Accelerated pubertal onset in short children with delayed bone age

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Maki Oyachi ◽  
Yoh Watanabe ◽  
Kana Kitayama ◽  
Yuki Yamada ◽  
Shinji Higuchi ◽  
...  
Keyword(s):  
Short Stature ◽  
Standard Deviation Score ◽  
Quadratic Function ◽  
Bone Age ◽  
Pubertal Onset ◽  
Pubertal Growth ◽  
Population Average ◽  
Short Children ◽  
Catch Up ◽  
Current Incidence

Abstract Objectives Constitutional delay of growth (CDG) is usually associated with a delay in pubertal onset (CDGP) and a catch-up growth after puberty. Some individuals, however, have earlier-than-expected pubertal onset resulting in a shorter adult height. We investigated the current incidence of such individuals and that of 30 years ago. Methods The study subjects are 1,312 consecutive Japanese children referred to Osaka City General Hospital (OCGH) for short stature during 2010–2018, and a cohort of 11,256 individuals in the Ogi Growth Research (OGR, 1979–1992). Individuals with the height standard deviation score <−1.0, the bone age (BA)/chronological age (CA) ratio <0.8 at first visits, and without other identifiable causes of short stature were extracted from the record of OCGH. Similarly, individuals meeting the height and bone age criteria were extracted from the OGR record. The pubertal growth onset was auxologically determined as the upward shift from the prepubertal growth curve fitted to a quadratic function. Earlier-than-expected onset was defined as the onset earlier than the population average +1 year. Results From the OCGH cohort, 55 children (38 boys, 17 girls) met the criteria, and earlier-than-expected onset was observed in 34.2% of boys and 29.4% of girls. In the 73 short individuals with delayed bone age in the OGR cohort, earlier-than-expected onset was less common (13.0% for boys and 14.8% for girls). There was no significant association between the timing of pubertal growth onset and the BA/CA ratio, IGF-1, and midparental height. Conclusions Earlier-than-expected pubertal growth onset is common in CDG and possibly increasing.

scholarly journals Undernutrition and Pubertal Timing in Female Survivors of Medulloblastoma and Other Embryonal Tumors

2020 ◽  
Vol 105 (10) ◽  
pp. e3650-e3659
Author(s):  
Jia Zhu ◽  
Henry A Feldman ◽  
Christine Chordas ◽  
Ari J Wassner ◽  
Peter E Manley ◽  
...  
Keyword(s):  
Pubertal Timing ◽  
Cohort Analysis ◽  
Standard Deviation Score ◽  
Bone Age ◽  
Embryonal Tumors ◽  
Pubertal Onset ◽  
Pediatric Medulloblastoma ◽  
Catch Up ◽  
The Impact ◽  
Age Discrepancy

Abstract Context Children with brain tumors may have pubertal onset at an inappropriately young chronologic age. Hypothalamic-pituitary irradiation ≥18Gy has been found to be a risk factor; age at irradiation is associated with pubertal timing. However, the underlying mechanisms are unknown. Objective To determine the impact of body mass index (BMI) and catch-up growth on pubertal timing in females treated for medulloblastoma and other embryonal tumors. Design, Setting, and Patients Retrospective cohort analysis of 90 female patients treated for medulloblastoma and other embryonal tumors at Dana-Farber Cancer Institute/Boston Children’s Hospital from 1996 to 2016. Eighteen individuals met inclusion criteria, with a mean ± SD follow-up period of 11.9 ± 3.4 years. Main Outcome Measures Multiple linear regression models for age at pubertal onset and bone age discrepancy from chronologic age at pubertal onset assessed the joint influences of age at irradiation, hypothalamic irradiation dose, undernutrition duration, BMI standard deviation score (SDS) at pubertal onset, and catch-up BMI SDS. Results The mean ± SD age of pubertal onset was 9.2 ± 1.3 years and hypothalamic radiation dose was 31.9 ± 9.9 Gy. There was a direct relationship between age at irradiation and age at pubertal onset (β = 0.323 ± 0.144 [standard error] year per year; P = 0.04) that was significantly attenuated after adjusting for BMI SDS at pubertal onset (P = 0.5) and catch-up BMI SDS (P = 0.08), suggesting that BMI is a mediator. Conclusions Both absolute and catch-up BMI SDS at pubertal onset are significant mediators of pubertal timing and bone age discrepancy in pediatric medulloblastoma and other embryonal tumors, and thus, are targetable risk factors to optimize pubertal timing.

