GH-deficient Children Research Articles

ENHANCING THE LONGEVITY AND IN VIVO POTENCY OF THERAPEUTIC PROTEINS: THE POWER OF CTP

The relatively short serum half-life of polypeptides poses a challenge in the design of protein therapeutics. Extending the half-life and bioavailability while maintaining safety and efficacy has been attempted using various techniques such as sustained-release preparations and long-acting conjugations. A novel, alternative approach involves the fusion of a natural polypeptide, the C-terminal peptide (CTP) of human chorionic gonadotropin (hCG), to the target protein. The fertility drug FSH-CTP (Elonva®) was the first CTP-containing protein to receive marketing approval. This versatile platform has been utilized to improve the pharmacokinetic (PK) and pharmacodynamic (PD) properties of additional target proteins from different families. This includes CTP fused to erythropoietin (EPO), interferon beta (IFNβ) and coagulation factors VII and IX, as well as thyroid-stimulating hormone (TSH), oxyntomodulin, and growth hormone (GH). Two long-acting, CTP-containing chimeras are currently in clinical development by OPKO Biologics. Long-acting FVIIa-CTP (MOD-5014) is being developed for the treatment of hemophilia with an expected dosing regimen of 2-3 times a week. MOD-5014 exhibited improved in vivo PK/PD, coagulation, and safety parameters in comparison to rFVIIa. This supports the upcoming clinical evaluation of MOD-5014 in hemophilic patients. Long-acting CTP-modified hGH (MOD-4023), currently in advanced clinical development by OPKO, may replace current GH therapy in patients suffering from GH deficiency (GHD) by requiring fewer injections. Animal studies showed that once-weekly administration of MOD-4023 resulted in favorable weight gain response in comparison to daily hGH and established an excellent safety profile. A Phase 1 study in healthy volunteers and Phase 2 trial in GHD patients confirmed the safety and tolerability of MOD-4023 in adults; a pivotal Phase 3 study in GHD adults in ongoing. A recently completed Phase 2 study in GHD children demonstrated an improved PK/PD profile and efficacy for once-weekly MOD-4023 in comparison to daily hGH, supporting OPKO's upcoming Phase 3 trial in pediatric GHD patients. Based on recent pre-clinical and clinical experience, CTP technology was proven a valid, flexible platform for the generation of safe and effective long-acting protein therapeutics, with the potential to offer an improved treatment for patients and better quality of life.

Brain Magnetic Resonance Imaging as First-Line Investigation for Growth Hormone Deficiency Diagnosis in Early Childhood

Background/Aims: The diagnosis of growth hormone (GH) deficiency (GHD) in infancy and early childhood is not straightforward. GH stimulation tests are unsafe and unreliable in infants, and normative data are lacking. This study aims to investigate whether brain magnetic resonance imaging (MRI) may replace GH stimulation tests in the diagnosis of GHD in children younger than 4 years. Methods: We examined a retrospective cohort, with longitudinal follow-up, of 68 children consecutively diagnosed with GHD before the age of 4 years. The prevalence of hypothalamic-pituitary (HP) alterations at MRI and the associations with age and either isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were assessed. Results: The prevalences of IGHD and MPHD were 54.4 and 45.6%, respectively. In the first group, brain MRI showed abnormalities in 83.8%: isolated pituitary hypoplasia in 48.7% and complex defects in 35.1%. In patients with MPHD, MRI showed complex alterations in 100%. All children younger than 24 months showed HP MRI abnormalities, regardless of the diagnosis. Complex defects were found in 94% of patients younger than 12 months and in 75% of patients between 13 and 24 months. Conclusion: Our data suggest that brain MRI may represent the first-line investigation for diagnosing GHD in infancy and early childhood.

