Risk Of Central Precocious Puberty Research Articles

Diet Quality Scores and Central Precocious Puberty Risk in Chinese Girls: A Case-Control Study.

Diet is an important factor influencing central precocious puberty (CPP). This study aimed to investigate the relationship among diet quality, pro-inflammatory diets, and CPP in Chinese girls. This case-control study enroled 112 Chinese girls with CPP and 131 healthy controls. Children's dietary intake was assessed using a validated food frequency questionnaire, anthropometric and sociodemographic data were collected and serum interleukin-6 levels were measured. We calculated the Children's Dietary Inflammatory Index (C-DII), Chinese Children's Dietary Index (CCDI), Dietary Approaches to Stop Hypertension (DASH) score, and the adjusted Dietary Approaches to Stop Hypertension (aDASH) score. The association between diet and the risk of CPP was analysed using logistic regression models. After adjustment, higher C-DII scores were associated with an increased risk of CPP (P for trend = 0.034), and aDASH scores were significantly negatively associated with the risk of CPP (P for trend = 0.048). Serum IL-6 levels were significantly higher in the case group than in the control group and were positively correlated with the risk of CPP (P for trend = 0.006). High-quality dietary patterns and an anti-inflammatory diet may contribute to the prevention of CPP in Chinese girls.

Development and application of a nomogram model for predicting the risk of central precocious puberty in obese girls.

The purpose of this study is to develop and assess a nomogram risk prediction model for central precocious puberty (CPP) in obese girls. We selected 154 cases of obese girls and 765 cases of non-obese girls with precocious puberty (PP) who underwent the gonadotropin-releasing hormone stimulation test at the Jiangxi Provincial Children's Hospital. Univariate analysis and multivariate analysis were conducted to identify predictors of progression to CPP in girls with PP. A predictive model was developed and its predictive ability was preliminarily evaluated. The nomogram was used to represent the risk prediction model for CPP in girls with obesity. The model was validated internally using the Bootstrap method, and its efficacy was assessed using calibration curves and clinical decision analysis curves. In obese girls with PP, basal luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels, as well as uterine volume, were identified as independent risk factors for progression to CPP. In non-obese girls, the basal LH level, bone age, and uterine volume were identified as independent risk factors for progression to CPP. With an AUC of 0.896, the risk prediction model for obese girls, was found to be superior to that for non-obese girls, which had an AUC of 0.810. The model displayed strong predictive accuracy. Additionally, a nomogram was used to illustrate the CPP risk prediction model for obese girls. This model performs well in internal validation and is well calibrated, providing a substantial net benefit for clinical use. A medical nomogram model of CPP risk in obese girls comprised of basal LH value, basal FSH value, and uterine volume, which can be used to identify those at high risk for progression of CPP in obese girls and develop individualized prevention programs.

THU195 6-Month Subcutaneous Leuprolide Acetate Achieved And Maintained Hormonal And Clinical Suppression In All Weight Groups Of Children With Central Precocious Puberty

Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Ascendis Pharma, Bristol Myers Squibb, BioMarin, Endo Pharmaceuticals, EMD Serono, Novo Nordisk, Pfizer, Tolmar Pharmaceuticals. Research Investigator; Self; Alexion, Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Prevail Therapeutics, Sangamo Therapeutics. D. Boldt-Houle: Employee; Self; Tolmar Pharmaceuticals, Inc. S.N. Atkinson: Employee; Self; Tolmar Pharmaceuticals, Inc. Background: Childhood obesity is associated with an increased risk of central precocious puberty (CPP).1 Thus, data on whether weight status affects the treatment of children with CPP would be valuable to help clinicians ensure correct management. We present secondary analyses of hormone and height velocity (HV) data from the pivotal trial of the first small-volume, long-acting, subcutaneously administered gonadotropin-releasing hormone agonists (GnRHa) for CPP, with the goal of assessing if the study drug adequately suppresses hormones in overweight and obese children. Methods: 62 children with treatment-naïve CPP received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals over the 48-week study period. The BMI percentile for children was calculated based on the Center for Disease Control growth charts, accounting for height, weight, age, and gender. Luteinizing hormone (LH) concentrations were assessed using a validated central Cobas ECLIA assay with a lower limit of detection of 0.100 IU/L. Estradiol (E2) concentrations were assessed using liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS) with a lower limit of detection of 10 pg/mL. HV was calculated as the change in height between visits/((number of weeks between visits)/52). Results: Mean GnRH-stimulated LH concentrations at screening, week 24, and week 48 were 24.5, 2.1, and 2.5 IU/L in non-overweight children, 10.5, 3.2, and 2.2 IU/L in overweight children, and 31.5, 4.8, and 1.9 IU/L in obese children, respectively. In these same groups, mean E2 concentrations at screening, week 24, and week 48 were 28.2, 10.5, and 10.3 pg/mL in non-overweight children, 17.8, 10.4, and 10.4 pg/mL in overweight children, and 25.9, 11.0, and 11.1 pg/mL in obese children, respectively. Mean HV at week 4, week 24, and week 48 was 10.2, 5.6, and 5.7 cm/year in non-overweight children, 7.7, 5.5, and 6.2 cm/year in overweight children, and 8.2, 4.9, and 6.6 cm/year in obese children, respectively. Conclusions: Subcutaneous leuprolide acetate effectively treated all overweight children without any requirement for weight-based dosing. This is consistent with results from previous studies of GnRHa efficacy in obese and normal-weight children with CPP.2 Clinicians should consider providing counseling and interventions that support healthy diets and lifestyles to children with above-normal BMI and their caregivers. References Cited 1.Liu G, Guo J, Zhang X, Lu Y, Miao J, Xue H. Obesity is a risk factor for central precocious puberty: a case-control study. BMC Pediatr. 2021;21(1):509.2. Chen M, Eugster EA. Central precocious puberty: update on diagnosis and treatment. Paediatr Drugs. 2015;17(4):273-281. Presentation: Thursday, June 15, 2023

C10 (Clinical Case) Precocious Puberty in Internationally Adopted Children: A Tale of Two Thelarches

Abstract Introduction/Background Internationally adopted (IA) children may commonly experience post-adoption medical issues in the infectious, nutritional, developmental and psychological domains. We present a rare endocrinologic case of 2 biologically unrelated children adopted into the same Canadian family with diagnoses of idiopathic central precocious puberty (CPP), years after adoption. Case Description A 13-month-old female was adopted from Kazakhstan with a past history of prematurity (29 weeks gestational age), grade II intraventricular hemorrhage, query hypoxic ischemic encephalopathy, perinatal CMV infection, and malnourishment. She demonstrated catch-up growth after adoption and was monitored for developmental concerns. She presented at 7 years 9 months with report of thelarche at 6 years 6 months, pubarche at 7 years 6 months and accelerated height velocity. Bone age was advanced by 3 years (+4 SD). By Endocrinology consultation at 8 years 1 month, gonadotropin-releasing hormone (GnRH) stimulation test confirmed CPP. There was no central nervous system (CNS) symptomatology. Leuprolide was initiated to minimize psychosocial impacts of CPP and not necessarily to improve final adult height. Seven years after their first adoption, the family welcomed a female child from Vietnam, aged 2 years 11 months. Medical profile included malnutrition and atopic dermatitis. Thelarche was noted at 5 years 4 months. By Endocrinology consultation at 5 years 5 months, she had isolated breast development with accelerated height velocity. Bone age was advanced by 2.5 years (+3 SD). GnRH stimulation test revealed CPP. Leuprolide was started. MRI brain showed no CNS lesion, which confirmed the diagnosis of idiopathic CPP. Discussion Whereas there is a rare, but documented, increased prevalence of CPP among IA children, etiology is unclear. Theories postulate that it may be related to rapid catch-up growth post-adoption or past exposure to endocrine disruptors. Awareness of this risk may vary. Initial post-adoption consults often focus on other medical and developmental screening. Depending on the age at adoption, counselling about puberty may seem remote. This may impact the timing at which pubertal concerns are identified. As early identification of CPP provides an opportunity to intervene to preserve adult height, as well as minimize psychosocial impact on the child, pubertal surveillance should not be overlooked. Based on caregiver feedback from our cases, we now include counselling on, and examination for, early pubertal changes in our IA clinic visits. Conclusion IA children are at increased risk of central precocious puberty. Paediatric clinicians and caregivers should be aware of this risk to allow for timely identification and treatment of this condition.

