Diagnostic Accuracy of Radiological Bone Age Methods for Assessing Skeletal Maturity in Central Precocious Puberty Girls from the Canary Islands

Management and outcome of central precocious puberty

Determining the skeletal age in patients with multiple epiphyseal dysplasia (MED) is essential for predicting the adult height and guiding the timing of limb lengthening, epiphysiodesis, and other surgical procedures. In the present study, we examined the patterns of skeletal age delay using 3 different methods, the Greulich-Pyle (GP) atlas method, the Tanner-Whitehouse 3 (TW3) method using radius-ulna-short bones (RUS) scoring system, and the TW3 method using the carpal bone maturity scoring system. Left hand radiographs from 23 patients (age range, 3 to 14 y) with MED were examined to determine the skeletal age. We examined the reliability of the 3 different methods and evaluated the difference between the chronological age and the skeletal age. The interobserver and intraobserver reliabilities were higher with the GP atlas method and the TW3 RUS method compared with the TW3 carpal bone maturity scoring system. There was significant skeletal age delay irrespective of the method used (P<0.01). When we used the TW3 carpal method, the pattern of skeletal age delay was significantly distinct from the other 2 methods. According to the measurement method, there was no statistically significant difference in the developmental skeletal age pattern among the COMP gene group, the MATN3 gene group, and other gene groups. Our findings indicate that there is a distinct skeletal maturation pattern in patients with MED. The skeletal age is relatively delayed compared with the chronological age irrespective of the measuring method utilized. However, use of either the GP atlas or the TW3 RUS method provided more accurate information on the skeletal development in the patients with MED than that provided by the TW3 carpal bone maturity scoring system. Level I. Diagnostic study.

Objective To compare the clinical characteristics of peripheral precocious puberty (PPP) and central precocious puberty (CPP) girls with a basal luteinizing hormone (LH) level less than 0.1 IU/L to guide the reasonable clinical diagnosis of precocious puberty by the gonadotropin-releasing hormone (GnRH) stimulating test. Methods From February 2016 to August 2018, PPP girls (263 cases) and CPP girls (20 cases) with a basal LH value<0.1 IU/L who visited the Subei Hospital of Clinical Medical College of Yangzhou University were studied. Data were compared between groups, and logistic regression analysis was perform to identify the relevant risk factors and ROC curve was used to evaluate the diagnostic value of related indicators. Results There were no significant differences between the PPP group and the CPP group in breast development age, age at visit, height at visit, body mass index, genetic target height, growth rate, endometrium appearance, proportion of>4 mm follicles, or basal FSH value. There were significant differences between the two groups in advanced bone age [(3.7±9.8) months vs (15.3±9.6) months, t=-4.908, P<0.001], ovary volume [1.1 (0.7, 1.7) ml vs 1.8 (1.3, 2.4) ml, Z=-3.916, P<0.001], uterine length [18 (16, 20) cm vs 21 (16, 24) cm, Z=-2.309, P=0.021], uterine volume [0.9 (0.6, 1.4) ml vs 1.3 (0.8, 2.4) ml, Z=-3.227, P=0.001], estradiol [18.4 (18.3, 25.3) pmol/L vs 33.3 (18.4, 43.0) pmol/L, Z=-3.182, P=0.001], and predicted compromised adult height (PAH-TH) [(-0.4±7.4) cm vs (5.5±5.7) cm, t=1.223, P=0.001]. Logistic regression analysis demonstrated that the months of advanced bone age (OR=0.844) and uterine volume (OR=0.330) were two independent risk factors for the diagnosis of CPP. ROC curve analysis showed that the area under the curve (AUC) of advanced bone age and uterine volume was 0.830 and 0.716, respectively. When the cutoff value for advanced bone age was 11.5 months, the sensitivity and specificity for diagnosis of CPP were 80.0% and 82.9%, respectively. When the cutoff value for uterine volume was 2.085 mL, the sensitivity and specificity for diagnosis of CPP were 45.0% and 95.1%, respectively. Conclusion The hypothalamic-pituitary-gonadal axis (HPGA) activation cannot be completely ruled out if basal LH is less than 0.1 IU/L. In these girls, GnRH stimulation test should be conducted to exclude CPP if the bone age is more than 11.5 months ahead or the uterine volume is greater than 2.085 ml. Key words: Luteinizing hormone; Hypothalamic-pituitary-gonadal axis; Peripheral precocious puberty; Central precocious puberty; 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.