Pituitary Hormone Secretion Profiles in IGSF1 Deficiency Syndrome

Background: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency. Methods: We collected blood samples every 10 min for 24 h in eight adult male IGSF1-deficient patients and measured circulating TSH, prolactin and gonadotropins. Deconvolution, modified cosinor and approximate entropy analyses were applied to quantify secretion rates, diurnal rhythmicity and regularity of hormone release. Results were compared to healthy controls matched for age and body mass index. Results: Compared to healthy controls, IGSF1-deficient patients showed decreased pulsatile secretion of TSH with decreased disorderliness and reduced diurnal variation. Basal and pulsatile secretion of FSH was increased by over 200%, while LH secretion did not differ from healthy controls. We observed a bimodal distribution of prolactin secretion, i.e. severe deficiency in three and increased basal and total secretion in the other five patients. Conclusion: The altered TSH secretion pattern is consistent with the previously hypothesized defect in thyrotropin-releasing hormone signaling in IGSF1 deficiency. However, the phenotype is more extensive and includes increased FSH secretion without altered LH secretion as well as either undetectable or increased prolactin secretion.

Growth hormone and the risk of atherosclerosis in growth hormone-deficient children

ObjectiveGrowth hormone-deficient (GHD) children have been found to have higher cardiovascular mortality rates and an increased carotid intima-media thickness (CIMT). This study investigated the risk of atherosclerosis and the effect of recombinant growth hormone (rhGH) replacement therapy on the lipid profile and CIMT in GHD children. DesignA total of 40 GHD children (mean age: 12.3±2.04years) were investigated before and after 1year of rhGH therapy at a dosage of 0.03mg/kg/day and 40 age- and sex-matched healthy children (mean age: 12.1±2.23years) were enrolled as a control group, in the same pubertal stage. Fasting blood samples were obtained for lipid profile, IGF-1, and IGFBP-3 analyses. The patients and controls underwent CIMT measurements before and after 1year of rhGH treatment. ResultsThe growth velocity and height standard deviation scores increased significantly over 1year of treatment in all patients. The total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and atherogenic index (Ai) values were increased while the high-density lipoprotein (HDL) cholesterol value was decreased in the GHD children, as compared to the controls; however, the triglyceride (TG) level was comparable. After 1year of treatment, a significant decrease in the TC, LDL cholesterol, and Ai values as well as a significant increase in the HDL value were observed in the GHD patients, with the values becoming similar to those in the control group. The mean CIMT was significantly greater in the GHD subjects than in the controls. After 1year of therapy, the CIMT in the GHD subjects had decreased significantly; however, it was still greater than that in the control group. IGF-1 was negatively correlated with TC, LDL cholesterol, Ai, right CIMT, and left CIMT. ConclusionsGHD is associated with increased atherosclerotic risk in children. An improved lipid profile and CIMT were detected after 1year of hormone replacement therapy.

Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence.

Growth hormone deficiency (GHD) is a rare but important cause of short stature in childhood with a prevalence of 1 in 4000. The diagnosis is currently based on an assessment of auxology along with supporting evidence from biochemical and neuroradiological studies. There are significant controversies in the diagnosis and management of GHD. Growth hormone (GH) stimulation tests continue to play a key role in GHD diagnosis but the measured GH concentration can vary significantly with stimulation test and GH assay used, creating difficulties for diagnostic accuracy. Such issues along with the use of adjunct biochemical markers such as IGF-I and IGFBP-3 for the diagnosis of GHD, will be discussed in this review. Additionally, the treatment of GHD remains a source of much debate; there is no consensus on the best mechanism for determining the starting dose of GH in patients with GHD. Weight and prediction based models will be discussed along with different mechanisms for dose adjustment during treatment (auxology or IGF-I targeting approaches). At the end of growth and childhood treatment, many subjects diagnosed with isolated GHD re-test normal. It is not clear if this represents a form of transient GHD or a false positive diagnosis during childhood. Given the difficulties inherent in the diagnosis of GHD, an early reassessment of the diagnosis in those who respond poorly to GH is to be recommended.