O-199 Imprinting disorders in singletons conceived by assisted reproductive technology in Sweden

Abstract Study question Is singleton birth from assisted reproductive technology (ART) associated with imprinting disorders (IDs) independent of parental infertility and other background factors? Summary answer Singletons conceived using intracytoplasmic sperm injection (ICSI) and frozen embryos have higher risks of Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Silver-Russell syndrome (SRS). What is known already Previous studies have suggested elevated risk of IDs in children conceived with ART compared with children conceived with spontaneous conception (SC). It is not clear to what extent the observed associations could be explained by parental infertility and related risk factors. Knowledge on specific ART procedures and their association with IDs is also limited. Study design, size, duration A nationwide register-based cohort study was carried out in which all liveborn singletons in 1997-2017 in Sweden were included with follow-up to 2018. Participants/materials, setting, methods Among 1 998 825 singletons, 60 210 were conceived using ART. The International Classification of Diseases (ICD) version 10 was used to identify three distinct ID groups: PWS/SRS, BWS, and central precocious puberty (CPP). Cox regression, combined with inverse probability treatment weights to account for birth year, parity, pregnancy loss history, parental age and country of origin, was used to compare ART singletons with all SC singletons and those born to couples with known infertility. Main results and the role of chance A total of 1012 children were diagnosed with the IDs of interest (654 PWS/SRS, 255 BWS, and 109 CPP), and 49 of them were conceived through ART. Compared with all SC singletons, higher risk of PWS/SRS and BWS was observed in ART singletons and the weighted hazard ratios (wHRs) were 1.57 [95% CI, 1.09-2.26] and 2.57 [95% CI, 1.60-4.12], respectively. The elevated risks remained when comparison was restricted to SC singletons of couples with known infertility, though the wHR for BWS was somewhat attenuated (1.87, 95% CI: 1.04-3.36). No difference in risk of CPP was observed between singletons conceived with and without ART irrespective of parental infertility. Further subgroup analysis revealed that ICSI in combination with frozen embryo transfer was responsible for the higher risks of PWS/SRS (wHR 6.32, 95% CI: 3.34-11.95) and BWS (wHR 9.04, 95% CI: 4.34-18.82). Limitations, reasons for caution The use of the Swedish ICD-10 did not allow distinction of PWS and SRS. The number of CPP cases in ART singletons was too small (N = 3) to make inference. Wider implications of the findings This study found that ART-conceived singletons, particularly those conceived using ICSI and frozen embryos, had a higher risk of IDs independent of parental infertility. However, the underlying mechanism is not clear, and the role of type and severity of infertility warrants further investigation. Trial registration number not applicable

New insights into precocious puberty and ADHD: a nationwide cohort study.