scholarly journals Stimulating effect of growth hormone on cytokine release in children

2003 ◽  
pp. 397-401 ◽  
Author(s):  
M Bozzola ◽  
F De Benedetti ◽  
M De Amici ◽  
B Jouret ◽  
P Travaglino ◽  
...  
Keyword(s):  
Short Stature ◽  
Standard Deviation Score ◽  
Bone Age ◽  
Serum Levels ◽  
Tnf Alpha ◽  
Cytokine Release ◽  
Normal Children ◽  
Short Children ◽  
Igf I ◽  
Design And Methods

OBJECTIVE: The aim of the present study was to investigate the effect of exogenously administered GH on serum levels of interleukin (IL)-1beta, IL-2, IL-12, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma and their relation with IGF-I levels in normal short stature children. DESIGN AND METHODS: 23 short prepubertal non GH-deficient children (10 females and 13 males) whose mean+/-s.d. chronological age was 11.95+/-1.85 Years (from 8.80 to 14.89 Years), and mean+/-s.d. bone age was 10.48+/-2.44 Years, were evaluated during a somatomedin generation test (human GH 0.1 IU/kg per day for 4 days) to exclude a partial GH resistance as the cause of short stature; 34 sex- and age-matched healthy subjects were studied as controls. Circulating cytokine values were measured in basal conditions in all children, and 12 h following the 4th GH subcutaneous injection in the 23 short children only. RESULTS: No significant differences were found between short children and controls in basal values of serum IGF-I (192.1+/-18.3 and 198.2+/-28.2 ng/ml respectively). In short subjects there was a significant increase in serum IGF-I levels after the 4th GH injection (from 192.1+/-18.3 ng/ml, i.e. -1.16+/-0.16 standard deviation score (SDS) to 338.2+/-27.1 ng/ml, i.e. 0.14+/-0.17; P<0.00001). No significant differences were found between short children and controls in basal concentrations of serum INF-gamma (19+/-4 and 26+/-5 mIU/ml respectively), IL-1alpha (24.950+/-3.613 and 20.896+/-2.778 pg/ml respectively), IL-2 (3.945+/-1.209 and 4.794+/-0.562 pg/ml respectively), IL-12 (1.093+/-0.269 and 1.976+/-0.596 pg/ml respectively), and TNF-alpha (1.794+/-0.559 and 2.188+/-0.346 pg/ml respectively). Likewise, a significant increase was found in serum INF-gamma (before 19+/-4 and after four GH injections 185+/-57 mIU/ml respectively; P<0.008), IL-1beta (24.950+/-3.613 to 43.339+/-5.431 pg/ml respectively; P<0.0001), IL-2 (3.945+/-1.209 to 9.165+/-2.331 pg/ml respectively; P<0.003), IL-12 (1.093+/-0.269 to 3.724+/-0.637 pg/ml respectively; P<0.0007) and TNF-alpha (1.794+/-0.559 to 9.266+/-3.066 pg/ml respectively; P<0.01). CONCLUSIONS: Cytokine release can be affected by short-term GH administration in normal children indicating a direct influence of GH on the immune system.

scholarly journals Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

2002 ◽  
pp. 319-323 ◽  
Author(s):  
Y Rakover ◽  
A Silbergeld ◽  
I Lavi ◽  
R Masalha ◽  
IB Shlomo
Keyword(s):  
Short Stature ◽  
Binding Protein ◽  
Standard Deviation Score ◽  
Bone Age ◽  
The Other ◽  
Provocative Test ◽  
Igf I ◽  
Parental Height ◽  
The Difference ◽  
Igfbp 3

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.

Efficacy of long-term growth hormone therapy in short non-growth hormone-deficient children

2017 ◽  
Vol 30 (2) ◽  
Author(s):  
Lucia Schena ◽  
Cristina Meazza ◽  
Sara Pagani ◽  
Valeria Paganelli ◽  
Elena Bozzola ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Final Height ◽  
Standard Deviation Score ◽  
Bone Age ◽  
Gh Treatment ◽  
Short Children ◽  
Igf I ◽  
Height Gain ◽  
The Cost