ApoE4 Determines the Reduction in LDL-C After GH Replacement Therapy in Children With an Idiopathic GH Deficiency.

GH activates the expression of low-density lipoprotein (LDL) receptors, leading to decreased LDL-cholesterol (LDL-C). Apolipoprotein (apo) E4 carriers suppress LDL receptor expression, rendering high LDL-C concentrations. We examined whether GH-deficient children carrying apoE4 exhibited a greater reduction in LDL-C after GH replacement therapy. We determined lipoprotein profiles after 0, 4, and 12 months of GH treatment in children with an idiopathic GH deficiency. We compared the effects of GH treatment on LDL-C by apoE phenotype. In total, 66 children with idiopathic GH deficiency and 89 healthy children were classified into subgroups according to apoE phenotype. The intervention included GH replacement therapy for 12 months. The relationship between apoE phenotype and reduced LDL-C induced by GH treatment was measured. Concentrations of LDL-C and apoB were highest in the apoE4/3 group (n = 13), second highest in the apoE3/3 group (n = 46), and lowest in the apoE3/2 group (n = 7), whereas apoE concentrations were highest in the apoE3/2 group and lowest in the apoE4/3 group. The apoE4/3 group had significantly reduced LDL-C and apoB concentrations at months 4 and 12, whereas the apoE3/3 and apoE3/2 groups showed no changes. LDL-C concentrations did not differ among the three groups after 12 months. The trend in apoE concentration did not change among the groups. Children with a GH deficiency carrying apoE4 had higher baseline LDL-C concentrations and experienced a greater reduction in LDL-C after GH replacement therapy than those without apoE4.

Imbalance in the blood antioxidant system in growth hormone-deficient children before and after 1 year of recombinant growth hormone therapy.

The aim of our study was to examine the effects of 12-month therapy with recombinant growth hormone (rGH) on the blood antioxidant system in children with growth hormone deficiency (GHD). Total antioxidant capacity (TAC) of plasma was measured by FRAP (ferric reducing antioxidant power or ferric reducing ability of plasma); activities of superoxide dismutase (SOD) and catalase (CAT) in erythrocytes were assessed; non-protein thiols (NT) and ceruloplasmin (CP) levels were also measured. These parameters were determined before and after 12 month of rGH treatment. Eleven treatment-naive prepubertal children with growth hormone deficiency were included in the study. Another 11 prepubertal children comprised a control group. Before rGH treatment, TAC of plasma and NT level in the control group were significantly lower (726 ± 196 vs. 525 ± 166 µmol/L, P = 0.0182 and 0.92 ± 0.18 vs. 0.70 ± 0.22 µmol/ml, P = 0.0319, before and after the therapy, respectively). The only parameter that significantly (19.6 ± 4.7 vs. 14.5 ± 3.4 Units/g Hb, P = 0.0396) exceeded the same in the control group after rGH therapy was SOD activity. However, none of the measured parameters of antioxidant system in GHD children, except for TAC (525 ± 166 vs. 658 ± 115 µmol/L, P = 0.0205), exhibited significant improvement toward the end of the 12-month treatment period, although non-significant changes in CAT activity and CP level were also observed. This work has demonstrated that some parameters of the blood antioxidant system are out of balance and even impaired in GHD children. A 12-month treatment with rGH resulted in a partial improvement of the antioxidant system.

Auxologic parameters and response to 2-year therapy with recombinant human growth hormone in growth hormone deficient children with an ectopic posterior pituitary.

