Yr In Girls Research Articles

SUN-090 Investigation of Imprinting Defects in MKRN3 and DLK1 in Children with Idiopathic Central Precocious Puberty Through Specific DNA Methylation Analysis

Background: Loss of imprinting has been implicated in the pathogenesis of several human diseases. Monogenic causes of central precocious puberty (CPP) were identified in families with loss-of-function mutations affecting mainly the coding region of two paternally expressed imprinted genes: Makorin ring finger 3 (MKRN3) and Delta-like 1 homolog (DLK1). The role of imprinting defects involving these two genes in CPP has not been described so far.Objective: To investigate the methylation status at primary differentially methylated regions (DMR) of MKRN3 and DLK1 in a cohort of children with idiopathic CPP.Patients and methods: One-hundred and twenty CPP patients (112 sporadic, 8 familial; 115 females, 5 males) were selected for analysis. Leukocyte DNA was obtained from all patients. MKRN3 and DLK1 pathogenic allelic variants were first excluded by DNA sequencing analysis. Bisulfite treatment followed by Allele-Specific Methylated Multiplex Real-Time Quantitative PCR was performed with leukocyte DNA, analyzing separately the methylation index (MI) of MKRN3:TSS-DMR and DLK1/MEG3:IG-DMR for each patient. The MI results were compared with controls with normal pubertal development.Results: Mean age at puberty onset was 5.8 ±1.9yr for girls and 7.2 ±2.6yr for boys. Hypomethylation at DLK1/MEG3:IG-DMR was identified in 3 patients (I, II and III) with sporadic CPP: MI 10%, 16% and 11%, respectively. Interestingly, cases II and III were both girls who had been firstly referred to pediatric endocrinology for presenting precocious menarche; while case I was a boy who had been referred for presenting mild growth retardation, and developed CPP during monitoring. In addition, during follow-up, other clinical findings were noticed: being born small for gestational age, prominent forehead, small hands/feet, overweight/obesity and early onset type 2 diabetes in case III. Additional genetic investigation included SNP array in cases I and II, identifying a maternal uniparental disomy at chromosome 14 (upd(14)mat). Meanwhile, case III had normal genomic microarray and microsatellites analysis, excluding copy number variants and upd(14)mat, and indicating a mechanism of epimutation at DLK1/MEG3:IG-DMR. Uniparental disomy and epimutation are molecular mechanisms associated with the imprinting disorder known as Temple syndrome. In the remaining cases, mean MI for DLK1/MEG3:IG-DMR was 49±2%. In all cases, mean MI for MKRN3:TSS-DMR was 49±6%. There were no significant correlations between age at puberty onset and MI for MKRN3 (p=0.69) and DLK1(p=0.45).Conclusion: There was no leukocyte DNA methylation defect at MKRN3 imprinting control region in the idiopathic CPP cohort. DLK1/MEG3:IG-DMR hypomethylation was identified in 3 patients with CPP and additional findings of Temple syndrome, indicating that loss of effective imprinting of DLK1 locus is a mechanism leading to CPP.

SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes

Background: Central precocious puberty (CPP) is mostly described as an isolated entity. Few studies have shown an association of CPP with complex cases or genetic syndromes, but without making inferences on molecular causalities.Objective: To genetically investigate a cohort of patients with CPP associated with complex phenotypes using high throughput methodologies.Patients and methods: From a large cohort of patients with idiopathic CPP followed at a university hospital outpatient clinic, thirty-eight patients were selected for high throughput genetic investigation for presenting at least 3 additional clinical features and conditions, characterizing complex phenotypes. All had normal brain MRI. Pathogenic allelic variants in CPP known genes were initially excluded. All patients were submitted to genomic microarray (SNP or CGH arrays). A subset of patients was also submitted to whole-exome sequencing (11 cases) or target panel sequencing (18 cases).Results: Among the group of 38 patients (35 girls, 4 boys; 21 sporadic, 17 familial), mean age at puberty onset was 5.8 ±2.1 and 8.3 ±3.0 yr in girls and boys, respectively. The more prevalent clinical features described included metabolic, growth and neurocognitive phenotypes; less prevalent features included dysmorphic features and congenital anomalies. Pathogenic or probably pathogenic genetic defects were identified in 9 cases: 5 sporadic (all identified as de novo) and 4 familial. Defects in sporadic cases were as follows: three cases with 7q11.23 deletion (Williams syndrome); one girl with ventricular arrhythmia presenting a rare 1p31.3 duplication, involving NFIA gene coding a transcription factor of NFI family with hypothalamic expression; and one girl with imperforate anus and learning difficulties with rare frameshift variants in AREL1 gene (p.Ser229Aspfs*3) coding an ubiquitin ligase, and TNRC6B gene (p.Gly665Leufs*35) coding a regulator of translational inhibition. In the four familial cases, the genetic defects segregated with CPP in a dominant inheritance mode. Three cases from unrelated families presented growth phenotypes and Xp22.33 deletions, including SHOX gene and other elements. One boy with maternal familial CPP and autism had two rare potentially pathogenic variants: a frameshift deletion in MKKS gene (p.Phe144Leufs*14); and a missense variant (p.Pro267Leu) in UGT2B4 gene. Interestingly, the later gene encodes a protein involved in estrogen hydroxylation and is associated to menarche timing in GWAS.Conclusion: Novel genetic defects were identified in 23% cases of CPP associated with complex phenotypes. Three chromosomal regions represented loci potentially implicated in CPP: Xp22.33, 7q11.23 and 1p31.3. Five genes were identified as candidate genes associated with CPP: NFIA, AREL1, TNRC6B, MKKS and UGT2B4.

