Change In Height Standard Deviation Score Research Articles

Turner syndrome and growth hormone therapy: a review on growth response

Results The mean age of initiation of therapy was 11.5 ± 3.4 and 55.0% were started after the age of 12 years. The mean height standard deviation score (SDS) increased from -3.84 (±0.94) SD at study entry to -3.47 (±0.97) SD at the end of the first year. This improvement was seen with subsequent year of treatment, though the degree of change in height SDS reduced with time. Age of initiation of therapy had a bearing on treatment response as those who had received growth hormone at an earlier age experienced better growth response. 75.0% of patients who achieved final height were able to achieve the final height within the target height. Of the patients who achieved final height, mean age of puberty was 16 ± 1.5 years and mean height SDS at onset of puberty was -3.3SD. There were no reported adverse events.

Effectiveness and Safety of rhIGF-1 Therapy in Children: The European Increlex® Growth Forum Database Experience

Background/Aims: We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children. Methods: Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013. Results: Mean ± SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 ± 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naïve to treatment, this was 7.3 ± 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%). Conclusion: Safety and effectiveness data on use of rhIGF-1 in a ‘real-world' setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia.

SHOX Gene Variants: Growth Hormone/Insulin-Like Growth Factor-1 Status and Response to Growth Hormone Treatment

Context: Short stature homeobox-containing gene (SHOX) variants of unknown clinical significance occur frequently among children with short stature, yet their growth hormone (GH)/insulin-like growth factor-1 (IGF-1) status and response to GH have not been studied. Objective: To define GH and IGF-1 status in children with SHOX variants and assess their response to GH. Patients and Methods: This is a retrospective review of children with short stature. Children with SHOX variants were compared to those with no variants. Height standard deviation scores (SDS) and IGF-1 SDS at baseline and during GH treatment at 6, 12, and 24 months were analyzed. Growth velocity (GV), maximum GH dose, IGF-BP3, and changes in height SDS, IGF-1 SDS, and GV were compared. Results: Among 355 children, 83 (23%) had SHOX variants. Nineteen different SHOX variants were detected. There was no difference in age, height SDS, IGF-1 SDS, or IGF-BP3 between children with SHOX variants and those with normal SHOX. Height SDS, IGF-1 SDS, IGF-BP3, GV, and GH dose were not different between patients with SHOX variants and those without. Conclusions: The GH and IGF-1 characteristics of children with short stature were not different between children with SHOX+ variants and children with no variants. Although these findings suggest that SHOX variants are polymorphisms, studies prospectively comparing individual SHOX variants are needed.

A Prospective Longitudinal Study of Growth and Pubertal Progress in Adolescents with Inflammatory Bowel Disease

Background: Puberty and growth may be affected in inflammatory bowel disease (IBD) but the extent is unclear. Methods: We performed a prospective study over 12 months in 63 adolescents (Crohn's disease, CD, n = 45; ulcerative colitis/IBD unclassified, UC, n = 18) with a median age of 13.4 years (range 10-16.6). Assessment included anthropometry, biochemical markers of growth and puberty and an assessment of quality of life by IMPACT-III. Results: Compared to the normal population, boys with CD were shorter, with a median height SDS (HtSDS) of -0.13 (-2.52 to 1.58; p < 0.05). In addition, the study cohort had a lower median IGF-1 SDS of -0.29 (-4.53 to 2.96; p = 0.008) and a higher median IGFBP3 SDS of 0.45 (-3.15 to 2.55; p = 0.002). Over the study period, the median Ht velocity (HV) was 5 cm/year (0.2-8.7) and the change in HtSDS was 0.06 (-0.48 to 0.57). The median difference between the chronological and bone age was 0.3 years (-2.5 to 3.0) and pubertal examination was not delayed. In the whole group, the erythrocyte sedimentation rate (ESR) showed an inverse association with HV (r = -0.29; p = 0.025) and IGF-1:IGFBP3 (r = -0.34; p = 0.016). The score in the body image domain, IMPACT-III, was inversely associated with HtSDS (r = -0.31; p = 0.03). Conclusion: Despite no evidence of pubertal delay, adolescents with IBD display growth retardation which may be associated with raised ESR, adverse quality of life measures and an abnormality of IGF-1 bioavailability.

Final height and body mass index in adult survivors of childhood acute lymphoblastic leukemia treated without cranial radiotherapy: a retrospective longitudinal multicenter Italian study.