Attention deficit-hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children; however, studies delineating the association between ADHD and central precocious puberty are limited. This study aimed to understand whether children with ADHD are at a higher risk of central precocious puberty. This population-based retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan to investigate the association between ADHD and the incidence of central precocious puberty between 2000-2015. We identified ADHD individuals treated with methylphenidate, atomoxetine or not. The control cohort consisted of individuals without ADHD. The outcome measure was central precocious puberty diagnosis. Among 290,148 children (mean age: 5.83 years), central precocious puberty incidence was 4.24 and 1.95 per 105 person-years in the ADHD and control groups, respectively. Children with ADHD treated with medication had a higher risk than those without ADHD. However, medication use did not affect the incidence of central precocious puberty among children with ADHD. This study showed an association between ADHD and a higher risk of central precocious puberty. Early referral of children with ADHD to a pediatric endocrinologist for evaluation may facilitate correct diagnoses and early interventions. ADHD is associated with a higher risk of central precocious puberty. This study provides relevant findings, as it is the first nationwide, population-based cohort study to investigate the association between ADHD and the risk of central precocious puberty with a 15-year follow-up. Early referral of children with ADHD to a pediatric endocrinologist for the evaluation of suspected precocious puberty could facilitate correct diagnosis. Early intervention treatment with gonadotropin-releasing hormone agonist might improve final height in children with central precocious puberty.

Clinical risk score for central precocious puberty among girls with precocious pubertal development: a cross sectional study

BackgroundThe gold standard for the diagnosis of central precocious puberty (CPP) is gonadotropin-releasing hormone (GnRH) or GnRH analogs (GnRHa) stimulation test. But the stimulation test is time-consuming and costly. Our objective was to develop a risk score model readily adoptable by clinicians and patients.MethodsA cross-sectional study based on the electronic medical record system was conducted in the Children’s Hospital, Fudan University, Shanghai, China from January 2010 to August 2016. Patients with precocious puberty were randomly split into the training (n = 314) and validation (n = 313) sample. In the training sample, variables associated with CPP (P < 0.2) in univariate analyses were introduced in a multivariable logistic regression model. Prediction model was selected using a forward stepwise analysis. A risk score model was built with the scaled coefficients of the model and tested in the validation sample.ResultsCPP was diagnosed in 54.8% (172/314) and 55.0% (172/313) of patients in the training and validation sample, respectively. The CPP risk score model included age at the onset of puberty, basal luteinizing hormone (LH) concentration, largest ovarian volume, and uterine volume. The C-index was 0.85 (95% CI: 0.81–0.89) and 0.86 (95% CI: 0.82–0.90) in the training and the validation sample, respectively. Two cut-off points were selected to delimitate a low- (< 10 points), median- (10–19 points), and high-risk (≥ 20 points) group.ConclusionsA risk score model for the risk of CPP had a moderate predictive performance, which offers the advantage of helping evaluate the requirement for further diagnostic tests (GnRH or GnRHa stimulation test).

Association of Polymorphisms in the Kisspeptin/GPR54 Pathway Genes With Risk of Early Puberty in Chinese Girls.

This case control study was designed to investigate the association between mutation of 10 single nucleotide polymorphism (SNP) loci (rs1132506, rs5780218, rs192636495, rs4889, rs184749, rs12985070, rs708910, rs932491, rs8074995, and rs2306877) in all 5 genes (KISS1, GPR54, PLCB1, PRKCA, and ITPR1) in the kisspeptin/GPR54 pathway and the risk of early puberty in Chinese Han girls. A total of 314 pairs of early puberty girls on their first visit to hospital and age-matched controls (± 3 months) were recruited. The genotypes of each SNP were determined and the effect of loci variation on early puberty was investigated. rs5780218 was significantly associated with early puberty in additive, dominant, and recessive models of inheritance after adjusting for confounding factors (Pr < .05). After stratification, rs5780218 variation (odds ratio [OR], 1.650, 95% confidence interval [CI], 1.155-2.355 in additive models and OR, 2.116; 95% CI, 1.187-3.770 in recessive models) increased the risk of central precocious puberty (CPP); mutation in rs708910 (OR, 2.768; 95% CI, 1.305-5.872 in recessive model) had a positive association with the risk of CPP; and rs932491 variation was negatively associated with early and fast puberty (EFP) (OR, 0.309; 95% CI, 0.144-0.661 in additive models and OR, 0.317; 95% CI, 0.141-0.713 in dominant models). Our study suggests that mutation in rs5780218 and rs708910 increases the risk of CPP. rs932491 variation may have a protective effect on the risk of EFP. Further studies in larger populations or with people from different regions are needed to verify our findings.