Changes In Body Height And Weight Of Children And Adolescents In China During 1943-2014

PURPOSE: To compare body height and weight of 5-19 years old children and adolescents between 1943 and 2014 in China, and to determine the change in morphological development in Chinese children and adolescents over 71 years. METHODS: Based on the Student Physical Standard (made by the Physical Education Committee of the Ministry of Education of China, with unknown sample size) in 1943 and the National Physical Fitness Surveillance Report (from the General Administration of Sport of China, with sample size of 358725.) in 2014, the data in body height and weight of 5-19yr boys and 5-17yr girls were compared. The difference of height and weight average of children and adolescents in each age, and the growth of each age were calculated. And contrast chart were generated. Due to the sample size data could not be obtained when the Student Physique Standard is established, in this study we couldn’t test the mean difference. Therefore this study used simple statistical description to reflect the growth trend of children and adolescents. RESULTS: The average height in each age for boys between 5-19yr and girls between 5-17yr in 2014 was significantly higher than that in 1943, the differences were 4.6(19yr)-20.4(13yr)cm for boys and 3.4(17yr)-14.7(11yr)cm for girls. The average weight in each age for boys between 5-19yr and girls between 5-17yr in 2014 was significantly higher than in 1943, and the differences were 2.4(5yr)-14.8(13yr)kg for boys and 1.2(5yr)-11.6(11yr)kg for girls. In 1943,boys between 5-14yr were at a lower physical development level than girls, but boys after 14yr were at a higher physical development level than girls. However, in 2104,boys between 10-11yr were at a similar physical development level compared to girls, in each of the other ages boys were at a higher level than girls. In 1943, the height growth spurt periods were from 12-13yr in girls and from 15yr in boys, and the weight growth spurt periods were from 12-15yr in girls, and from 14-15yr in boys. In 2014, the growth spurt periods for both height and weight were 11yr in girls and 13yr in boys. CONCLUSION: Compared to the data collected in 1943, Chinese children in 2014 were higher and heavier. Moreover, a 1-2 years gap was also observed in terms of the growth spurt age. Supported by the Sports Medicine key laboratory of General Administration of Sport of China(A2015C06).

Prevalence of Auditory Processing Disorder in School-Aged Children in the Mid-Atlantic Region.