BackgroundYoung adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with protocols including cranial radiotherapy demonstrate a persistent weight gain and reduced final height. Published reports on the effects on growth of different oncologic therapies are conflicting and difficult to interpret because they combined children treated with both cranial irradiation and multi-agent chemotherapy. Our study investigated the effect of chemotherapy alone on body mass index (BMI) and on growth at the achievement of final height in a homogeneous cohort of Italian childhood ALL survivors.MethodsWe retrospectively studied 162 Caucasian patients treated on the Italian Association of Pediatric Hematology and Oncology protocols without radiotherapy between 1989 and 2000 at five Italian centers with 107 inclusions (58 males). Height- and BMI-standard deviation score (SDS) were collected at diagnosis of ALL, at the end of treatment and at the achievement of final height. Changes in height SDS and BMI SDS with time were analyzed using dependent sample Student's t-test.ResultsA significant reduction of height-SDS was documented during treatment in both genders. This reduction of height-SDS was not followed by an appropriate catch-up growth, despite the achievement of a mean final height within the normal range. At diagnosis females showed a lower mean BMI-SDS than males. During treatment, in the whole population, BMI-SDS increased significantly. After it, while males lost BMI-SDS, females showed its persistent increase.ConclusionsSurvivors of childhood ALL generally seemed to achieve a normal final height with a BMI within the normal range. These parameters appeared to be only minimally affected by chemotherapy. Nevertheless, height catch-up growth was not completed after chemotherapy in both genders and all patients experienced an increase of BMI-SDS during chemotherapy that only females seemed to conserve until the achievement of final height.

Effect of growth hormone treatment on quality of life in Japanese children with growth hormone deficiency: an analysis from a prospective observational study.

The aim of this study was to assess changes in quality of life (QoL) in Japanese children with GH deficiency (GHD) after 12 mo of GH treatment or with idiopathic short stature (ISS) after 12 mo without treatment. Children with GHD were treated with GH after enrollment. Outcome measures included the parent-rated Child Behavior Checklist (CBCL), the Youth Self-Report Form (YSR), and height standard deviation scores (SDS). Total CBCL scores significantly decreased in children with GHD (n = 152, mean change (standard deviation [SD]) = –3.42 [11.21]) and ISS (n = 129, mean change = –4.82 [10.09]) after 12 mo (p < 0.001). Total YSR scores (mean change = –9.21 [14.07]) and height SDS (mean change = 0.35 [0.38]) significantly decreased in children with GHD (p < 0.001), but were unchanged in children with ISS. The change in total YSR score was significantly correlated with the change in height SDS in children with GHD (r = –0.516, p = 0.003). Our findings demonstrate that GH treatment can improve QoL in Japanese children with GHD. The correlation between the changes in total YSR score and height SDS demonstrated that increased height resulted in improved QoL.

Comparison of Growth Hormone Treatment in Patients with Idiopathic Short Stature and Idiopathic Growth Hormone Deficiency

After recombinant human growth hormone (rhGH) was introduced in the treatment of patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS), many studies have addressed the effect of GH treatment and changes in the height standard deviation score (SDS) after GH treatment. However, few studies comparing the effect of GH in Korean patients with idiopathic GHD and ISS have been designed. Therefore, this study focused on the difference in effect of GH treatment between the two groups. We retrospectively reviewed the height SDS of 34 patients with idiopathic GHD and 12 patients with ISS. The mean ages of the patients with idiopathic GHD and ISS were 9.84±2.09 and 10.72±1.48 years, respectively. All patients were treated with GH for 1 year and body parameters were recorded before and after the GH treatment. Change in height SDS in patients with idiopathic GHD was significantly higher than that in patients with ISS (0.62±0.33 vs. 0.40±0.27, p=0.03). However, body mass index, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were not significantly different between the two groups after GH treatment. These results suggest that GH treatment has a more powerful effect on increasing height SDS in patients with idiopathic GHD than in patients with ISS.

Outcome analysis of aromatase inhibitor therapy to increase adult height in males with predicted short adult stature and/or rapid pubertal progress: a retrospective chart review.