Gonadotropin-dependent pubertal disorders are common in patients with virilizing adrenocortical tumors in childhood.

ObjectiveTo investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood.MethodsRetrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared.ResultsThe study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 months; duration of signs, 6 months; stature SDS, 0.5 (−3.6 to 3.9) and bone age advancement, 14.7 months (−27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04–8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12–8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to −0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with normal puberty and pubertal disorders (P = 0.75).ConclusionsGonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess.

Associations among IGF-1, IGF2, IGF-1R, IGF-2R, IGFBP-3, insulin genetic polymorphisms and central precocious puberty in girls

BackgroundInsulin and insulin-like growth factor (IGF)-1 coupled with growth hormone helps control timing of sexual maturation. Mutations and variants in multiple genes are associated with development or reduced risk of central precocious puberty (CPP).MethodsWe assessed single nucleotide polymorphisms (SNPs) in the IGF-1, IGF-2, IGF-3, IGF-1 receptor (IGF1R), IGF-2 receptor (IGF2R), and IGF -binding protein 3 (IGFBP-3) genes, and their association with demographics and metabolic proteins in girls with CPP. Z-scores of height, weight, and body mass index (BMI) were calculated with the WHO reference growth standards for children.ResultsIGF-1 serum levels of CPP group exhibited a higher correlation with bone age, z-scores of height and weight, and luteinizing hormone (LH) than those of control group, regardless of BMI adjustment. In the CPP group, height was associated with IGF-2(3580), an adenine to guanine (A/G) SNP at position + 3580. BMI in the CPP group was associated with IGF-2(3580), IGF1R, and the combinations of [IGF-2(3580) + IGF2R], and [IGF-2(3580) + IGFBP-3]. Body weight in the CPP group was associated with the combination of [IGF-2(3580) + IGFBP-3] (p = 0.024). Weight and BMI were significantly associated with the combination of [IGF-2(3580) + IGF2R + IGFBP-3] in the CPP group. These associations were not significantly associated with z-scores of weight, height, or BMI. The distribution of these genotypes, haplotypes, and allele frequencies were similar between control and CPP groups.ConclusionsThese known SNPs of these IGF-1 axis genes appear to play minor roles in the risk for development of CPP.

Serum bisphenol A levels in girls with central precocious puberty

Bisphenol A (BPA) is a chemical widely used to make polycarbonate plastics and epoxy resins lining food and beverage containers. A number of in vitro and in vivo studies have demonstrated that BPA has an estrogenic effect by binding to the nuclear estrogen receptor, and early BPA exposure could in induce early puberty. However, effects of human exposure to BPA on pubertal onset and the association of gonadotropin levels have not been fully evaluated. We aimed to study whether serum bisphenol A levels are associated with central precocious puberty (CPP) in Korean children. A total of 103 girls (51 CPP cases and 52 controls, aged 7 to 9 yr) were enrolled. Pubertal staging, anthropometry, bone maturation were assessed. Gonadotropin releasing hormone-stimulation test were conducted to determine the basal and peak levels of luteinizing hormone (LH). Serum bisphenol A levels were analysed by gas chromatography/mass spectrometry method. Geometric mean serum BPA levels were higher in CPP girls than in controls (6.5±5.9 vs. 3.4±4.1 ng/mL, P<0.0001). In partial correlation analysis controlling for age and body mass index, serum BPA level showed significant positive correlation with bone age (r=0.343, P=0.001), fat mass (r=0.241, P=0.021), waist circumference (r=0.223, P=0.034), basal LH levels (r=0.243, P=0.02), and peak LH levels (r=0.294, P=0.005). Bone age, height, basal/peak LH levels and prevalence of CPP increased significantly with increasing tertile of serum BPA. Increased risk of CPP [Odds ratio(95% Confidence Interval)] was observed across increasing serum BPA tertile [2.61(0.86-7.93) for tertile 2, 7.68(2.34-25.19) for tertile 3] after adjusting for age and BMI. Serum BPA level was higher in CPP girls compared with controls, and higher serum BPA level was associated with increased risk of CPP. Prospective studies are needed to determine potential causal links between BPA exposure and CPP. Table Multivariate logistic regression analysis for obesity according to the quartiles of BPA concentrations