Although auditory processing disorder (APD) is a widely recognized impairment, its prevalence and demographic characteristics are not precisely known in the pediatric population. To examine the demographic characteristics of children diagnosed with APD at a tertiary health-care facility and the prevalence of pediatric APD. A cross-sectional study. A total of 243 children (149 boys and 94 girls) who were referred to the Nemours Audiology Clinics in the Delaware Valley for an APD evaluation. The mean ages were 9.8 yr for boys and 9.7 yr for girls. Out of 243 children referred for an APD evaluation, 94 children exhibited one or more auditory processing deficits in the areas of auditory closure, auditory figure ground, binaural integration, binaural separation, and temporal processing. Demographic and audiological data, clinical history (parental reports on prenatal and postnatal information, birth weight and height, medical and developmental history, otologic/audiological history, education information, behavioral characteristics), and results of the APD test battery were retrospectively obtained from the electronic medical records of each participant. The prevalence of APD was estimated using the total number of students enrolled in the same school attended by each participant in the 2011 academic year as cohort. The prevalence of APD was 1.94 per 1,000 children in this study. We found that prevalence of APD among the children who attended private schools was more than two times higher than the children who attended public schools. The results also revealed that the majority of children referred to the clinics were Caucasian (85.6%), whereas minority groups were underrepresented for this geographical area with only 3.7% of Hispanic or Latino children and 5.8% of Black or African American children. The estimated prevalence of APD in the current study was lower than the previously published estimates. The difference might be due to the diagnosis criteria of APD among studies as well as the use of school enrollment number as the referenced population to estimate prevalence in our study. We also found a significant difference in APD prevalence depending on the school types. The findings of higher prevalence rates among the children attending private schools and higher proportion of Caucasians children referred for APD evaluation suggest that more children among those in public schools and in the Hispanic and African American groups should have been referred for an APD evaluation. Hence, the current estimate is likely an underestimate of the actual APD prevalence. The low percentage of Hispanic or African American children referred to the clinic for APD evaluations may be related to the socioeconomic status and linguistic differences among the concerned families. The results of this study raise the importance of adapting the APD test battery for children with a different linguistic background as well as increasing awareness of available clinical resources to all families in our area.

Efficacy and Safety of Leuprolide Acetate 3-Month Depot 11.25 Milligrams or 30 Milligrams for the Treatment of Central Precocious Puberty

GnRH agonist (GnRHa) monthly injections are frequently used in the treatment of central precocious puberty (CPP). The 3-month leuprolide depot 11.25- and 30-mg formulations are newly approved treatment options. The aim of the study was to investigate the safety and efficacy of leuprolide acetate 3-month depot formulations for the treatment of CPP in children. This was a phase III, randomized, open-label, dose-ranging 6-month study. Twenty-two U.S. medical centers (including Puerto Rico) participated. Children diagnosed with CPP (n = 84), who were either treatment naive or previously treated with GnRHa, were recruited. Chronological age at onset of pubertal signs was less than 8 yr in girls and less than 9 yr in boys, and bone age was advanced over chronological age at least 1 yr. Leuprolide acetate depot (11.25 or 30 mg) was administered im every 3 months. Biochemical [peak-stimulated LH, estradiol (girls), and testosterone (boys)] and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed. Peak-stimulated LH was suppressed in the 11.25- and 30-mg dose groups in 78.4 and 95.2%, respectively, of children from months 2 through 6. There were nine treatment failures (peak-stimulated LH >4 IU/liter) in the 11.25-mg group and two in the 30-mg group. Basal sex steroid suppression, growth rates, pubertal progression, bone age advancement, and adverse events were similar with either dose. Treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, was well tolerated, and may positively impact patient convenience and compliance.

Oral glucose tolerance testing in children with cystic fibrosis

Cystic fibrosis (CF) related diabetes is the most common comorbidity in persons with CF. International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend annual oral glucose tolerance testing (OGTT) screening starting at age 10. The OGTT might be recommended in younger children if, as in adults, it provided clinically relevant prognostic information. A database review was performed to determine whether OGTT findings in children with CF predict subsequent clinical course. A retrospective matched-pair cohort study was based on OGTTs performed during 1998-2003. Children aged 6-9 were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT). Children with AGT were matched by age and gender to those with NGT. Clinical status was assessed at baseline and 5 yr later. In a separate investigation, diabetes and prior AGT status of children aged 10-18 were used to assess predictions derived from the cohort study. In 1998-2003, 39 of 94 children had AGT. Of these, 31 had sufficient follow-up data to be included. Both at baseline and 5 yr later there was no significant difference in height, weight, body mass index (BMI) or lung function between AGT and NGT. Diabetes developed in 13 AGT (42%) and one NGT (3%) [odds ratio (OR) 11, p = 0.0009]. Age of diabetes onset was 12 ± 1 yr in boys and 11 ± 1 yr in girls, compared to approximately 23 yr in the general CF population. Fifteen current children age 10-18 who had AGT before age 10 have diabetes, close to the prediction of 19. AGT in children with CF age 6-9 yr identifies those at high risk for progression to early onset diabetes.