Aromatase inhibitors (AIs) have been used off-label to increase adult height in short adolescent males. Studies have shown that AIs increase the predicted adult height (PAH) while delaying bone age (BA) maturation. We sought to determine whether AI therapy increases PAH in boys with short stature or rapid pubertal progression, and to evaluate any untoward effects. The charts of 27 boys with BA ≥ 13 and short stature [height ≥ 2 standard deviation (SD) below the mean or ≥ 2 SD below mid-parental target height (MPTH)] or rapid pubertal progress, treated with anastrozole were reviewed. Outcome measures included anthropomorphic, hormonal, and metabolic data. The AI therapy averaged 21 months (range 14-30 months) for all, with Rx group 1 receiving <18 months therapy (n=7) and Rx group 2 receiving 18-30 months therapy (n=20). Post-therapy, in Rx group 1 and all subjects, there was no significant change in the PAH, height SDS, or BA/chronological age (CA). In Rx group 2, there was a small, nonsignificant increase in PAH, no change in height SDS, and a small decrease in BA/CA. Post-therapy PAH was different from MPTH in all and in both Rx groups 1 and 2, p<0.02. Eight of them achieved near-final height, averaging 6.73 ± 1.40 cm less than MPTH and 1.91 ± 0.86 cm less than the pre-therapy PAH. Post-therapy, the initially decreased estradiol did not persist but mildly increased testosterone and decreased high-density lipoprotein were noted, as was an increase in hematocrit, and decrease in growth velocity. We suggest that although bone age progression may be slightly delayed with longer duration of therapy, an overall short-term AI therapy does not lead to a final height that is greater than the predicted pre-therapy height.

Spontaneous Alleviation Of Growth Impairment In Tyrosine Kinase Inhibitor-Treated Chronic Myeloid Leukemia Children

Although tyrosine kinase inhibitor (TKI) is popular in controlling chronic myeloid leukemia in the chronic phase (CML-CP), its long-term adverse effects in children are an issue of concern. One such concern is the negative impact on growth in these children. We previously demonstrated that growth impairment was a major adverse effect in imatinib-treated CML children. However, severity of impairment was not completely elucidated because of the short follow-up period.The Japanese Pediatric Leukemia/Lymphoma Study Group CML committee reviewed the clinical records of 107 Japanese children diagnosed with CML-CP (<18 years of age) between 2001 and 2011, and treated with TKI for more than a year with no history of hematopoietic stem cell transplantation. Concurrent hydroxyurea administration was permitted (n = 7). Cumulative change in height was assessed using the height standard deviation score (height-SDS) and converted height data from age- and sex-adjusted Japanese norms. Children who reached final height at the time of diagnosis (n = 5), those afflicted by a chronic disease (n = 10), those treated for a disease that could affect growth (n = 7), and those without height data (n = 8) were excluded.In total, 77 children (47 boys and 30 girls) met these criteria. Median age at diagnosis was 10 years (2 to 15 years) and median observation period was 38 months (12 to 119 months). Median height-SDS at diagnosis and during the study was −0.14 SD (−2.3 to 2.3 SD) and −0.75 SD (−3.2 to 1.9 SD), respectively. Decrease in height-SDS (change in height-SDS from initiation of TKI till last follow-up point) was observed in 84.4% of children, which was >1 SD in 21 children (27.2%). Decrease in height-SDS was more severe in prepubertal children than in pubertal children (0.85 vs. 0.36, p< 0.01). However, in prepubertal children median annual change in height-SDS significantly decreased 2 years after TKI initiation, and was<0.1 SD 3 years after TKI initiation. There was no significant difference in median height-SDS at 3 years and thereafter from TKI initiation. Similar tendency was observed in pubertal children, with median annual change in height-SDS shifting to an increasing trend since 3 years after TKI initiation.Because of the possibility of TKI discontinuation, growth impairment is assumed to be a huge issue particularly in children who are inevitable of prolonged exposure to TKI. We previously discussed the possibility that growth velocity may recuperate in prepubertal children as they reach pubertal age, suggesting that imatinib had less impact on growth during puberty. However, this updated study data demonstrated that period of TKI treatment may influence alleviation of growth impairment by TKI to a greater extent than puberty. We suggest that severity of growth impairment could be mitigated 2 years after TKI initiation. Thus, therapeutic intervention, such as reduced-intensity hematopoietic stem cell transplantation and discontinuation of TKI, may not be necessary for improvement of growth in TKI-treated CML children. Disclosures:No relevant conflicts of interest to declare.

