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Neurosecretory dysfunction (NSD) causes growth hormone deficiency (GHD). Data on adult height after recombinant human growth hormone (rhGH) treatment are lacking.We collected treatment data of all patients with NSD seen between 1990 and 2017 at our outpatient department (tertiary centre) and measured adult height. For comparison, patients with idiopathic GHD were used. Diagnoses were based on short stature (-2 standard deviation score [SDS]), continuously low height velocity (25th percentile), delayed bone age (by1 SD) and low serum IGF-1 concentration (-2 SDS). NSD was defined by normal GH challenge results, but subnormal spontaneous GH secretion. Exclusion criteria were no information on adult height, underweight and other short stature disorders.Out of 67 patients diagnosed with NSD, six were still growing, 31 had test results exceeding validated GH cut-offs and three had other disorders causing short stature. Out of the 25 eligible patients with NSD, 21 could be recruited. These patients reached an adult height of -0.85 SDS (mean); 0.34 SDS below midparental height. Height gain during treatment was 2.01 SDS. This outcome was not different to 32 patients with idiopathic GHD.Long-term results suggest the viability of the diagnosis of NSD and the efficacy of rhGH treatment.

Multiple factors influence intrauterine growth and lead to low birth sizes. The impact of genetic alterations on both pre- and post-natal growth is still largely unknown. The aim of this study was to investigate the prevalence of CNVs in an Italian cohort of SGA children with persistent short stature and complex clinical phenotype. rhGH treatment efficacy was evaluated according to the different genotypes. Twenty-four SGA children (10F/14M) with persistent short stature associated with dysmorphic features and/or developmental delay underwent CNV evaluation. CNVs were present in 14/24 (58%) SGA children. Six patients had a microdeletion involving the following regions: 3q24q25.1, 8p21.2p12, 15q26, 19q13.11, 20q11.21q12, 22q11.2. In three females, the same microdeletion involving 17p13.3 region was identified. In two different patients, two microduplications involving 10q21.3 and Xp11.3 region were observed. A further female patient showed both an 11q12.1 and an Xq27.1 microduplication, inherited from her mother and from her father, respectively. In a boy, the presence of a 12p13.33 microdeletion and a 19q13.43 microduplication was found. GH treatment efficacy, expressed by height gain and height velocity in the first 12 months of therapy, was similar in subjects with and without CNVs. These results show that pathogenic CNVs are common in SGA children with short stature associated with additional clinical features. Interestingly, the involvement of 17p13.3 region occurs with a relative high frequency, suggesting that genes located in this region could play a key role in pre- and post-natal growth. rhGH therapy has similar efficacy in the short term whether CNVs are present or not.

Pituitary dysfunction, specifically growth hormone (GH) deficiency, can occur following traumatic brain injury. Our objective was to characterize the prevalence of GH deficiency (GHD) testing and response to recombinant human GH (rhGH) treatment in adults with persistent symptoms following mild traumatic brain injury (mTBI) referred for assessment of pituitary dysfunction. A retrospective chart review was conducted of patients seen at an outpatient brain injury clinic with a diagnosis of mTBI and persistent post-concussive symptoms who were referred to endocrinology. Clinical assessments of symptoms were collected. Investigations and results of GHD were collected, including initiation of rhGH treatment and treatment response. Of the 253 patients seen in both brain injury and endocrinology clinics, 97 with mTBI were referred for investigation of pituitary dysfunction and 73 (75%) had dynamic testing for assessment of GHD. Of the 26 individuals diagnosed with GHD, 23 (88%) started rhGH. GH therapy was inconsistently offered based on interpretation of GH dynamic testing results. Of those who started rhGH, 18 (78%) had a useful treatment response. This study suggests that clinical management of these patients is varied, highlighting a need for clear guidelines for the diagnosis and management of GHD following mTBI.