Reference Ranges for Serum IGF-1 and IGFBP-3 Levels in Chinese Children During Childhood and Adolescence

Serum levels of insulin-like growth factor-1(IGF-1) and insulin-like growth factor binding protein-3(IGFBP-3) reflect endogenous growth hormone secretion, and serum IGF-1 and IGFBP-3 values should be ethnic-specific, thus we established the reference ranges for serum IGF-1 and IGFBP-3 in Chinese children aged 6-18 yr according to age, sex, puberty stage and BMI. The study was included 837 children (age 6-18 yr, 416 boys and 421 girls) from different schools in Daqing, Beijing and Shanghai. Serum IGF-1 and IGFBP-3 were determined by a chemiluminescent assay system (IMMULITE 1000). The results show that IGF1 reached peak levels at around 13 yr in boys and 11 yr in girls while IGFBP-3 peaked at 14 yr in boys, and 11 yr in girls. Both IGF-1 and IGFBP-3 were at platform or decreased slightly after these ages. At each corresponding age, IGF-1 levels tended to be higher in boys compared to girls, while girls had higher IGFBP-3 levels than boys. A model for calculation of standard deviation scores of IGF-1 and IGFBP3 according to age, sex and pubertal stage was established. These normative data should facilitate child care, growth monitoring, clinical diagnosis and to follow up on GH treatment.

Recurrent headache in Indian adolescents

To analyze the epidemiology and characteristics of primary recurrent headaches in Indian adolescents. This cross sectional study was conducted in three urban public schools. Adolescents of 9(th) to 12(th) grades were included and they were given a questionnaire in their classrooms in the presence of at least one of the authors, who assisted them in filling it. They were asked to provide responses based on most severe recurrent headache they had experienced rather than the more frequent one. Diagnosis was based upon the information contained in questionnaire, however, where it was inadequate, those subjects were approached telephonically. Statistical analysis was done with the help of SPSS v. 11.0. Descriptive analysis, Chi-Square test, Fisher's Exact test, and independent sample't' test were run. 2235 adolescents were included in the present study (boys: girls 1.6:1). 57.5% adolescents reported recurrent headaches in past one year. Migraine was the most prevalent (17.2%) headache followed by unspecified (14.9%) and tension type headache (11%). Family history of headache was more common in adolescents with headache (p < 0.001) compared to those without headache. Average age of headache onset was 11.33 yr (10.72 yr in girls vs. 11.75 years in boys; p < 0.001). 37.1% adolescents complained of progression of headache since its onset. A significantly higher proportion of girls suffered headache (p=0.018), particularly migraine, than boys. However, other characteristics of headache were not dependent upon gender. Headache was more prevalent in higher grades. Primary Recurrent headaches are prevalent in Indian adolescents and migraine is comparatively the most prevalent type of headache. Female gender and increasing age is associated with higher chances to have headache, particularly migraine. It progresses in approximately one third of sufferers and aura increases the chances of worsening of headache.

Trends, associations and predictions of insulin resistance in prepubertal children (EarlyBird 29)

Rising obesity has been observed in all age groups. Anthropometric cut-points have been used to predict metabolic risk in children, although they are not based on known outcomes. We examined the trends, associations and predictions of metabolic health from anthropometry in prepubertal children. Three hundred and seven healthy children were examined annually between 5 and 8 yr. height, weight, body mass index (BMI), sum of skinfold thickness at five sites (SSF) and waist circumference (WC). homeostasis model assessment of insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Two hundred and thirty-one [131 boys (B) and 100 girls (G)] children had complete data sets at all four time points. (i) All measures of adiposity rose from 5 to 8 yr (BMI - B: +3.4%, G: +5.7%; WC - B: +10.4%, G: +11.8%; SSF - B: +23.3%, G: +30.7%, all p < 0.001). HOMA-IR unexpectedly fell (B: -16.6%, p = 0.01; G: -32.5%, p < 0.001). This fall was significant between 5 and 6 yr in both genders (5-6 yr - B: -17.8%, p < 0.001; G: -20.0%, p = 0.002) and between 6 and 7 yr in girls only (6-7 yr - B: -10.8%, p = 0.12; G: -19.2%, p = 0.001). HDL-C rose (B: +17.8%, G: +17.1%, both p < 0.001) and TG fell (B: -4.8%, p = 0.16; G: -11.6%, p = 0.006). (ii) Correlations between insulin resistance (IR) and anthropometry were poor at 5 yr but strengthened by 8 yr (BMI - B: r = 0.20/0.38, G: r = 0.28/0.49; WC - B: r = 0.25/0.40, G: r = 0.32/0.58; SSF - B: r = 0.11/0.36, G: r = 0.18/0.53). (iii) In girls, but not boys, adiposity at 5 yr predicted IR better at 8 yr (BMI - r(2 )= 0.17; WC - r(2 )= 0.28; SSF - r(2 )= 0.17, all p < 0.001) than it did at 5 yr (BMI - r(2 )= 0.08, p < 0.01; WC - r(2 )= 0.10, p < 0.01; SSF - r(2 )= 0.03, p = 0.07). Cross-sectional association cannot indicate direction of trend or predict the future. Predicting metabolic health from anthropometric measures in prepubertal children requires longitudinal data, tracking variables from childhood into adulthood. Until the data set reaches adulthood, it is probably not safe to make recommendations on which children to 'target' or whether early intervention would be of benefit.