Structural defects of the hypothalamic-pituitary area in MRI are suggested as being a more accurate marker of growth hormone deficiency (GHD) than laboratory assays. To compare auxological characteristics in GHD children with normal pituitary (NP) function and with ectopic posterior pituitary (EPP), prior to therapy with recombinant human growth hormone (rhGH), extending the follow-up to two years following treatment. Eighty-six (86) GHD patients were divided into two groups depending on the pituitary MRI: the EPP (23 children, 3.2-16.8 years old) and the NP group (63 children, 3.3-14.8 years old). Height deficits in the population (hSD) and parents (hSD-mpSD) and the change of hSD and bone/chronological age ratio were assessed before and after 12 and 24 months of rhGH therapy. Height deficits before treatment were significantly greater in EPP compared to NP [median -4.07 (-7.06, -2.75) vs -3.15 (-4.9, -2.35) for hSD, and -3.65 (-7.06, -1.21) vs -1.83 (-4.31, -0.28) for hSD-mpSD; p<0.05]. Bone age was significantly delayed in the EPP group [0.62 (0.27, 0.92) vs 0.75 (0.21, 0.71); p<0.05]; differences remained significant during follow-up. After 12 months of rhGH therapy, EPP showed significantly greater catch-up growth compared to NP [ΔhSD=1.2 (0.42, 2.69) vs 0.74 (0.05, 1.48); p<0.05]. In the 2nd year, height velocity slowed down and was comparable in the two groups. At the conclusion of the study, hSD was similar in both groups, but hSD-mpSD was more deviated in EPP [-1.79 (-3.71, -1.21) vs -1.1 (0.98, -0.07); p<0.05]. The study showed relevant auxologic differences between EPP and NP children, as well as beneficial effects of rhGH therapy in both groups.

Decreased 6-Sulfatoxymelatonin Excretion in Male GH-Deficient Children and Adolescents

Aim: To evaluate melatonin secretion in a group of untreated and treated male growth hormone (GH)-deficient children and adolescents. Methods: We studied 44 male subjects: 8 untreated GH-deficient patients (GHDnt), 16 treated GH-deficient patients (GHDt) and 20 healthy children and adolescents as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24-hour samples), nocturnal (18.00-8.00 h) and diurnal samples (8.00-18.00 h). Levels of 6-SM were expressed as micrograms excreted per time interval and Δ values (difference between nighttime and daytime values). Results: Significant differences were observed among the 3 groups of pediatric subjects studied for total 6-SM (p < 0.0001), nocturnal 6-SM (p < 0.0001) and Δ values (p < 0.0001). Subsequent analysis showed significantly higher levels for total 6-SM, nocturnal 6-SM and nighttime-daytime Δ in the CG versus the GHDnt (p < 0.01) and in the CG versus the GHDt group (p < 0.01). No significant correlations were found between 6-SM excretion and insulin-like growth factor-1 values in the children and adolescents studied. Conclusions: GH-deficient patients showed lower levels of 6-SM. Our findings provide a different insight to a further understanding of some chronobiological disorders involved in GH deficiency in children.

Is there a link between lipid profile and thyroid function modification during somatropinum treatment for GH deficiency in children?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Exogenous administration of GH increases linear growth velocity at higher doses during pre- and early puberty in GH deficient short stature children

Exogenous administration of GH increases linear growth velocity at higher doses during pre- and early puberty in GH deficient short stature children

Effects of growth hormone therapeutic supplementation on hematopoietic stem/progenitor cells in children with growth hormone deficiency: focus on proliferation and differentiation capabilities.