High serum isoflavone concentrations are associated with the risk of precocious puberty in Korean girls

The gradual decrease in the age of onset of puberty raises concerns about the contribution of phytoestrogen intake on sexual maturation. However, no data are available on the association between serum isoflavone (genistein, daidzein) concentration and central precocious puberty (CPP). The aim of the study was to test the association between serum isoflavone concentrations and the risk of CPP in Korean girls. A case-control study was conducted at Inje University Hospital in Korea. One-hundred and eight girls with CPP (aged 8·6 ± 0·8 year) and 91 age-matched controls (aged 8·5 ± 0·8 year) were examined. Serum concentrations of daidzein (P = 0·0202), genistein (P = 0·0021) and total isoflavones (P = 0·0009) were higher in children with CPP than in normal children. When the children were categorized into three groups according to total serum isoflavone as follows: <30, 30-70 and ≥70 nmol/l, serum concentrations of daidzein, genistein and total isoflavones significantly increased across three categories of serum isoflavone (P < 0·0001). The prevalence of CPP was significantly higher in children with serum isoflavone level of ≥30 nmol/l than those with serum level of <30 nmol/l (P = 0·0008). The adjusted OR for precocious puberty increased significantly across a range of total serum isoflavone (OR = 4·39; 95% CI: 1·83-10·51 vs OR = 5·22; 95% CI: 2·07-13·20; P = 0·001). These results suggest that elevated serum isoflavones may be associated with the risk of CPP in Korean girls.

High incidence of central precocious puberty in a bounded geographic area of northwest Tuscany: An estrogen disrupter epidemic?

The potential health consequences of human exposure to environmental estrogen disrupters are not known. Because many chemical compounds are environmentally persistent, toxic and estrogen-active, they can dysregulate the hypothalamic–pituitary–gonadal axis, potentially inducing reproductive disorders such as central precocious puberty (CPP). We performed a multi-center analysis of CPP distribution in northwest Tuscany (NWT), an area of 5990 km2 with 1 280 895 inhabitants. Study criteria consisted of recorded CPP diagnoses and prescriptions of gonadotropin-releasing hormone analogs from January 1, 1998 to December 1, 2003. Although similar CPP prevalences were found in four major cities of NWT (Livorno, Lucca, Massa and Pisa) (mean 30.4 per 100 000 children, standard deviation 18.6; p > 0.05), Viareggio area (< 300 km2) with 19 219 child inhabitants (0–14 years of age) had the highest CPP prevalence: more than 161 CPP cases per 100 000 children. Living in Viareggio area significantly increased the risk of CPP (relative risk (RR) 5.73, 95% confidence interval (CI) 3.5–9.3; rate/risk difference 0.133%, p < 0.05). Annual CPP incidence in the Viareggio area was relatively constant and significantly higher than in other NWT areas (RR 5.04, 95% CI 2.3–11.2; rate/risk difference 0.03%, p < 0.05). Indeed, 47% of total NWT cases were distributed in the countryside (300 km2) surrounding Viareggio. Specifically, three villages – Camaiore, Pietrasanta and Stazzema – in Viareggio presented the highest CPP frequency: 216.1, 393.5 and 274.0 CPP cases per 100,000 children, respectively (RR 9.59, 95% CI 1.71–16.6; rate/risk difference 0.26%, p < 0.05). Owing to the definite geographic distribution of CPP and because increasing distance (km) from Pietrasanta rarefied CPP frequency, we suggest environmental factors (e.g. estrogen disrupter pollution) as major CPP determinants in NWT.