Monitoring Bone Growth Using Quantitative Ultrasound in Comparison with DXA and pQCT

Quantitative ultrasound (QUS) is a safe, inexpensive, and nonradiation method for bone density assessment. QUS correlates with, and predicts fragility fractures comparable to, dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) in postmenopausal women. However, its validity in monitoring bone growth in children is not well understood. Two hundred and fifty-eight 10–13 yr pubertal girls and 9 37–43 yr adults without diseases or history of medications known to affect bone metabolism were included in the 2-yr prospective study. Calcaneal broadband ultrasound attenuation (cBUA) was assessed using QUS-2 (Quidel, Santa Clara, CA), speed of sound of tibial shaft (tSOS) using Omnisense (Sunlight Technologies, Israel), apparent volumetric BMD (vBMD) of tibial shaft using peripheral quantitative computed tomography (pQCT; XCT2000, Stratec), and femoral neck (FN) and lumbar spine 2–4 (LS) areal BMD (aBMD) using DXA (Prodigy, GE). Over the 2 yr in girls, FN and LS aBMD showed the largest increases (17 ± 8% and 20 ± 8%, respectively), followed by tibial vBMD and cBUA (10 ± 5% and 9 ± 9%, respectively). There was no apparent change in tSOS (2 ± 3%). The increase in FN and LS aBMD attenuated 48% and 40%, respectively, after adjustment of the change in body size. The change of cBUA correlated significantly with change in tibial vBMD and FN and LS aBMD ( r = 0.24–0.40). At the matched location, tSOS correlated only with cortical vBMD, not with cortical thickness, apparent vBMD, or bone size. The long-term reproducibility, assessed using the concordance correlation coefficient of young adults' pre-post measurements, was substantially lower in tSOS than cBUA, tibial vBMD, FN, and LS aBMD (0.65 vs 0.97, 0.95, 0.98, and 0.96; p < 0.05). The transverse transmission method-derived calcaneal BUA, but not the axial transmission method-derived SOS, is comparable to DXA and pQCT for monitoring bone densitometric change in pubertal girls. The role of QUS in fracture-risk prediction in children and adolescents needs further investigation.

Puberty onset in Northern Italy: A random sample of 3597 Italian children

Entering puberty is one of the most important milestones in life. Studies from around the world have shown that age of pubertal changes onset can vary with race and ethnicity, environmental conditions, geographical location and nutrition. In the last century, the onset of puberty progressively shifted back towards younger ages in several European countries, with a levelling off in the last decades. The aim of our study was to describe the prevalence of secondary sexual characteristics in a group of children living in Northern Italy comparing them with the percentile values published by Tanner in 1976. We enrolled 3496 children drawn from public schools and evaluated height, weight and pubertal stages. The analysis of our data evidenced that the 50th percentile age of puberty onset in both sexes decreased by about 1 yr compared to data published by Tanner. Mean body mass index (BMI) z-score was significantly higher (p = 0.01) in pubertal than in pre-pubertal girls, on the contrary it was higher (p = 0.005) in pre-pubertal than in pubertal boys. In conclusion, our study found that girls and boys of our region are beginning pubertal development about 1 yr earlier than Tanner's British population. Taking into consideration the 3rd percentile age for Tanner's breast stage 2 in girls and testicular volume (TV) of 4 ml in boys, the current internationally used cut-off age for precocious puberty, i.e. 8 yr for girls and 9 yr for boys, can be maintained in our population.