Objective: Short stature in Turner Syndrome (TS) may be accompanied by skeletal disproportion. This retrospective study investigates growth and disproportion from early childhood to adult height. Study design: Data were collected from 59 girls prior to growth hormone (rhGH) treatment and in 30 girls followed‐up longitudinally. Standard deviation scores (SDS) for height (Ht), sitting height (SH) and sub‐ischial leg length (LL) were compared and a disproportion score (SH SDS – LL SDS) calculated. Results: In 59 girls, mean (SD) age 6.6 (2.1) years prior to rhGH treatment, LL SDS of ‐3.4 (1.1) was significantly lower than SH SDS of ‐1.2 (0.8) [p +2.0 in 27 (63%), cf eight (50%) with Ht SDS ≥ ‐2.0. For the longitudinal analysis, skeletal disproportion prior to rhGH was +2.4 (1.1) and +1.7 (1.0) on rhGH but prior to introduction of oestrogen [p

Purpose Recombinant human growth hormone (rhGH) has been used to improve growth in children with Noonan syndrome (NS). This study aimed to investigate the efficacy of rhGH therapy in Korean children with NS. Methods Seventeen prepubertal children (10 boys, 7 girls) with NS who received rhGH therapy for at least 3 years between 2008 and 2017 were included. To compare the response, age- and sex-matched children with GH deficiency (GHD; n=31) were included. Height and growth velocity before and during treatment were analyzed. Results The mean age of NS patients was 6.34±2.32 years. After treatment, the height standard deviation score (SDS) increased from -2.93±0.81 to -1.51±1.00 in patients with NS and from -2.45±0.42 to -1.09±0.47 in patients with GHD. There were no significant differences in growth velocity or change in height SDS between patients with NS and GHD. Growth velocity in the first year of treatment was higher in patients with PTPN11 mutations than those without PTPN11 mutations, but the change in height SDS was not significantly different between those 2 groups. Conclusion rhGH therapy can increase linear growth in prepubertal children with NS. The growth response between patients with NS and patients with GHD was not significantly different. Furthermore, we observed that lower doses of growth hormone have a similar effect on height compared to previous studies in patients with NS. Our study indicates that rhGH treatment is useful for growth promotion.

A significant increase in growth velocity is observed during recombinant human growth hormone (rhGH) therapy in patients with growth hormone deficiency (GHD), especially just after the beginning of treatment. This phenomenon is referred to as catch-up growth". After some time, the growth velocity decreases to the physiological value, i.e. the value that is observed in healthy children. The treatment is continued until the time of the growth process is completed. The continuity of the therapy makes it impossible to assess whether the catch-up phenomenon occurs only at the beginning of the treatment or may be observed after treatment cessation and its re-introduction.Growth velocity was evaluated in a group of 35 patients with GHD after repeated therapy application, in which, due to non-medical reasons, the rhGH treatment was abandoned for a short time.Patients with GHD after treatment re-introduction presented the catch-up growth phenomenon and obtained growth velocity results that were significantly higher than those observed during primary treatment.Re-introduction of rhGH treatment after short-term therapy cessation leads to the re-occurrence of catch- up growth in patients with GHD.Podczas terapii rekombinowanym ludzkim hormonem wzrostu (rhGH) u pacjentów z niedoborem hormonu wzrostu (GHD) obserwuje się znaczne przyspieszenie tempa wzrastania, szczególnie tuż po rozpoczęciu leczenia. Zjawisko to nazywane jest catch-up growth – nadrabianiem zaległości. Po pewnym czasie tempo wzrastania spada do wartości fizjologicznej, obserwowanej u zdrowych dzieci, a leczenie kontynuuje się do czasu zakończenia procesu wzrastania. Ciągłość terapii uniemożliwia ocenę, czy zjawisko catch-up growth występuje tylko na początku leczenia, czy też może być obserwowane po przerwaniu leczenia i jego ponownym rozpoczęciu.Tempo wzrastania oceniano w grupie 35 pacjentów z GHD po powtórnym rozpoczęciu leczenia rhGH, które z przyczyn pozamedycznych zostało na krótko przerwane.Pacjenci z GHD po ponownym wprowadzeniu leczenia wykazywali przyspieszone tempo wzrastania, a uzyskane wyniki były wyższe niż obserwowane podczas leczenia pierwotnego.Powtórne rozpoczęcie leczenia rhGH po krótkotrwałym zaprzestaniu terapii prowadzi do ponownego wystąpienia zjawiska catch-up growth u pacjentów z GHD.