AbstractBackground:In recent years, several studies have been published showing different responses to growth hormone (GH) treatment in idiopathic short stature children. The aim of the present study was to investigate whether non-growth-hormone-deficient (non-GHD) short children could benefit from long-term GH treatment as GHD patients.Methods:We enrolled 22 prepubertal children and 22 age- and sex-matched GHD patients, with comparable height, body mass index (BMI), bone age, and insulin-like growth factor 1 (IGF-I) circulating levels. The patients were treated with recombinant human GH (rhGH) and followed until they reach adult height.Results:During GH treatment, the two groups grew in parallel, reaching the same final height-standard deviation score (SDS) and the same height gain. On the contrary, we found significantly lower IGF-I serum concentrations in non-GHD patients than in GHD ones, at the end of therapy (p=0.0055).Conclusions:In our study, the response to GH treatment in short non-GHD patients proved to be similar to that in GHD ones. However, a careful selection of short non-GHD children to be treated with GH would better justify the cost of long-term GH therapy.

scholarly journals Association between serum uric acid and triglycerides in Chinese children and adolescents with short stature

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuntian Chu ◽  
Qianqian Zhao ◽  
Mei Zhang ◽  
Bo Ban ◽  
Hongbing Tao
Keyword(s):  
Uric Acid ◽  
Standard Deviation ◽  
Children And Adolescents ◽  
Linear Relationship ◽  
Short Stature ◽  
Serum Uric Acid ◽  
Standard Deviation Score ◽  
Short Children ◽  
Non Linear ◽  
Males And Females

Abstract Background Elevated triglyceride (TG) levels are a biomarker for cardiovascular disease (CVD) risk. The correlation between serum uric acid (SUA) and TG concentrations in adults or obese children is well established. However, studies on SUA and TG in children with short stature are limited. Aim To determine the relationship between SUA and TG levels in short children and adolescents. Method This was a cross-sectional evaluation of a cohort of 1095 patients with short stature (720 males and 375 females). The related clinical characteristics, including anthropometric and biochemical parameters, were determined. Results Smooth curve fitting, adjusted for potential confounders was performed, which indicated the existence of a non-linear relationship between these measures. Piecewise multivariate linear analysis revealed a significant positive relationship between SUA and TG at SUA concentrations over 7 mg/dL (β = 0.13, 95% CI: 0.05–0.22, P = 0.002) but no significant correlation at lower SUA levels (β = 0.01, 95% CI: 0.01–0.04, P = 0.799). Furthermore, a stratified analysis was performed to appraise changes in this relationship for different sexes and standard deviation levels of body mass index (BMI). The non-linear relationship remained consistent in males and females with BMI standard deviation scores (BMI SDS) ≥ 0, with inflection points of 6.71 mg/dL and 3.93 mg/dL, respectively. Within these two groups, SUA and TG levels showed a positive association when SUA levels were higher than the inflection point (β = 0.21, 95% CI: 0.11–0.31, P < 0.001 for males and β = 0.1, 95% CI: 0.03–0.17, P = 0.005 for females). However, a specific relationship was not observed at lower SUA levels. No significant relationships were found between SUA and TG levels in males and females with BMI SDS < 0. Conclusion The present study identified the non-linear association of SUA and TG levels with short children and adolescents. This relationship was based on BMI status. This finding suggests that health status should be considered for short stature children with high SUA levels, especially in children with a high BMI standard deviation score.

scholarly journals ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment

2016 ◽  
Vol 102 (5) ◽  
pp. 1458-1467 ◽  
Author(s):  
Manouk van der Steen ◽  
Rolph Pfundt ◽  
Stephan J.W.H. Maas ◽  
Willie M. Bakker-van Waarde ◽  
Roelof J. Odink ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Bone Age ◽  
Hormone Treatment ◽  
Gh Treatment ◽  
Midface Hypoplasia ◽  
Short Children ◽  
Hormone Analog

Abstract Background: Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA. Objective: To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment. Methods: BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age. Results: Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation. Conclusion: This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.

scholarly journals Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations

2016 ◽  
Vol 102 (2) ◽  
pp. 460-469 ◽  
Author(s):  
Alexandra Gkourogianni ◽  
Melissa Andrew ◽  
Leah Tyzinski ◽  
Melissa Crocker ◽  
Jessica Douglas ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Short Stature ◽  
Early Onset ◽  
Autosomal Dominant ◽  
Standard Deviation Score ◽  
Bone Age ◽  
Skeletal Maturation ◽  
Disc Disease ◽  
Phenotypic Spectrum ◽  
Median Height

Abstract Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, −2.8 standard deviation score (SDS); range, −5.9 to −0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype–phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, −2.0 SDS; range, −4.2 to −0.6). Most children with ACAN mutations had advanced bone age (bone age − chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

scholarly journals Long-Term Growth Hormone Therapy Does Not Advance Skeletal Maturation in Children and Adolescents