Results of Long-Term Follow-Up after Treatment of Central Precocious Puberty with Leuprorelin Acetate: Evaluation of Effectiveness of Treatment and Recovery of Gonadal Function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty

We evaluated the effect of leuprorelin treatment on adult height (AH) and followed recovery of reproductive function in 63 girls and 13 boys with central precocious puberty (CPP). Mean treatment durations were 3.8 +/- 2.0 and 4.1 +/- 2.5 yr, and posttreatment follow-up durations were 3.5 +/- 1.3 and 2.6 +/- 1.1 yr for girls and boys, respectively. AH was 154.5 +/- 5.7 cm for girls, and 89.5% of girls reached AH within their target height range. For boys, AH was 163.2 +/- 13.0 cm, and 90.9% reached target height range. It appeared that the Bayley-Pinneau method, modified for Japanese children, using a table for advanced bone age (BA), overestimated AH in CPP; and this method, using a table for average BA and projected height for BA, was suitable for prediction of AH in CPP. Menarche or remenarche occurred in 96.8% of girls at the age of 13.1 +/- 1.5 yr. Of 11 girls who contributed urine samples, all seven idiopathic and two organic cases were considered to have ovulation. Serum testosterone levels reached normal adult level in all boys. In conclusion, long-term leuprorelin treatment for children with CPP improved AH and had no adverse effects on recovery of reproductive function.

Short children born small for gestational age and treated with growth hormone for three years have an important catch-down five years after discontinuation of treatment.

The potential benefits of GH treatment, resulting in a significant height gain in children born small for gestational age (SGA), have been well documented for the last 10-15 yr. There is, however, no consensus on how to treat patients to attain a normal adult height. We have previously reported in a controlled study that recombinant human GH (1.4 IU/kg.wk or 0.47 mg/kg.wk) given daily induces an important increase in height velocity (HV) in young SGA children with severe short stature. Consequently, a total gain of 2 SD score (SDS) in height resulted in a mean height of -1.3 +/- 0.8 SDS after 3 yr of treatment. The aim of the present report was to assess the consequences of interruption of GH treatment during a 5-yr follow-up period on HV, height, bone age (BA), puberty, and glucose tolerance in SGA children. There was a dramatic decrease of HV SDS, especially evident during the early part of the observation period, with a loss of 3.9 HV SDS during the first year. After 5 yr off treatment, mean HSDS was -2.2 +/- 1.2, still above the pretreatment level (P < 0.0001). Consequently, the interruption of GH administration resulted in a reduction of 1 SDS in height. However, BA did not advance more than 4 yr, and the ratio Delta BA/Delta chronological age at follow-up was similar to pretreatment values. Sixty percent of the children started puberty during the follow-up, and the chronological age and BA at the onset of puberty were 11.4 +/- 1.0 yr and 10.9 +/- 0.5 yr in girls, and 12.1 +/- 1.4 yr and 11.3 +/- 1.1 yr in boys, respectively. Oral glucose tolerance testing after 1 yr and up to several years after discontinuation of GH therapy showed only minor, variable, and inconclusive changes in glucose tolerance. In conclusion, we have shown that tolerance and safety data during and after GH treatment continue to be reassuring. A reduction of HV SDS and height SDS 5 yr after interruption of GH therapy is a strong argument for a continuous GH treatment or a discontinuous treatment with short fall-off intervals at least until puberty.

Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience.

We report 98 children who have reached final adult height in a long-term trial of LHRH agonist treatment. These children were 5.3 +/- 2.1 yr old at the start of treatment and were treated with either deslorelin (4 microg/kg.d sc) or histrelin (4-10 microg/kg.d) for an average of 6.1 +/- 2.5 yr. Final height averaged 159.8 +/- 7.6 cm in the 80 girls, which was significantly greater than pretreatment predicted height (149.3 +/- 9.6 cm) but still significantly less than midparental height (MPH) (163.7 +/- 5.6). Final height averaged 171.1 +/- 8.7 cm in the 18 boys, which was significantly greater than pretreatment predicted height (156.1 +/- 14.2 cm) but still significantly less than MPH (178.3 +/- 5.2 cm). However, the average adult height of the 54 children who had less than a 2-yr delay in the onset of treatment was not significantly different from their MPH, and 21 children exceeded MPH. Final height SD score correlated positively with duration of treatment (P < 0.01), midparental height (P < 0.001), predicted height at the start of treatment (P < 0.001), and growth velocity during the last year of treatment (P < 0.001) and correlated inversely with delay in the onset of treatment (P < 0.001), age at the start of treatment (P < 0.001), bone age at the start of treatment (P < 0.001), bone age at the end of treatment (P < 0.001), breast stage at the start of treatment (P = 0.02), and bone age minus chronological age at the start of treatment (P = 0.001). We conclude that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 yr for girls or 9 yr for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronological and bone age at the onset of treatment all lead to greater final height. All children with onset of pubertal symptoms before age 8 in girls and age 9 in boys should be evaluated for possible treatment. Treatment is appropriate in children with rapidly progressing puberty, accelerated bone maturation, and compromise of adult height prediction, regardless of bone age or chronological age at time of evaluation. However, once treatment is considered appropriate, it should be initiated quickly, because longer delays lead to shorter final height. In addition, the longer the treatment is continued, the greater is the final height outcome.