Introduction: Omnitrope® was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Objective: The purpose of this work was to evaluate the long-term safety and effectiveness of Omnitrope® in PATRO Children – an ongoing, international, longitudinal, non-interventional study in children who require rhGH treatment. Methods: The study population includes infants, children, and adolescents receiving Omnitrope®. Adverse events (AEs) are monitored for safety and rhGH effectiveness is evaluated by calculation of the height standard deviation score (HSDS), height velocity (HV), and HVSDS using height measurements and country-specific references. Results: As of November 2017, 6,009 patients from 298 centers across 14 countries were enrolled in PATRO Children. Overall, 57.7% of patients had growth hormone deficiency (GHD), 25.8% were born small for gestational age (SGA), and 4.8% had Turner syndrome (TS). In total, 84.1% were rhGH treatment naïve at study entry. The mean duration of Omnitrope® treatment in the study was 36.1 months (range 0–133.7). Overall, 10,360 AEs were reported in 2,750 patients (45.8%). Treatment-related AEs were reported in 396 patients (6.6%; 550 events), and serious AEs (SAE) in 636 patients (10.6%; 1,191 events); 50 SAEs in 37 patients (0.6%) were considered treatment related. Following 5 years of therapy in patients who were rhGH treatment naïve at study entry, improvement from baseline in mean HSDS was +1.85 in GHD, +1.76 in SGA, and +1.0 in TS patients. In total, 912 (17.9%) patients reached adult height (n = 577 GHD, n = 236 SGA, n = 62 TS). Conclusions: This analysis of PATRO Children indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice.

Context Gonadotropin-releasing hormone analogues (GnRHa) and recombinant human growth hormone (rhGH) have been widely used to treat idiopathic central precocious puberty (CPP) or early and fast puberty (EFP). However, large-scale studies to evaluate the treatment effects on final adult height (FAH) are still lacking. Objective To assess the effects of long-term treatment for CPP/EFP on FAH and its main influencing factors. Design and Setting Retrospective, multicenter observational study from 1998 to 2017. Participants Four hundred forty-eight Chinese girls with CPP/EFP received GnRHa and rhGH treatment (n = 118), GnRHa alone (n = 276), or no treatment (n = 54). Main Outcome Measures FAH, target height (Tht), and predictive adult height (PAH). Results The height gain (FAH–PAH) was significantly different among the GnRHa and rhGH treatment, GnRHa alone, and no treatment groups (P < 0.05; 9.51 ± 0.53, 8.07 ± 0.37, and 6.44 ± 0.91 cm, respectively). The genetic height gain (FAH–Tht) was 4.0 ± 0.5 cm for the GnRHa + rhGH group and 2.0 ± 0.27 cm for the GnRHa group, while the control group reached their Tht. In addition, 5 critical parameters derived from PAH, bone age, and Tht, showed excellent performance in predicting which patients could gain ≥5 cm (FAH–PAH), and this was further validated using an independent study. Conclusions The overall beneficial effect of GnRHa + rhGH or GnRHa on FAH was significant. The control group also reached their genetic target height. Clinicians are recommended to consider both the potential gains in height and the cost of medication.