Background:There are several methods of bone age (BA) assessment, which include Gruelich-Pyle (GP), Gilsanz-Ratib (GR), and Tanner Whitehouse-3 (TW-3) methods. Although GP atlas is the most widely used, there are concerns about its accuracy in children of different ethnicities, making the use of the TW-3 method an attractive option in Indian children.Objectives:1) To assess the relationship of BA with chronological age (CA) as assessed by different methods (GP, GR, and TW-3) in healthy Indian children 2) To assess which of the three methods of BA assessment is more suitable in Indian children.Methodology:X-rays of 851 children (438 boys and 413 girls, aged 2–16.5 years) were analyzed by four independent observers using three different methods of BA estimation (GP, GR, and TW-3). Mean BAs were converted to Z-scores. For purpose of deciding which method of BA was most suitable in our cohort, a test of proportions and root mean square (RMS) deviations were computed.Results:Using the test of proportions, the TW-3 method was most suitable overall (P < 0.05). TW-3 method was again most applicable in prepubertal boys (P < 0.05), in prepubertal girls (although not significant, P > 0.1), and pubertal girls (P < 0.05). However, in pubertal boys, the GR atlas method was most suitable (P < 0.05). The same results were obtained when root mean square (RMS) deviations were computed. Interestingly, BA was underestimated in Indian boys irrespective of the method used. In Indian girls, however, the BA was underestimated till the pubertal growth spurt, after which there was rapid advancement of BA.Conclusions:Among the three methods (GP, GR, and TW-3), the BAs estimated by the TW-3 method were closest to CAs. Hence, it seems reasonable to recommend the use of the TW-3 method for BA estimation in the Indian population till an Indian standard bone age atlas is developed.

Background: The aim of this study was to investigate the favorable factors for gonadotropin-releasing hormone (GnRH) agonist treat ment with regard to the growth velocity and the predicted adult height (PAH) in central precocious puberty (CPP) girls. Methods: We reviewed the clinical and auxological parameters in 46 CPP girls who were treated with GnRH agonist at the pediatric endocrinology clinic of Korea University Hospital from January 2001 to August 2007. We divided the two groups according to the growth velocity of 5 cm/yr and we assessed the related factors associated with growth velocity. We also assessed the changes in PAH for two years. Results: The pretreatment chronological age and bone age were significantly younger in the high growth velocity group (> 5 cm/yr) compared to that of the low growth velocity group (7.8 ± 0.9 year vs. 8.4 ± 0.5 year, 9.4 ± 1.2 year vs. 10.1 ± 0.9 year, respectively) (P 5 cm/yr)( P < 0.05). Growth velocity during treatment had negative correlation with the pretreatment chronological age and positive correlation with the PAH after one and two years of treatment (r = -0.45, P < 0.05 and r = 0.51, P < 0.01). PAH had positive correlation with the treatment duration (r = 0.31, P < 0.05). Conclusion: In our study, the growth velocity during GnRH agonist treatment was negatively related to age at the initiation of treatment. Therefore, earlier treatment is important to improve the outcomes and to maintain appropriate growth velocity in CPP girls. (Endocrinol Metab 25:206-212, 2010)

Premature thelarche (PT) is characterised by precocious breast development without any other sign of puberty, normal height velocity (HV) and normal bone maturation, while girls with central precocious puberty (CPP) show increased HV, bone maturation and increased serum IGF-I and IGFBP-3 levels. This prompted us to study serum IGF-I and IGFBP-3 concentrations in girls with PT. Thirty-nine girls with premature breast development were studied and classified as PT or CPP according to clinical and laboratory evaluation. Normal prepubertal and pubertal girls were studied as controls. Serum IGF-I and IGFBP-3 were determined in all girls by IRMA. IGF-I levels in PT (155 +/- 61 microg/l) were lower than in CPP (337 +/- 149 microg/l) or late-pubertal controls (355 +/- 84 microg/l) and similar to those found in prepubertal (113 +/- 72 microg/l) and early-pubertal (222 +/- 81 microg/l) girls. Considering the SDS of IGF-I for chronological age (CA), the values observed in PT were in an intermediate position between CPP and prepubertal controls and statistically similar to those observed in CPP and prepubertal girls. IGFBP-3 levels in PT (2.1 +/- 0.5 mg/l) were similar to those found in CPP (2.5 +/- 0.8 mg/l), but only the latter were higher than in prepubertal girls (1.9 +/- 0.9 mg/l). IGF-I/IGFBP-3 molar ratios in PT were in an intermediate position between CPP and prepubertal controls. In conclusion, IGF-I and IGF-I/IGFBP-3 values in PT are intermediate between those observed in prepubertal children and in CPP, suggesting that PT could be a very early stage of puberty with slight but real changes in the GH-IGF axis.

