deceleration was calculated in both the first and second years. Multivariate logistic regression analysis was used to identify predictors indicative of growth deceleration.
RESULTS: Growth velocity (GV) trajectories showed gradual decreases to the nadir at 18 months of treatment, and then they recovered till the 24th month of treatment, especially in girls with CPP. Nevertheless, the recovery was significantly greater in the CPP group than EFP. In the first year, no significant difference in the incidence of growth deceleration was found between the CPP group and the EFP group [17.35 vs. 25.53 %, p=0.249]; in the second year, the CPP group had a lower incidence than the EFP group [42.86 vs. 76.92 %, p=0.027]. The multivariate logistic regression analysis suggested that bone age (BA) was an independent predictor of growth deceleration (OR=2.264, 95 % CI: 1.268-4.042, p=0.006). The result of ROC curves showed the cut-off value of BA was 11.05 years.
CONCLUSIONS: GV varies at different periods during GnRHa treatment. GnRHa should be used with more caution for EFP treatment than for CPP. BA can be used to predict the occurrence of growth deceleration during GnRHa treatment.

UNASSIGNED: The study aimed to investigate the correlation between the change of sex hormone levels and ocular surface parameters in girls with idiopathic central precocious puberty(ICPP).
UNASSIGNED: Eighteen girls with ICPP and 18 age-matched normal girls participated in this study, all of the participants had undergone physical measurements, laboratory tests, imaging examination and ocular surface assessments.
UNASSIGNED: The Objective Scatter Index (OSI) in the ICPP group was significantly higher than in the control group (P = 0.031), girls with ICPP showed slightly lower MNITBUT compared to the normal control group, although this difference was not statistically significant. Bivariate analysis revealed a positive association between estradiol and OSI (r=0.383, P=0.021), Additionally, in the study population, both Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) were negatively correlated with Mean noninvasive tear breakup time (MNITBUT) (r=-0.359, P=0.031)(r=-0.357, P=0.032).
UNASSIGNED: In comparison with the normal control group, alterations in the OSI were observed in girls with ICPP. This alteration may be associated with an elevation in estrogen levels. Although there was a slight non-significant decrease in NITBUT in ICPP girls, the negative correlation between LH and FSH with MNITBUT suggests new perspective for further investigation.

Central precocious puberty (CPP) is a rare disease of poorly understood etiology. The cause is mostly idiopathic. However, congenital and acquired structural changes in the central nervous system are also involved. Prevalent organic changes in the central nervous system, especially among boys, prompt imaging assessment in each case of CPP. In addition, genetic and environmental factors have been reported. Safe and effective treatment is available. The time of treatment implementation is crucial to the successful outcome. Proper diagnosis and treatment make it possible to avoid a number of complications of untreated CPP. There are only a few studies analyzing the prevalence and risk factors for the disease. The aim of this paper is to discuss the current causes of CPP with particular consideration of neurological aspects.

UNASSIGNED: The peptide hormone Insulin-like Factor 3 (INSL3) is a biomarker of testicular Leydig cells in the male but is also expressed by the theca cells of the ovaries. With the advent of sensitive assays INSL3 can be quantified in female circulation, and we suggest that circulating INSL3 is a novel biomarker for pubertal development in girls. The aim of the study is to quantify INSL3 by LC-MS/MS in sera from normal girls during pubertal transition, and during gonadal suppression by GnRH agonist therapy in girls with central precocious puberty (CPP).
UNASSIGNED: The sensitivity of an established LC-MS/MS-based method for serum INSL3 was improved by switching to a state-of-the-art triple quadruple mass spectrometer (Altis Plus, Thermo).
UNASSIGNED: The limit of detection of the improved LC-MS/MS method for serum INSL3 was 0.01 ug/L (1.5 pM) and the inter-assay CV was < 12%. Serum INSL3 increased during the pubertal transition in healthy girls and changes correlated with the concomitant rise in other measured hormones. In some girls, but not all, INSL3, FSH, inhibin B and estradiol serum concentrations increased prior to first clinical signs of puberty. Serum INSL3 concentrations were increased at baseline in girls with CPP compared to prepubertal controls and decreased during treatment with GnRH agonist followed by a steep rise and normalization after cessation of treatment.
UNASSIGNED: The improved method allowed for quantification of INSL3 in longitudinally collected serum samples during pubertal transition in healthy girls as well as in girls with CPP before, during and after treatment with GnRH agonist. Future studies are needed to clarify if INSL3 in combination with other biomarkers enhances the predictive value of differentiating between premature thelarche and CPP.

OBJECTIVE: Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS.
METHODS: A chart review of children with PWS treated at our institution between 1990 and 2021 was performed. PP was defined as Tanner stage 2 (TS2) pubic hair in girls <8 and boys <9 years old. Demographic, anthropometric, and laboratory data were collected to assess predisposing factors and consequences of PP in comparison to patients with PWS who had normal pubarche (NP).
RESULTS: Analysis included 43 children with PWS, 23 (53.5%) with PP and 20 (46.5%) with NP. Median age at pubarche was 7.0 years in PP group and 10.0 years in NP group. Age at pubarche was not correlated with age of recombinant human growth hormone (rhGH) initiation, body mass index (BMI) z-score, or homeostasis model assessment of insulin resistance (HOMA-IR) at pubarche. BMI z-score at pubarche was modestly correlated with degree of pubarchal BA advancement (p = 0.033). Those with PP were more likely to have a lower high-density lipoprotein (HDL) (1.05 mmol/L vs. 1.41 mmol/L in the NP group, p = 0.041). The difference between target and final height did not differ between groups (p = 0.507).
CONCLUSIONS: PP is common in PWS but does not compromise final height in comparison to the NP group. Obesity and insulin resistance were not associated with PP in children with PWS, contrary to what has been seen in obese children without PWS.

Background: A correlation between plasma lipids and timing of pubertal development has been hypothesized, though lipid influence remains unclear in central precocious puberty (CPP). Aim: To assess any possible alterations in the lipid profile and triglyceride glucose index (TyG) in children diagnosed with CPP. Patients and Methods: Retrospective single-center study conducted on children (aged 6.3 ± 2.1 years) evaluated for the suspicion of CPP. Results: Based on the results of the gonadotropin releasing hormone (GnRH) test, considering 5 IU/L as cut-off of the luteinizing hormone peak, CPP was confirmed in 43 patients (57.3%). Sixteen (37.2%) had a pathologic body mass index (BMI), with 9 (20.9%) being overweight and 7 (16.27%) obese. High total cholesterol was found in 3 patients with CPP (6.97%), high triglycerides were found in 11 patients with CPP (25.58%), high LDL cholesterol was found in 5 patients with CPP (11.62%), low HDL cholesterol was found in 12/43 patients with CPP (27.9%), a pathologic TyG was found in 13/43 patients with CPP (30.23%). No significant association was observed in the lipid profile for patients with or without CPP, except for HDL cholesterol, which was lower in the CPP group (47.1 ± 10.9; p = 0.033). However, the association between serum HDL cholesterol and CPP was not confirmed at the multivariate logistic regression analysis adjusted for patients\' sex and age (p = 0.1; OR: 1.035; 95% CI: 0.993-1.078). Conclusion: The overall lipid profile of our pediatric patients diagnosed with CPP did not differ from patients having idiopathic precocious thelarche or normal variants of puberty development.