Serum insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3) levels can be used to monitor the safety of recombinant human growth hormone (rhGH) therapy. In this study, we evaluated the changes in serum IGF-I and IGFBP-3 levels during rhGH therapy as a marker of height outcome in prepubertal children. Totally, 705 prepubertal children with short stature were enrolled from the LG Growth Study Database. Data for three groups of subjects were obtained as follows: Idiopathic GH deficiency (IGHD; n = 486); idiopathic short stature (n = 66); small for gestational age (n = 153). Serum IGF-I and IGFBP-3 levels at the baseline and after the 1st and 2nd year of rhGH therapy, as well as the Δheight standard deviation score (SDS), were obtained. Δheight SDS after the 1st and 2nd year of rhGH therapy had notably increased compared to that at the baseline for all three groups. IGF-I and IGFBP-3 levels in all three groups were significantly increased compared to those at the baseline (p st year of therapy, ΔIGFBP-3 SDS after the 2nd year of therapy in the IGHD group, and ΔIGF-I SDS and ΔIGFBP-3 SDS after the 2nd year of therapy (p < 0.05), regardless of whether the height at the baseline was a covariate. The increase in IGF-I and IGFBP-3 levels during rhGH therapy was related to the growth response in children with IGHD. Therefore, it may be valuable to measure the change in serum IGF-I and IGFBP-3 levels, especially the latter, during rhGH treatment to predict the growth response upon long-term treatment.

Objectives. The standard of treatment for pediatric growth hormone deficiency (GHD) is daily subcutaneous recombinant human growth hormone (rhGH) injections. The efficacy of rhGH treatment given as daily intravenous (IV) boluses is not known. Case Presentation. A female with protein C deficiency, a severe bleeding disorder characterized by thrombosis formation, was diagnosed with GHD at age four years. She has been receiving daily protein C infusion through a permanent port since the newborn period. GHD was treated with daily IV rhGH boluses given through the port following protein C infusion. She has reached a growth rate of 12 cm/year and had no side effects. Surprisingly, serum insulin-like growth factor-1 (IGF1) levels did not rise despite an excellent clinical response. Conclusions. IV administration may be an alternative route for GHD treatment in eligible patients with permanent vascular access. A rise in serum IGF1 levels may not be needed to achieve the growth-promoting effect of rhGH.

Children born small for gestational age (SGA), and failing to catch-up growth in their early years, are a heterogeneous group, comprising both known and undefined congenital disorders. Care for these children must encompass specific approaches to ensure optimal growth. The use of recombinant human growth hormone (rhGH) is an established therapy, which improves adult height in a proportion of these children, but not with uniform magnitude and not in all of them. This situation is complicated as the underlying cause of growth failure is often diagnosed during or even after rhGH treatment discontinuation with unknown consequences on adult height and long-term safety. This review focuses on the current evidence supporting potential benefits from early genetic screening in short SGA children. The pivotal role that a Next Generation Sequencing panel might play in helping diagnosis and discriminating good responders to rhGH from poor responders is discussed. Information stemming from genetic screening might allow the tailoring of therapy, as well as improving specific follow-up and management of family expectations, especially for those children with increased long-term risks. Finally, the role of national registries in collecting data from the genetic screening and clinical follow-up is considered.

Purpose Adherence to growth hormone (GH) treatment impacts clinical outcomes. The aim of this study is to assess the impact of adherence to rhGH treatment (2 years) on auxological outcomes. Methods Multicentric, retrospective observational study in rhGH-naive GHD/SGA children treated with Saizen (R) during >= 2 years. Growth response was assessed by evaluating the change in height standard deviation score (Delta H SDS) and the index of responsiveness (IoR). Adherence was monitored using EasyPod (TM) Connect device. Results A total of 110 patients (3 Spanish centers) were evaluable (GHD n = 76, SGA n = 34). Adherence was 95.6 and 93.9% (year 1, 2). SGA and GHD children showed an increase of 0.6 cm/year and 1.1 cm/year for each 10% adherence modification. Lower adherence was observed in patients with lower pretreatment height velocity (HV) and in patients whose parents had a lower level of education. A positive correlation between index of responsiveness (IoR) during the first and second years with HV SDS during the second year and between IoR2 and adherence (year 1, 2) was observed. The frequency of patients with HV > 1 SD was higher (p = 0.025) among patients with adherence >90%. The best model to predict the height gain(cm) reaching an adjusted R squared of 0.489 involved percentage of adherence, Tanner stage, pretreatment HV, dose of rhGH, and whether the treatment was initiated before or after puberty. Conclusions Adherence during the first 2 years of response was very high >90% and showed a negative association with age, pretreatment HV and treatment duration and a positive correlation with the level of parent education.

Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

Introduction: Growth retardation is one of the main complications of chronic kidney disease (CKD) in children and induces a negative impact on quality of life.Materials and Methods: Retrospective analysis of all consecutive patients younger than 18 years old who received a first KT in our center between 2008 and 2018.Results: 95 first KT recipients, median age at KT of 7.83 years. At the time of KT, 65.52% of males and 54.05% females showed normal height. After transplantation, linear growth improved from −1.53 at transplant to −1.37 SDS height at the last visit. We detected a different linear growth pattern according to patient age at KT. Children younger than 3 years old exhibited the most significant growth retardation at baseline and the greatest linear growth over time (−2.29 vs. −1.82 SDS height), whereas catch-up was not observed in older patients. Multivariate analysis showed that use of corticosteroids was negatively related to SDS height at 1 year after transplantation and final SDS height only was positively associated with SDS height at KT. 44.2 and 22.1% patients received rhGH treatment before and after KT. 71.88% patients reached adulthood with normal final height.Conclusions: In our study, pediatric KT recipients exhibited a normal height in more than half of cases at KT and in more than two thirds at the final adult height. Only children younger than 6 years old presented a relevant growth catch-up after KT. Treatment with rhGH was used before and after KT with significant improvement in height.

Context Recombinant human growth hormone (rhGH) is approved for treatment of pediatric growth hormone deficiency (GHD), with greatest growth responses observed in those with severe GHD. Orally administered GH secretagogues (GHS) may be useful treatment in patients with moderate GHD. Distinguishing children with severe vs moderate GHD could identify children who would be better treated with rhGH or GHS. Objectives Evaluate baseline insulin-like growth factor-I (IGF-I) and stimulated peak GH response as predictors of 12-month height velocity (HV) in children with GHD. Design Data on children with GHD were analyzed in a legacy data base (GeNeSIS data). Participants 514 naïve to rhGH-treatment, prepubertal children with idiopathic isolated GHD for whom stimulated GH, baseline serum IGF-I, and first-year HV during rhGH treatment data are available. Outcome Measures Children with severe or moderate GHD were categorized based on GH and IGF-I data and evaluated based on baseline auxologic and hormone profiles and first-year growth response to rhGH. Results Cohorts of severe and moderate GHD were 81/514 (15.8%) and 433/514 (84.2%). Cohorts differed significantly with regard to indicators of GHD [eg, baseline height SD score (SDS), height SDS minus target height SDS, HV, HV SDS, and change in height SDS during rhGH treatment]. Multiple regression analysis showed IGF-I and stimulated GH were significant predictors of HV independent of other known variables. Expected first-year HV in moderate GHD was 8.3 cm/y. Conclusions The combination of peak GH to GH stimulation testing and baseline IGF-I concentration are predictive enrichment markers for annualized HV responses to rhGH therapy.

Severe growth hormone deficiency causes lean body mass loss in male adolescents and increased fat mass in both sexes. The changes appear after a 6 month GH pause.The aim was to examine bone density and structure changes in adolescents with severe GHD during a 6-month rhGH treatment interruption.In total, 113 adolescents (20 females) paused rhGH treatment for 6 months at near-final height, and they were retested with arginine-GHRH challenge and basal IGF-1. Severe GHD was diagnosed in 19 individuals (5 females, GH peak16 ng/ml and IGF-1 -1.9 SDS) and excluded in 94 (15 females). Bone density and structure were measured by pQCT of the forearm and DXA of the total body at cessation of rhGH and 6 months later.In severe adolescent GHD (sGHD) patients, trabecular density (mg/cmDuring a 6-month pause of rhGH treatment, the bone structure and density of adolescents with sGHD did not show changes implying harm. Routine retesting of adolescents, including 6 months without GH, is unlikely to be detrimental to the bone.