We investigated the direct effects of growth hormone (GH) replacement therapy (GH-RT) on hematopoiesis in children with GH deficiency (GHD) with the special emphasis on proliferation and cell cycle regulation. Peripheral blood (PB) was collected from sixty control individuals and forty GHD children before GH-RT and in 3rd and 6th month of GH-RT to measure hematological parameters and isolate CD34+-enriched hematopoietic progenitor cells (HPCs). Selected parameters of PB were analyzed by hematological analyzer. Moreover, collected HPCs were used to analyze GH receptor (GHR) and IGF1 expression, clonogenicity, and cell cycle activity. Finally, global gene expression profile of collected HPCs was analyzed using genome-wide RNA microarrays. GHD resulted in a decrease in several hematological parameters related to RBCs and significantly diminished clonogenicity of erythroid progenies. In contrast, GH-RT stimulated increases in clonogenic growth of erythroid lineage and RBC counts as well as significant up-regulation of cell cycle-propagating genes, including MAP2K1, cyclins D1/E1, PCNA, and IGF1. Likewise, GH-RT significantly modified GHR expression in isolated HPCs and augmented systemic IGF1 levels. Global gene expression analysis revealed significantly higher expression of genes associated with cell cycle, proliferation, and differentiation in HPCs from GH-treated subjects. (i) GH-RT significantly augments cell cycle progression in HPCs and increases clonogenicity of erythroid progenitors; (ii) GHR expression in HPCs is modulated by GH status; (iii) molecular mechanisms by which GH influences hematopoiesis might provide a basis for designing therapeutic interventions for hematological complications related to GHD.Electronic supplementary materialThe online version of this article (doi:10.1007/s12020-015-0591-0) contains supplementary material, which is available to authorized users.

Bone mineral content in growth hormone deficient children treated with growth hormone after withdrawal of 1 year of supplementation with calcium, vitamin D and zinc

Supplementation with calcium (ca), vitamin d (vit D), zinc has been shown to have a positive effect on bone mineral content (BMC) gain in growth hormone deficient (GHD) children on GH therapy[1]. It is unknown if this gain is sustained after supplement withdrawal. We aimed to investigate the influence of prior supplementation with ca, vitD and zinc on BMC accretion after supplement withdrawal. 31 prepubertal GHD children were randomly allocated to receive A) calcium (500mg/d), vitamin d (30,000 IU/3 months) and B) calcium (500mg/d), vitamin D (30,000 IU/3 months) & zinc (8 mg) for 1 year with GH. Ht measurement, bone mineralization by dual energy x-ray absorptiometry, tanner staging were performed at 4 timepoints, baseline, post 1 year of supplementation and 1 & 2 years after withdrawal of supplementation. Height for age z-scores (HAZ) were calculated from ethnic growth references. At baseline, children (18 boys, 9.6±2.8 years) from group A & B were similar in their HAZ (-4 ±1.5, -4 ±1.3) and BMC (370±215 g, 440±167g). 1 year post supplementation, 40% & 36% children and by the end of 2nd year of supplementation withdrawal, 47% & 80% from group A & B respectively had entered puberty. Since Ht has strong correlation with BMC, % change in ht adjusted BMC was analyzed. The gain in BMC was greater (p < 0.05) in group B (51 %) children than in group A (49 %) children2. However, after the withdrawal of the supplementation, the % gain in ht as well as ht adjusted BMC was similar in both groups. The % gain in ht adjusted BMC was lower (p <0.05) in the 1st year of supplement withdrawal (22 %). In 2nd year, the ht adjusted BMC showed a significantly greater (53 %, p < 0.05) gain than the supplementation year and first year after supplementation withdrawal. Effect of short term supplementation with ca, vit D & zn in GH treated GHD children may not continue after the withdrawal of supplementation. However, the greater gain in the 2nd year after supplementation withdrawal was possibly due to the effect of puberty.

Growth hormone responsiveness: why does it vary and can it be predicted?