Premature adrenarche.

Adrenarche is the puberty of the adrenal gland. The descriptive term "pubarche" indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys. The chief hormonal products of adrenarche are DHEA and DHEAS. The well-documented evolution of adrenarche in primates and men is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspects of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche and/or final height. Mechanisms for initiation of adrenal androgen secretion at adrenarche are still not well understood. Maturational increases in 17-hydroxylase and 17,20-lyase are seen together with a lower activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). There is good evidence that the zona reticularis is the source of adrenal androgens. Adrenarche and gonadarche are regulated differently. Although premature adrenarche has been thought to be a benign, normal variant of puberty, our findings indicate that, for certain girls, premature adrenarche represents an early clinical feature of syndrome X (obesity, hypertension, dyslipidemia, insulin resistance). Perhaps the early identification of these patients will permit early therapy, such as lifestyle changes, including dietary and activity level intervention. As insulin resistance is an underlying feature of premature adrenarche, it seems rational to assess the efficacy and safety of using insulin-sensitizing agents to treat these individuals. In the absence of controlled longitudinal studies, the cross-sectional data available from our studies suggest that premature pubarche driven by premature adrenarche and hyperinsulinemia may precede the development of ovarian hyperandrogenism, and this sequence may have an early origin with low birth weight serving as a marker. Premature adrenarche may thus be a forerunner of syndrome X in some girls.

Premature adrenarche--normal variant or forerunner of adult disease?

Adrenarche is the puberty of the adrenal gland. The descriptive term pubarche indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys. The chief hormonal product of adrenarche is dehydroepiandrosterone (DHEA) and its sulfated product DHEA-S. The well documented evolution of adrenarche in primates and man is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspect of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche in final height. Both extra- and intraadrenal factors regulate adrenal androgen secretion. Recent studies have shown that premature adrenarche in childhood may have consequences such as functional ovarian hyperandrogenism, polycystic ovarian syndrome, and insulin resistance in later life, sometimes already recognizable in childhood or adolescence. Premature adrenarche may thus be a forerunner of syndrome X in some children. The association of these endocrine-metabolic abnormalities with reduced fetal growth and their genetic basis remain to be elucidated.

Advanced dental maturity in children with juvenile rheumatoid arthritis.

The subjects of the investigation comprised 95 girls and 73 boys with juvenile rheumatoid arthritis (JRA), and 102 girls and 66 boys representing healthy controls, all with a chronological age from 6.3 to 14.4 yr. The dental development was assessed from panoramic radiographs using a seven-tooth model. The radiographs were evaluated on three separate occasions with a minimum interval of one month in a randomized order, and blind with respect to absence or presence of JRA. In both JRA patients and healthy controls, dental maturity was ahead of chronological age. In addition, dental maturity was significantly advanced in JRA patients with 0.26 yr in girls and 0.28 yr in boys. It is tentatively suggested that the advanced dental development in JRA patients compared with healthy children was partly an effect of treatment with cortisone, while the influence of the disorder per se remains to be elucidated.

Neurofibromatosis type 1 and precocious puberty.