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A679-A679
Author(s):  
Benjamin Udoka Nwosu ◽  
Sadichchha Parajuli ◽  
Gabrielle Jasmin ◽  
Austin F Lee
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Adult Height ◽  
Recombinant Human Growth Hormone ◽  
Bone Age ◽  
Skeletal Maturation ◽  
Z Score ◽  
Rhgh Therapy ◽  
Catch Up

Abstract Context: There is no consensus on the effect of recombinant human growth hormone (rhGH) therapy on skeletal maturation in children despite the current practice of annual monitoring of skeletal maturation with bone age in children on rhGH therapy. Aims: To investigate the effects of long-term rhGH therapy on skeletal age in children and explore the accuracy of bone age predicted adult height (BAPAH) at different ages based on 13 years of longitudinal data. Methods: A retrospective longitudinal study of 71 subjects aged 2-18 years, mean 9.9 ± 3.8y, treated with rhGH for non-syndromic short stature for a duration of 2-14y, mean, 5.5 ± 2.6y. Subjects with syndromic short stature and systemic illnesses such as renal failure were excluded. Results: Bone age minus chronological age (BA-CA) did not differ significantly between baseline and the end of rhGH therapy (-1.05 ± 1.42 vs -0.69 ± 1.63, p=0.09). Piece-wise regression however showed a quantifiable catch-up phenomenon in BA of 1.6 months per year of rhGH therapy in the first 6.5y, 95%CI 0.023 - 0.229, p=0.017, that plateaued thereafter, β=0.015, 95% CI -0.191-0.221, p=0.88. There was no relationship between BAPAH z score – height z score and the duration of rhGH therapy, p=0.68. BAPAH overestimated final adult height in younger subjects but became more precise in older subjects (p&lt;0.0001). Conclusion: Long-term rhGH therapy demonstrated an initial catch-up phenomenon in skeletal maturation in the first 6.5y that plateaued thereafter with no overall significant advancement in bone age. These findings are reassuring and do not support the practice of yearly monitoring of skeletal maturation with bone age in children on rhGH therapy, especially in younger subjects where BAPAH is imprecise.

scholarly journals Final Height in Pubertal Short Stature Boys Treated with GH Combination with Letrozole: A retrospective study

2021 ◽  
Author(s):  
Yaping Ma ◽  
Ruofan Jia ◽  
Bingyang Xia ◽  
Bin Tang ◽  
Zhuangjian Xu
Keyword(s):  
Retrospective Study ◽  
Short Stature ◽  
Adult Height ◽  
Final Height ◽  
Standard Deviation Score ◽  
Bone Age ◽  
Growth Potential ◽  
Target Height ◽  
Final Adult Height ◽  
Epiphyseal Fusion

Abstract BackgroundThe growth potential of pubertal short stature boys is limited by the effect of estrogen on epiphyseal fusion. This study aims to identify the efficacy and safety of growth hormone (GH) combination with letrozole on final adult height (FAH) in pubertal short stature boys. MethodsThis is a retrospective study. Among pubertal short stature boys who treated with GH and letrozole were be followed up in our hospital, 20 cases reached FAH. ResultsBaseline chronological age were 12.12±1.14yr, bone age were 13.00±0.93yr. The treatment duration was 1.94±0.67yr. The height standard deviation score for bone age was increased from -1.46±0.51 to -0.12±0.57 (p<0.000). The predicted FAH before treatment, predicted FAH after treatment, FAH, and genetic target height were 161.02 ±4.12 cm, 172.11±4.20 cm, 172.67±2.72cm and 167.67±3.56 cm, respectively. There was significant differences between predicted FAH before treatment and after treatment (p<0.000), as well as predicted FAH before treatment and genetic target height (p<0.000).The predicted FAH after treatment was higher than that of genetic target height (p<0.001), as well as FAH and genetic target height (p<0.000). ConclusionsThe GH combination with letrozole can enhance the FAH in pubertal short stature boys. No significant side effects were observed.

scholarly journals Growth failure: “idiopathic” only after a detailed diagnostic evaluation

2021 ◽  
Author(s):  
Robert Rapaport ◽  
Jan M Wit ◽  
Martin O Savage
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Short Stature ◽  
Growth Failure ◽  
Diagnostic Techniques ◽  
Gh Treatment ◽  
Genetic Sequencing ◽  
Short Children ◽  
The Us ◽  
Catch Up

The terms idiopathic short stature (ISS) and small for gestational age (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term SGA was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms SGA and ISS as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.

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