Initial response to growth hormone (GH) varies considerably. In severe GH deficiency initial response varies across the group by almost 100%. In common non-GH deficient disorders such as idiopathic short stature (ISS) and children born small for gestational age (SGA) initial response varies by more than 100%. The explanation for the wide response to GH treatment can be clustered into three broad groups; (i) non-compliance with GH therapy, (ii) clinical characteristics associated with GH responsiveness and (iii) mutations and common gene variants in the GH-IGF-I axis. (i) Non-compliance with GH therapy: The commonest explanation for variable GH response is missed GH doses. In a national prospective study of GH compliance in New Zealand children; 34% of children missed more than one GH dose per week. Maori and Pacific children missed an additional GH dose each week than Caucasian children. Predictably, poor compliance (≥4 doses/week missed) was associated with a far poorer growth response than good compliance (height velocity SDS +0.4 vs +2.8). Even moderate compliance (2-3 doses/week missed) was associated with a poorer growth response (height velocity SDS +1.4 versus +2.8). Interestingly, paediatricians were unaware of GH non-compliance. GH response can only be maximised when more effective GH delivery devices are developed that record the date and time GH is administered to enable paediatricians to more effectively address compliance. (ii) Clinical characteristics associated with GH responsiveness: There is a differential response to GH therapy according to the underlying disorder. GH deficient children are more responsive than those with Turner Syndrome or idiopathic short stature who are in turn more responsive than SGA children (as shown by height velocity and serum IGF-I for a given GH dose). Furthermore, across the normal birth weight range we have recently shown that progressive reduction in birth weight SDS is associated with a progressively lower IGF-I response during IGF-I generation testing. Across growth disorders; more severe GH deficiency, taller parents, shorter stature, younger age at the start of treatment and heavier children are all parameters found to be associated with greater initial and sustained response to GH treatment. Michael Ranke has pioneered individualised GH dosing through GH prediction modelling across growth disorders. GH response can be predicted by inserting common clinical characteristics into a prediction equation that includes adjusting the dose. Prediction modelling is of greatest benefit to children with adverse clinical characteristics in whom greater initial GH doses will lead to greater growth response. (iii) Mutations and common gene variants in the GH-IGF-I axis: Downstream gene mutations in this axis (GH receptor, IGF-I and IGF-I receptor) are relatively rare causes of short stature, poor growth and GH response. Conversely common gene variants are being increasingly sought that influence stature, growth and GH responsiveness. Initial reports suggested a common GH receptor exon 3 deletion was associated with a better response to GH than the full length form in SGA and ISS children. Further studies have found little if any effect of the GH receptor deletion on initial or sustained growth response in SGA, Turner Syndrome or GH deficiency. Future studies are likely to focus on panels of common gene variants across the GH axis rather than examining individual genes to better characterise GH responsiveness.

Growth Hormone Treatment Improves Cognitive Function in Short Children with Growth Hormone Deficiency

Background/Aims: We investigated the association between cognition and growth hormone (GH) status and GH treatment in short prepubertal children with broadly ranging GH secretion. Methods: A total of 99 children (age 3-11 years), 41 with GH deficiency (GHD) and 58 with idiopathic short stature (ISS), were randomized to a fixed dose (43 µg/kg/day) or a prediction model-guided individualized dose (17-100 µg/kg/day) and followed up for 24 months. In a longitudinal and mixed within- and between-subjects study, we examined clinical effect size changes, measured by Cohen's d, in full-scale IQ (FSIQ) and secondary IQ indices. Results: Significant increases giving medium effect size in FSIQ (p = 0.001, Cohen's d = 0.63), performance IQ (p = 0.001, Cohen's d = 0.65) and processing speed (p = 0.005, Cohen's d = 0.71) were found in the GH-deficient group. In contrast, perceptual organization only increased in the ISS group (p = 0.001, Cohen's d = 0.53). Baseline IQ was normally distributed with small but significant differences between the groups: GH-deficient children had lower FSIQ (p = 0.042) and lower performance IQ (p = 0.021). Using multiple regression analysis, 40% of the variance in delta processing speed scores (0-24 months) was explained by GH_max and IGF-I_SDS at baseline. Conclusion: IQ, specifically fluid intelligence, increased in the GH-deficient children. The pretreatment status of the GH/IGF-I axis was significantly predictive for these changes.