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

The objectives of treatment for children with central precocious puberty (CPP) are to avoid psychosocial problems caused by early pubertal development and to normalize adult height (AH). A long-acting GnRH analog is the treatment of choice for CPP. GnRH analog administration effectively arrests further development of secondary sex characteristics, slows bone age (BA) maturation, increases pubertal height gain, and is believed to eventually improve AH prognosis. However, the improvement of AH is not well established. It is reported that GnRH analog is effective to improve adult height only in early onset (girls <6 years) CPP [1]. Although BA maturation is decelerated by suppressing gonadotropins with GnRH analog and pubertal period is elongated, growth rate diminishes due to suppressed sex steroid hormone and, in part due to decreased GH secretion. For the evaluation of efficacy of GnRH analog for adult height improvement, one problem is that the prediction method for adult height in CPP is not established. It is reported that predicted adult height (PAH) using the Bayley-Pinneau table for accelerated BA overestimated AH in untreated patients with CPP, and the PAH based on the projected height SD score for BA is useful [2]. Most Asian countries use a starting dose of 100 µg/kg/month of leuproride acetate depo [3]. During GnRH analog treatment, serum concentrations of LH, testosterone or estradiol should be monitored as well as pubertal changes and bone age, height and height velocity. For some older patients, a dose of up to 180µg/kg/month of leuproride acetate depo is necessary to suppress LH concentration less than 0.5 mIU/ml. When growth velocity is decreased, possible options is to add growth hormone or anabolic steroid hormone only in boys. The decision to stop therapy should be individualized and based on various factors such as growth velocity, bone age, chronological age, predicted adult height, emotional maturity, and patient’s wish. After treatment discontinuation, long-term follow up is recommended for adult height, reproductive function and bone mineral density.

Objectives The assessment of hand-wrist films to identify skeletal maturation stage is a commonly used method for the determination of the status of a growing patient. However, there is limited information available regarding skeletal growth evaluation in subjects with a unilateral cleft lip and palate (UCLP). Therefore, the current study aimed to examine skeletal and chronological ages in subjects with a UCLP for comparison with those of a non-cleft control group to derive clinical guidelines. Methods Hand-wrist films of 45 UCLP subjects (24 male, 21 female) and 45 Angle Class I orthodontic patients (17 male, 28 female) were evaluated. Skeletal age was assessed by comparing ossification events with standard radiographs illustrated in the Greulich-Pyle atlas and recording based on the best match of maturity criteria. Results A high correlation coefficient was observed between skeletal and chronological ages in the overall study sample (p &lt; 0.01) (N = 90). Skeletal age (11.4 years) was delayed in the UCLP group when compared with chronological age (12.3 years), although the difference between the two was statistically insignificant. Skeletal age (13.6 years) was similar to chronological age in the control group (13.1 years). Conclusions The discrepancy between chronological and skeletal age was greater in UCLP subjects compared with controls. Given that the skeletal age of male and female UCLP subjects was delayed in comparison with their chronological ages, it is of particular importance that hand-wrist films should be used instead of chronological age to assess the growth status of UCLP subjects.

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.

Purpose This study investigated the influence of obesity on the clinical course and effect of gonadotropin-releasing hormone analog (GnRHa) treatment in girls with central precocious puberty (CPP).Methods Medical records of 182 girls with CPP treated with GnRHa were reviewed. They were divided into 2 groups: normal weight (n=108) and overweight/obesity (n=74). Chronological age (CA), bone age (BA), difference between BA and CA (BA–CA), standard deviation score (SDS) of height, body mass index (BMI), predicted adult height (PAH), and laboratory findings were compared at baseline, after 1 year, and at the end of GnRHa treatment in both groups.Results Mean BMI SDS at baseline was 0.08±0.60 in the normal weight group and 1.55±0.36 in the overweight/obesity group. Initial CA, BA, midparental height, and PAH were similar between the 2 groups. BA–CA after treatment was significantly decreased compared to baseline in both groups (P<0.001). Between the 2 groups, a decrease in BA–CA during treatment showed no significant difference. PAH at the end of treatment was significantly increased compared to baseline in both groups (P<0.001). PAH at the end of treatment in the overweight/obesity group (159.88±3.41 cm) was similar to that of the normal weight group (159.19±3.25 cm). Comparing the 2 groups according to change in BMI after treatment, there were no differences in ΔPAH, ΔBA–CA, and Δheight SDS for BA.Conclusions GnRHa treatment in obese girls with CPP improved the height outcome and had similar results in normal weight CPP girls. Obesity might not affect the efficacy of GnRHa in girls with CPP.