Response to growth hormone therapy in children with Noonan syndrome: correlation with or without PTPN11 Gene mutation

Background/Aims: The objective of this study was to evaluate the efficacy of recombinant human growth hormone (rhGH) therapy and the influence of genotype on the response to rhGH therapy in children with Noonan syndrome (NS). Methods: 14 male and 4 female subjects with NS with short stature, whose height was ! 3rd percentile, were included. The rhGH was subcutaneously administered at a dose of 66 g/kg/day. Mutations in the PTPN11 gene were identified in 10 subjects (55.6%). Mutations in the SOS1 (2 children, 11.1%), MEK1 (1 child, 5.6%) and KRAS (1 child, 5.6%) genes were also found. Results: Height SDS increased from –2.8 8 0.9 at the start of rhGH therapy to –2.0 8 0.9 12 months later (p ! 0.001). Height velocity increased from 5.0 8 0.9 cm/year in the year before treatment to 8.9 8 1.6 during treatment (p ! 0.001). Changes in height SDS, height velocity, and serum IGF-1 level did not differ significantly between those children with or without PTPN11 mutations.

The association between growth response to growth hormone and baseline body composition of children with growth hormone deficiency

ObjectiveWe wanted to examine the relationship between initial growth response to recombinant human Growth Hormone (rhGH) treatment and body composition in children with growth hormone deficiency (GHD). Design and methodsForty-two patients (21 boys and 21 girls) aged between 5.7–15.5years (mean age: 10.8±2.6years) with isolated GHD. The auxological and laboratory data (GH and IGF-I levels) and results of bioelectrical impedance analyses were evaluated. Children with GHD were followed up for 12months and categorized according to growth response to rhGH into good and poor responders (change in height of >0.7 SDS or <0.7 SDS over one year respectively). Mean doses of rhGH per kg of fat free mass (FFM) were calculated. ResultsForty-eight percent of patients showed a good growth response to rhGH therapy. At study entry, mean age, height SDS, weight SDS, serum IGF-1 SDS, IGFBP-3 SDS, growth velocity prior to rhGH therapy, GH after clonidine and l-dopa were similar in the two groups. At baseline, BMI SDS and waist–hip ratio were significantly higher in good responders (p=0.02 and p=0.006, respectively). Good responders had lower percentages of FFM (73.4±8.9 vs. 83.1±5.9) and total body water (TBW) (56.5±5.3 vs. 63.1±4.4), compared to poor responders (p<0.05). There were significant correlations between changes in height SDS over one year and baseline body composition in children with GHD on rhGH treatment (r=−0.617 for percentage of FFM, r=−0.629 for percentage of TBW, p<0.001). A correlation between BMI SDS, waist–hip ratio, mean rhGH dose per FFM and growth response was observed only in prepubertal subjects. ConclusionBaseline body composition data in children with GHD can be used to predict the growth response to rhGH treatment. A management strategy that involves titrating rhGH dose according to FFM as a means of optimizing the growth response to intervention requires further study.

Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients

Concerns have been raised that mammalian target of rapamycin inhibitors in pediatric transplant recipients might interfere with longitudinal bone growth by inhibition of growth factor signaling and growth plate chondrocyte proliferation. We therefore undertook a prospective nested, case-control study on longitudinal growth over 2 years in steroid-free pediatric renal transplant recipients. Fourteen patients on a steroid-free maintenance immunosuppressive regimen consisting of low-dose everolimus (EVR) in conjunction with low-dose cyclosporine (CsA) were compared to a matched cohort of 14 steroid-free patients on a standard dose mycophenolate mofetil (MMF) regimen in conjunction with a standard dose calcineurin inhibitor (CNI). The mean change in height standard deviation (SD) score in the first study year was 0.31 ± 0.71 SD score in the EVR group compared to 0.31 ± 0.64 SD score in the MMF group (P = 0.20). For the entire study period of 2 years, the change in height SD score in the EVR group was 0.43 ± 0.81 SDS compared to 0.75 ± 0.85 SDS in the MMF group (P = 0.32). The percentage of prepubertal patients experiencing catch-up growth, defined as an increase in height SD score ≥0.5 in 2 years, was similar in the EVR group (5/8, 65%) and the MMF group (6/8, 75%; P = 1.00). Longitudinal growth over 2 years in steroid-free pediatric patients on low-dose EVR and CsA is not different to that of a matched steroid-free control group on an immunosuppressive regimen with standard-dose CNI and MMF. Hence, low-dose EVR does not appear to negatively impact short-term growth in pediatric renal transplant recipients.