Worrisome growth can be a sign of underlying pathology but usually reflects healthy variation. It is often recognized through short stature, which is defined by arbitrarily separating height, a physical trait on a continuum, into "normal" and "abnormal." In some cases of worrisome growth, recombinant human growth hormone (rhGH) treatment is indicated to hasten growth/increase height. This review addresses the two most frequently treated indications for rhGH, growth hormone deficiency (GHD) and idiopathic short stature (ISS). A review of worrisome growth itself, of the history of GH treatment, of the blurry line between partial GHD and ISS, of the GH stakeholders, and of the outside pressures involved in these cases demonstrates the ambiguous platform upon which treatment decisions are made. The rhGH treatment decision process can be examined further by considering the three most impactful factors on parental height-related medical decision-making: treatment characteristics, child health, and psychosocial function. While it is important to note that treatment for classical GHD is uncontroversial and supported, treatment decisions for partial GHD and ISS are more complicated and require careful evaluation of both patient needs and the supporting evidence. As the rhGH community grows, physicians, parents, and patients are encouraged to engage in a shared decision-making process to navigate the many challenges facing the GH field. Although this review addresses GHD and ISS specifically, the issues discussed are often applicable to pediatrics as a whole.

AIM We analysed near final height (NFH) data in children with growth hormone deficiency (GHD) treated with recombinant human GH (rhGH). METHODS We divided the idiopathic GHD patients into two groups, isolated GHD (IGHD) and multiple pituitary hormone deficiency, to evaluate NFH. Then, data were grouped according to gender, pre-pubertal/pubertal status and spontaneous or induced puberty. The trial was performed as a retrospective study. Median values are given, and measurements are expressed as standard deviation scores (SDSs). RESULTS rhGH therapy was started at a median age of 12.1 (range 9.1-14.9) years in the IGHD group (n = 162, 83 males) and 9.1 (range 4.9-13.4) years in the multiple pituitary hormone deficiency group (n = 33, 22 males) at a median dose of 0.20 mg/kg/week. Height SDSs at the onset of therapy were -3.2 (range -4.4 to -2.6) and -3.9 (-6.8 to -2.8) in the two groups, respectively (P

The efficacy and safety of recombinant human GH (rhGH) treatment were assessed in Japanese children with small-for-gestational-age short stature. A total of 88 patients were enrolled in the comparative and extension studies. At the end of the comparative study (24 mo), the mean height SD score for chronological age had significantly increased in the 0.23 mg/kg/wk and 0.47 mg/kg/wk groups with increments of 0.84 ± 0.42 and 1.50 ± 0.44 SD, respectively. In the extension study, the dose could be increased based on the pre-defined growth criteria. Increments in height SD scores over the 24 to 36 mo period at doses of 0.23 mg/kg/wk, 0.23 to 0.47 mg/kg/wk, and 0.47 mg/kg/wk were 0.25 ± 0.28, 0.46 ± 0.21, and 0.28 ± 0.16 SD, respectively. The growth effect increased following dose escalation even in the low responders in the initial 2-yr treatment at 0.23 mg/kg/wk, indicating the effectiveness of dose escalation in accordance with the Japanese guidelines. rhGH at 0.47 mg/kg/wk provided a greater degree of growth promotion after 24 mo. The safety profile appeared to be tolerable and was similar in all groups. Considering the increased insulin resistance, the recommendations of the regulatory authorities should be followed to minimize the risks of rhGH treatment.