Since neurofibromatosis type 1 (NF1) is a well known cause of precocious puberty (PP), we reviewed 412 NF1 pediatric patients to evaluate the prevalence of PP, the association with optic pathway tumors (OPT), and other clinical, auxological and hormonal data. Thirty-one of 412 patients had OPT (7.5%), 10/412 PP (2.4%), and in seven of these PP was associated with OPT (7/31, 22.6%). OPT in patients with PP involved the chiasm in four patients, and the optic nerves alone in three patients. The age at the onset of puberty (or better at diagnosis) ranged from 5.2 to 7.5 yr in girls (n=6) and from 7.9 to 8.9 yr in boys (n=4). LHRH agonist therapy was used in only three children because in the others the predicted height at diagnosis was good, treatment was refused or the patients were referred to us too late. The three treated patients attained a final height within the familial range. In the untreated patients the progression of puberty was not too rapid and final height was slightly below the genetic target in four patients; however, three patients had a final height markedly below the familial range. In conclusion, the prevalence of PP is increased in children with NF1, and frequently but not exclusively is associated with OPT. Moreover, sexual precocity does not seem to be necessarily bound to chiasmatic OPT. Treatment seems to be useful in the children with younger age at the onset of puberty or with a progressive decline in predicted final height.

Final Height after Long-Term Treatment with Triptorelin Slow Release for Central Precocious Puberty: Importance of Statural Growth after Interruption of Treatment

The impact of treatment of central precocious puberty (CPP) with GnRH agonists on final statural height (FH) remains controversial, and guidelines on the optimal time point for interruption of these treatments have not been established. We analyzed the long term results of 58 girls and 8 boys uniformly treated with triptorelin slow release formulation (Decapeptyl, triptorelin-SR) for CPP and compared their FH with predicted height before treatment and with the FH of a historical group of patients not treated with GnRH agonist. The FH sd score was close to 0 and was not different from the genetic target height. In girls, FH was improved by 4.8 ± 5.8 cm compared with predicted height before treatment and by 8.3 cm by comparison with a historical group. In boys, comparison with a historical group revealed a 13.7-cm improvement, whereas predicted height before treatment was similar to FH. Three variables were independently associated with FH in girls: the bone age/statural age ratio at the onset of treatment (negatively), the height sd score at the end of treatment, and the posttreatment growth spurt (Δ FH − height at the end of treatment). The influence of the posttreatment growth spurt, itself dependent on age and bone age at the interruption of treatment, suggests that continuing treatment beyond the age of 11 yr in girls does not improve and could actually decrease FH. This point should be evaluated in a formal controlled trial.

Envelope and site specific bone loss in estrogen deficient rats and their response to anabolic therapy with intermittent PTH-treatment

Quantitative ultrasound (QUS) is a safe, inexpensive, and nonradiation method for bone density assessment. QUS correlates with, and predicts fragility fractures comparable to, dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) in postmenopausal women. However, its validity in monitoring bone growth in children is not well understood. Two hundred and fifty-eight 10–13 yr pubertal girls and 9 37–43 yr adults without diseases or history of medications known to affect bone metabolism were included in the 2-yr prospective study. Calcaneal broadband ultrasound attenuation (cBUA) was assessed using QUS-2 (Quidel, Santa Clara, CA), speed of sound of tibial shaft (tSOS) using Omnisense (Sunlight Technologies, Israel), apparent volumetric BMD (vBMD) of tibial shaft using peripheral quantitative computed tomography (pQCT; XCT2000, Stratec), and femoral neck (FN) and lumbar spine 2–4 (LS) areal BMD (aBMD) using DXA (Prodigy, GE). Over the 2 yr in girls, FN and LS aBMD showed the largest increases (17 ± 8% and 20 ± 8%, respectively), followed by tibial vBMD and cBUA (10 ± 5% and 9 ± 9%, respectively). There was no apparent change in tSOS (2 ± 3%). The increase in FN and LS aBMD attenuated 48% and 40%, respectively, after adjustment of the change in body size. The change of cBUA correlated significantly with change in tibial vBMD and FN and LS aBMD (r = 0.24–0.40). At the matched location, tSOS correlated only with cortical vBMD, not with cortical thickness, apparent vBMD, or bone size. The long-term reproducibility, assessed using the concordance correlation coefficient of young adults' pre-post measurements, was substantially lower in tSOS than cBUA, tibial vBMD, FN, and LS aBMD (0.65 vs 0.97, 0.95, 0.98, and 0.96; p < 0.05). The transverse transmission method-derived calcaneal BUA, but not the axial transmission method-derived SOS, is comparable to DXA and pQCT for monitoring bone densitometric change in pubertal girls. The role of QUS in fracture-risk prediction in children and adolescents needs further investigation.