G95 Endocrine Late-Effects Post-Haematopoietic Stem Cell Transplant(HSCT) in Children with Haemoglobinopathies

Children with haemoglobinopathies undergoing HSCT are not exposed to total body irradiation but have specific endocrine issues, especially pubertal and growth delay related to iron toxicity. Experience is growing in...

Profile and Height Outcomes of Children with Short Stature in North India: An Experience from a Tertiary Care Centre

To the Editor: The ongoing dynamicity in the populationin terms of change in nutritional status, improved edu-cation, awareness and access to health care is expectedto bring changes in the etiologies causing short stature(SS). This study aimed to evaluate the current etiolog-ical trends for SS and the effect of treatment on finalheight. Retrospective analysis of records of childrenreferred for SS from2003–2007withatleast4yearsfollowup was done in the Department of Endocrinology,Vardhman Mahavir Medical College & Safdarjung Hos-pital, New Delhi. (Fig. 1). SS was defined as height<3rd percentile and/or height velocity <5th percentilefor chronological age.Records of 139 children [68 girls; 71 boys; age of pre-sentation: 11.34±3.71 y (Range 2–21 y)] were analyzed ofwhich74(53.24%)hadreached18yage.Thisstudyhighlights the predominantly late presentation of childrenwith SS in India. Familial short stature (FSS)(36, 26 %) wasthe most common cause of SS followed by hypothyroidism(26, 19 %), growth hormone deficiency (GHD) (19, 14 %),constitutional delay in growth and puberty (CDGP) (17,12 %), genetic syndromes [Turner’s(n=7); Down’ssyndrome (n=4)] (11, 8 %), Celiac disease (8, 6 %),nutritional (8, 6 %), achondroplasia/hypochondroplasia(6, 4 %), chronic disease (2, 1 %) and idiopathic(6,4 %). FSS and CDGP together constitute normalvariant SS (NVSS) and is the most common cause ofSS in our country, constituting 9 % [3], 16 % [4]and20 % [5] of all SS children in different studies and38 % in our study. This increased proportion of childrenwith NVSS in our series may reflect the increasedawareness in the society and increased healthcare seek-ing. Being a referral centre our patient profile is likelyto be skewed and it is likely that NVSS is even morecommon in the population.There was a significant difference in the presenting heightstandard deviation score (SDS) (P=0.002), final height SDS(P<0.001) and the change in height SDS (Δ Ht SDS)(P<0.001) depending on the etiology of SS (Table 1). Maxi-mum height improvement (ΔHt SDS) was seen in treatedGHD children followed by treated hypothyroid andCDGP. Poor height outcomeofchildrenwithCeliacdiseaseinourstudymaybetheresultofdelayeddiagnosisandlackofcompliance to gluten free diet. Poor height outcomes in chil-drenwithachondroplasia/hypochondroplasia and SS due tosyndromes reflect the limited growth potential in thesechildren. Endocrine disorders should be actively lookedfor, since they comprise of a third of children with SS andshowmaximumimprovementinheightontreatment.Thoughthere has been increased healthcare seeking,it is quite late asevident from our study. Increased awareness among generalpopulation and pediatricians would help early detection oftreatable cases and better height of the population.

Efficacy of IGF‐based growth hormone (GH) dosing in nonGH‐deficient (nonGHD) short stature children with low IGF‐I is not related to basal IGF‐I levels

Weight-based GH dosing is the standard for treating children with short stature. The current study validates the usefulness of IGF-based GH dosing for GH therapy in nonGH-deficient (nonGHD) children and its relationship with pretreatment serum IGF-I concentration. In this twelve-month, open-label, randomized controlled study, 151 nonGHD (based on GH-stimulation tests), prepubertal children with short stature and IGF-I levels ≤ 33rd percentile [-0.44 standard deviation score (SDS)] were randomly assigned to receive GH (dose based on IGF-I titration algorithm; n = 114) or to observation (n = 37). GH dose (initially 40 μg/kg/d) was adjusted every 3 months to achieve an IGF-I SDS in the upper normal range (66-99 th percentile). In treated children, mean height SDS (HSDS) increased from -2.5 at baseline to -1.7 at 12 months and mean IGF-I SDS increased from -1.7 to 0.1. These parameters remained unchanged in untreated children. There was no relationship between change in HSDS (ΔHSDS) and degree of IGF-I deficiency at baseline. No safety problems were observed. Both groups had a similar advance in bone age. At the end of study, ΔHSDS in treated children showed a positive correlation with IGF-I SDS, but not with GH dose [mean 59 μg/kg/d (range 29-92)], basal IGF-I SDS or 1-month IGF parameters. In nonGHD subjects with short stature and serum IGF-I concentrations within and below the lower third of normal, adjusting GH dose to achieve an IGF-I level in the upper normal range resulted in a significant increase in HSDS, regardless of basal IGF-I levels.