A case of Rubinstein‐Taybi syndrome associated with growth hormone deficiency in childhood

Clinical EndocrinologyVolume 83, Issue 3 p. 437-439 Letter to the Editor A case of Rubinstein-Taybi syndrome associated with growth hormone deficiency in childhood Gianluca Tornese, Gianluca Tornese Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalyThe authors equally contributed to the manuscript draft.Search for more papers by this authorPierluigi Marzuillo, Pierluigi Marzuillo pierluigi.marzuillo@gmail.com Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalyThe authors equally contributed to the manuscript draft.Search for more papers by this authorMaria Chiara Pellegrin, Maria Chiara Pellegrin University of Trieste, Trieste, ItalySearch for more papers by this authorClaudio Germani, Claudio Germani Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalySearch for more papers by this authorElena Faleschini, Elena Faleschini Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalySearch for more papers by this authorFloriana Zennaro, Floriana Zennaro Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalySearch for more papers by this authorAnna Grandone, Anna Grandone Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalySearch for more papers by this authorEmanuele Miraglia del Giudice, Emanuele Miraglia del Giudice Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalySearch for more papers by this authorLaura Perrone, Laura Perrone Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalySearch for more papers by this authorAlessandro Ventura, Alessandro Ventura University of Trieste, Trieste, ItalySearch for more papers by this author Gianluca Tornese, Gianluca Tornese Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalyThe authors equally contributed to the manuscript draft.Search for more papers by this authorPierluigi Marzuillo, Pierluigi Marzuillo pierluigi.marzuillo@gmail.com Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalyThe authors equally contributed to the manuscript draft.Search for more papers by this authorMaria Chiara Pellegrin, Maria Chiara Pellegrin University of Trieste, Trieste, ItalySearch for more papers by this authorClaudio Germani, Claudio Germani Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalySearch for more papers by this authorElena Faleschini, Elena Faleschini Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalySearch for more papers by this authorFloriana Zennaro, Floriana Zennaro Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, ItalySearch for more papers by this authorAnna Grandone, Anna Grandone Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalySearch for more papers by this authorEmanuele Miraglia del Giudice, Emanuele Miraglia del Giudice Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalySearch for more papers by this authorLaura Perrone, Laura Perrone Department of Woman, Child and General and Specialized Surgery, Seconda Univesità degli Studi di Napoli, Napoli, ItalySearch for more papers by this authorAlessandro Ventura, Alessandro Ventura University of Trieste, Trieste, ItalySearch for more papers by this author First published: 14 February 2015 https://doi.org/10.1111/cen.12748Citations: 3 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume83, Issue3September 2015Pages 437-439 RelatedInformation

Current practice in diagnosis and treatment of growth hormone deficiency in childhood: a survey from Turkey.

Objective:Approaches to diagnosis and treatment of growth hormone deficiency (GHD) in children vary among countries and even among centers in the same country. This survey, aiming to facilitate the process of preparing the new consensus on GHD by the Turkish Pediatric Endocrinology and Diabetes Society, was designed to evaluate the current practices in diagnosis and treatment of GHD in different centers in Turkey. Methods:A questionnaire covering relevant items for diagnosis and treatment of GHD was sent out to all pediatric endocrinology centers.Results:Twenty-four centers returned the questionnaire. The most frequently used GH stimulation test was L-dopa, followed by clonidine. Eighteen centers used a GH cut-off value of 10 ng/mL for the diagnosis of GHD; this value was 7 ng/mL in 4 centers and 5 ng/mL in 2 centers. The most frequently used assay was immunochemiluminescence for determination of GH, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 concentrations. Sex steroid priming in both sexes was used by 19 centers. The most frequently used starting dose of recombinant human GH (rhGH) in prepubertal children was 0.025-0.030 mg/kg/day and 0.030-0.035 mg/kg/day in pubertal children. Growth velocity was used in the evaluation for growth response to rhGH therapy in all centers. Anthropometric measurements of patients every 3-6 months, fasting blood glucose, bone age and thyroid panel evaluation were used by all centers at follow-up. Main indications for cessation of therapy were decreased height velocity and advanced bone age. Fourteen centers used combined treatment (rhGH and gonadotropin-releasing analogues) to increase final height.Conclusion: Although conformity was found among centers in Turkey in current practice, it is very important to update guideline statements and to modify, if needed, the approach to GHD over time in accordance with new evidence-based clinical studies.