The question as to whether treatment with short-acting or with slow-release gonadotropin-releasing hormone (GnRH) agonists has different effects on growth and bone maturation when treating girls with central precocious puberty has not yet been studied. In a meta-analysis, we compared 21 naive girls with central precocious puberty who were treated with buserelin with 22 naive girls with central precocious puberty who received Decapeptyl in depot form. Treatment lasted for at least 18 months. At the start of therapy, chronological age, bone age, growth velocity and pubertal stage in the two groups were very similar. During the first 6 months of treatment, significantly more phases of incomplete suppression of pituitary-gonadal activity occurred in the buserelin group. As a result, growth velocity and bone maturation (delta bone age/delta chronological age) remained significantly higher than in the Decapeptyl Depot group (p < 0.0001 and p < 0.01, respectively). In contrast to the Decapeptyl Depot group, the height standard deviation score (SDS) for bone age in the buserelin group did not change significantly in the first 6 months of treatment, and the predicted adult height decreased. Between the 6th and 18th months of therapy, the development of growth rate, delta bone age/delta chronological age, height SDS for bone age and predicted adult height in both groups became almost identical. However, the rate of growth and bone maturation in the buserelin group remained faster than in the Decapeptyl group, though not significantly so. The mean predicted adult height had risen significantly after 18 months in the Decapeptyl Depot group but not in the group treated with buserelin.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Skeletal age (SA) tends to be advanced for chronological age (CA) in adolescent male soccer players.Aim: The study compared SA assessments with the TW3 and Fels methods in a sample of male, elite youth soccer players.Methods: SAs were assessed with the Tanner–Whitehouse 3 (TW3) radius–ulna–short bone (RUS) and Fels methods in a sample of 40 elite youth soccer players 12.5–16.1 years of age. Players were classified as late, on time or early on the basis of relative SA, the difference between SA and CA. Players who reached skeletal maturity were labeled mature.Results: SA was in advance of CA. Among 14 players >15.0 years, two are skeletally mature with the Fels method (CA 15.7 and 15.9 years), while 11 are skeletally mature with the TW3 method (CA 15.0–16.1 years).Conclusion: The TW3 and Fels methods yield different SAs in elite youth soccer players. Significantly more 15-year-old boys are classified as skeletally mature with the TW3 method than with the Fels method. These observations have implications for international age group competitions as well as for medico-legal circumstances that require CA verification. SA is not a valid measure of CA and should not be used as such.

PurposeThe progressivity of central precocious puberty (CPP) seems to depend on the age at presentation. We evaluated the clinical courses of CPP girls according to their age at initiation of treatment.MethodsOne hundred thirty five girls with CPP diagnosed between Jan. 2003 and Dec. 2009 and regularly followed for more than one year were included. They were treated with gonadotropin-releasing hormone agonists (GnRHa) every four weeks. Subjects were divided into two groups based on whether they were treated before (Group I, N=20) or after seven years of age (Group II, N=115). We compared the anthropometric parameters, the predicted adult height (PAH), predicted treatment periods, and the laboratory findings of the two groups every six months.ResultsOut of 135 CPP patients, 123 were idiopathic and twelve had neurogenic problems. At the baseline, patients' average bone age (BA) was significantly older than chronologic age (CA) and PAH was significantly shorter than target height (TH). BA and CA were significantly older in group II, but the BA/CA ratio was significantly greater in group I. The average treatment period required to overcome the CA-BA difference was 4.64 yr (group I vs II; 7.98 yr vs 4.24 yr, P < 0.01), and the period needed to overcome PAH-TH difference was 2.49 yr (group I vs II; 4.37 yr vs 2.32 yr, P < 0.01).ConclusionAmong the girls with CPP, the younger age group had more advanced BA than CA, and needed significantly longer treatment periods to overcome the BA-CA gap and PAH-TH gaps.