An observational study of the effectiveness and safety of growth hormone (Humatrope&lt;sup&gt;®&lt;/sup&gt;) treatment in Japanese children with growth hormone deficiency or Turner syndrome

This study assessed the effectiveness and safety of growth hormone (GH; Humatrope(®)) therapy in Japanese children with GH deficiency (GHD) or Turner syndrome (TS) enrolled in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). GeNeSIS is an open-label, multinational, multicenter, observational study conducted in 30 countries. In this interim report, there were 1129 GH treatment-naïve children with GHD, with a mean chronological age (± standard deviation) of 8.75 (3.32) years, and 90 girls with TS, with a mean chronological age of 8.93 (3.67) years. The mean height standard deviation score (SDS) increased from -2.73 (0.63) SD and -2.71 (0.63) SD at study entry to -2.22 (0.68) SD and -2.20 (0.60) SD after 1 year of treatment in the GHD and TS groups, respectively. In both groups, mean height SDS increased further with each year of treatment to 4 years; however, the magnitude of change in height SDS declined with time. The mean insulin-like growth factor-I SDS increased from below the mean of the reference population at study entry to a level similar to (GHD group) or higher than (TS group) the mean of the reference population during the 4-year treatment period. The incidence of serious adverse events (AEs), treatment-related AEs, and AEs related to glucose intolerance was low in both groups (0.1% to 3.0%). In conclusion, GH treatment in Japanese children with GHD or TS resulted in increased growth over a 4-year treatment period with a favorable safety profile; however, the improvements in growth declined with time.

Insulin Sensitivity Modulates the Growth Response during the First Year of High-Dose Growth Hormone Treatment in Short Prepubertal Children Born Small for Gestational Age

Aim: To study the relationship between insulin sensitivity and growth response in short children born small for gestational age (SGA) treated with growth hormone (GH). Methods: Randomized, open-label, 24-month intervention study in 40 short prepubertal SGA children [age (mean ± SD) 5.3 ± 1.5 years], who either remained untreated (n = 20) or were treated with GH (66 µg/kg/day; n = 20). Changes in fasting glucose, insulin, quantitative insulin sensitivity check index (QUICKI), IGF-1 and leptin after 1 and 2 years were studied. Results: Mean height SDS increased from –3.3 ± 0.7 to –2.3 ± 0.7 after 1 year, and to –1.9 ± 0.7 after 2 years of treatment. QUICKI decreased significantly (p = 0.008) in the first year of GH treatment and stabilized in the second year. Baseline QUICKI was positively associated (r = 0.40; p < 0.05) with the change in height SDS in the first year. Conclusion: Higher insulin sensitivity at the start of GH therapy is associated with greater first-year growth response to GH, and could be a promising parameter in selecting prepubertal short SGA children for GH treatment. However, this finding needs to be confirmed in larger studies.

Comparison of response to 2-years’ growth hormone treatment in children with isolated growth hormone deficiency, born small for gestational age, idiopathic short stature, or multiple pituitary hormone deficiency: combined results from two large observational studies

BackgroundFew studies have compared the response to growth hormone (GH) treatment between indications such as isolated growth hormone deficiency (IGHD), born small for gestational age (SGA), idiopathic short stature (ISS), and multiple pituitary hormone deficiency (MPHD). The aim of this analysis of data, collected from two large ongoing observational outcome studies, was to evaluate growth and insulin-like growth factor-I (IGF-I) response data for children of short stature with IGHD, MPHD, SGA, or ISS following two years of treatment with the recombinant GH product Norditropin® (Novo Nordisk A/S, Bagsværd, Denmark).MethodsAnalysis of auxologic data from two ongoing prospective observational studies, NordiNet® International Outcomes Study (NordiNet® IOS) and NovoNet®/American Norditropin® Studies: Web-enabled Research (ANSWER) Program®.Results4,582 children aged <18 years were included: IGHD, n = 3,298; SGA, n = 678; ISS, n = 334; and MPHD, n = 272. After two years’ GH treatment, change in height standard deviation score (SDS) was +1.03 in SGA and +0.84 in ISS vs. +0.97 in IGHD (p = 0.047; p < 0.001 vs. IGHD, respectively). Height gain was comparable between IGHD and MPHD. In pre-pubertal children vs. total population, height SDS change after two years was: IGHD, +1.24 vs. +0.97; SGA, +1.17 vs. +1.03; ISS, +1.04 vs. +0.84; and MPHD, +1.16 vs. +0.99 (all p < 0.001).ConclusionsAfter two years’ GH treatment, change in height SDS was greater in SGA and less in ISS, compared with IGHD; the discrepancy in responses may be due to the disease nature or confounders (i.e. age). Height SDS increase was greatest in pre-pubertal children, supporting early treatment initiation to optimize growth outcomes.