Neural modelling of growth hormone therapy for the prediction of therapy results

Abstract In this paper, we presented the problem of predicting response to recombinant human growth hormone (GH) treatment in GH-deficient children. Such a prediction can be done by techniques of mathematical modelling and is important because the therapy consists of daily injections and is expensive; thus, it should be administered only to those patients who will, with high probability, benefit from it. Until now, the leading methodological approach to this problem was multiple regression analysis. Several authors demonstrated that it is possible to derive useful models by this method; however, it has some obvious limitations that can be avoided with the use of the proposed neural network approach.

Natural History of Growth Hormone Deficiency in a Pediatric Cohort

Background/Aims: Controversies still exist regarding the evaluation of growth hormone deficiency (GHD) in childhood at the end of growth. The aim of this study was to describe the natural history of GHD in a pediatric cohort. Methods: This is a retrospective study of a cohort of pediatric patients with GHD. Cases of acquired GHD were excluded. Univariate logistic regression was used to identify predictors of GHD persisting into adulthood. Results: Among 63 identified patients, 47 (75%) had partial GHD at diagnosis, while 16 (25%) had complete GHD, including 5 with multiple pituitary hormone deficiencies. At final height, 50 patients underwent repeat stimulation testing; 28 (56%) recovered and 22 (44%) remained growth hormone (GH) deficient. Predictors of persisting GHD were: complete GHD at diagnosis (OR 10.1, 95% CI 2.4-42.1), pituitary stalk defect or ectopic pituitary gland on magnetic resonance imaging (OR 6.5, 95% CI 1.1-37.1), greater height gain during GH treatment (OR 1.8, 95% CI 1.0-3.3), and IGF-1 level <-2 standard deviation scores (SDS) following treatment cessation (OR 19.3, 95% CI 3.6-103.1). In the multivariate analysis, only IGF-1 level <-2 SDS (OR 13.3, 95% CI 2.3-77.3) and complete GHD (OR 6.3, 95% CI 1.2-32.8) were associated with the outcome. Conclusion: At final height, 56% of adolescents with GHD had recovered. Complete GHD at diagnosis, low IGF-1 levels following retesting, and pituitary malformation were strong predictors of persistence of GHD.

Cost effectiveness of proton versus photon radiation therapy with respect to the risk of growth hormone deficiency in children.

Proton therapy in pediatrics may improve the risk/benefit profile of radiotherapy at a greater upfront financial cost, but it may prove to be cost effective if chronic medical complications can be avoided. Tools to assist with decision making are needed to aid in selecting pediatric patients for protons, and cost-effectiveness models can provide an objective method for this. A Markov cohort-simulation model was developed to assess the expected costs and effectiveness for specific radiation doses to the hypothalamus with protons versus photons in pediatric patients. Costing data included cost of investment and the diagnosis and management of growth hormone deficiency. Longitudinal outcomes data were used to inform risk parameters for the model. With costs in 2012 US dollars and effectiveness measured in quality-adjusted life years, incremental cost-effectiveness ratios were used to measure outcomes. Proton therapy was cost effective for some scenarios based on the difference in hypothalamic sparing. Although some scenarios were not cost effective, others were not only cost effective for proton therapy but also demonstrated that protons were cost saving compared with photons. The current results provide the first evidence-based guide for identifying children with brain tumors who may benefit the most from proton therapy with respect to endocrine dysfunction. Proton therapy may be more cost effective for scenarios in which radiation dose to the hypothalamus can be spared, but protons may not be cost effective when tumors are involving or directly adjacent to the hypothalamus if there is a high dose to this structure.