Response to Growth Hormone Therapy in Children with Noonan Syndrome: Correlation with or without PTPN11 Gene Mutation

Background/Aims: The objective of this study was to evaluate the efficacy of recombinant human growth hormone (rhGH) therapy and the influence of genotype on the response to rhGH therapy in children with Noonan syndrome (NS). Methods: 14 male and 4 female subjects with NS with short stature, whose height was <3rd percentile, were included. The rhGH was subcutaneously administered at a dose of 66 µg/kg/day. Mutations in the PTPN11 gene were identified in 10 subjects (55.6%). Mutations in the SOS1 (2 children, 11.1%), MEK1 (1 child, 5.6%) and KRAS (1 child, 5.6%) genes were also found. Results: Height SDS increased from –2.8 ± 0.9 at the start of rhGH therapy to –2.0 ± 0.9 12 months later (p < 0.001). Height velocity increased from 5.0 ± 0.9 cm/year in the year before treatment to 8.9 ± 1.6 during treatment (p < 0.001). Changes in height SDS, height velocity, and serum IGF-1 level did not differ significantly between those children with or without PTPN11 mutations. Conclusion: The rhGH therapy significantly improved the growth velocity and increased the serum IGF-1 level. Long-term correlation between genotype and rhGH therapy responsiveness needs to be addressed in a large population.

Effect of 4 years of growth hormone therapy in children with Noonan syndrome in the American Norditropin Studies: Web-Enabled Research (ANSWER) Program® registry

BackgroundNoonan syndrome (NS) is a genetic disorder characterized by phenotypic features, including facial dysmorphology, cardiovascular anomalies, and short stature. Growth hormone (GH) has been approved by the United States Food and Drug Administration for short stature in children with NS. The objective of this analysis was to assess the height standard deviation score (HSDS) and change in HSDS (ΔHSDS) for up to 4 years (Y4) of GH therapy in children with NS.MethodsThe American Norditropin Studies: Web-Enabled Research (ANSWER) Program®, a US-based registry, collects long-term efficacy and safety information on patients treated with Norditropin® (somatropin rDNA origin, Novo Nordisk A/S) at the discretion of participating physicians. A total of 120 children (90 boys, 30 girls) with NS, naïve to previous GH treatment, were included in this analysis.ResultsThe mean (SD) baseline age of subjects (n = 120) was 9.2 (3.8) years. Mean (SD) HSDS increased from –2.65 (0.73) at baseline to –1.32 (1.11) at Y4 (n = 17). Subjects showed continued increase in HSDS from baseline to Y4 without significant differences between genders at Y1 or Y2. The mean (SD) GH dose was 47 (11) mcg/kg/day at baseline and 59 (16) mcg/kg/day at Y4. There was a negative correlation between baseline age and ΔHSDS at Y1 (R = –0.3156; P = 0.0055) and Y2 (R = –0.3394; P = 0.017). ΔHSDS at Y1 was significantly correlated with ΔHSDS at Y2 (n = 37; R = 0.8527, P < 0.0001) and Y3 (n = 20; R = 0.5145; P = 0.0203), but not Y4 (n = 12; R = 0.4066, P = 0.1896).ConclusionsGH treatment-naïve patients with NS showed continued increases in HSDS during 4 years of treatment with GH with no significant differences between genders up to 2 years. Baseline age was negatively correlated with ΔHSDS at Y1 and Y2. Whether long-term therapy in NS results in continued increase in HSDS to adult height remains to be investigated.Trial registrationClinicalTrials.gov NCT01009905