Since the appearance of recombinant human growth hormone (rhGH) in the 1980s, its expansion and acquisition through the black market has increased, so the detection of its abuse continues to be a challenge. New biomarkers that are more reliable and sensitive, allowing a larger detection window, are still needed. In this line, Fibronectin 1 (FN1) has been proposed as a potential genetic and protein biomarker of rhGH abuse in peripheral blood lymphocytes, serum, and plasma. However, logistic problems associated with current blood collection in sports drug testing point towards potential new alternative matrices that could be good candidates to be evaluated. Results obtained in this study showed high ELISA FN1 levels in one dried blood spot and in urine samples in ten healthy male volunteers treated with rhGH. Results showed that especially dried blood spots appear as a potential good matrix to detect rhGH abuse by means of FN1 biomarker. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives To study the efficacy and influence on metabolism of recombinant human growth hormone (rhGH) treatment in short children born small for gestational age (SGA). Methods Retrospective, observational, multicenter study in 305 short children born SGA, treated with rhGH during a mean ± SD of 5.03 ± 1.73 years at a mean ± SD dose of 37 ± 8 μg/kg/day. Auxological and metabolic assessment including glucose and lipids profile were collected. Results Mean ± SD age at the start of treatment was 7.11 ± 2.78 years. Height and weight improved significantly until the end of treatment from mean −2.72 (CI95%: −2.81 to −2.63) standard deviation score (SDS) to −1.16 (CI95%: −1.44 to −0.88) SDS and from −1.62 (CI95%: −1.69 to −1.55) SDS to −0.94 (CI95%: −1.14 to −0.74) SDS respectively. Mean height gain was 1.27 (CI95%: 0.99–1.54) SDS. Prepubertal patients showed higher height gain than pubertal children (mean [CI95%] = 1.44 [CI95%: 1.14–1.74] vs. 0.73 [CI95%: 0.22–1.24], p=0.02). Height gain SDS during treatment negatively correlated with chronological age (CA) and bone age (BA) delay and positively correlated with duration of treatment, height gain during first year of treatment, years on prepubertal treatment and height SDS from target height (TH). Glucose, insulin, and triglycerides increased significantly but remained within the normal range. Total and LDL-cholesterol decreased significantly, and HDL-cholesterol remained unchanged. Conclusions rhGH treatment in short SGA children effectively normalized height in most of the patients and showed a safe metabolic profile. Children who benefit the most are those with greater height SDS distance from TH, BA delay, longer duration of treatment and prepubertal treatment initiation.

The growth hormone is involved in skin homeostasis and wound healing. We hypothesize whether it is possible to improve pressure ulcer (PU) healing by locally applying the recombinant human growth hormone (rhGH) in a human skin mouse model. Non-obese diabetic/severe combined immunodeficient mice (n = 10) were engrafted with a full-thickness human skin graft. After 60 days with stable grafts, human skin underwent three cycles of ischemia-reperfusion with a compression device to create a PU. Mice were classified into two groups: rhGH treatment group (n = 5) and control group (n = 5). In the rhGH group for local intradermal injections, each had 0.15 mg (0.5IU) applied to the PU edges, once per week for four weeks. Evaluation of the wound healing was conducted with photographic and visual assessments, and histological analysis was performed after complete wound healing. The results showed a healing rate twice as fast in the rhGH group compared to the control group (1.25 &plusmn, 0.33 mm2/day versus 0.61 &plusmn, 0.27 mm2/day, p-value &lt, 0.05), with a faster healing rate during the first 30 days. The rhGH group showed thicker skin (1953 &plusmn, 457 &micro, m versus 1060 &plusmn, 208 &micro, m, 0.05) in the repaired area, with a significant decrease in collagen type I/III ratio at wound closure (62 days, range 60&ndash, 70). Local administration of the rhGH accelerates PU healing in our model. The rhGH may have a clinical use in pressure ulcer treatment.

Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked disease caused by PHF6 mutations. Classic BFLS has been associated with intellectual disability (ID), developmental delay (DD), obesity, epilepsy, typical facial features and anomalies of fingers and toes. Endocrinological phenotypes and outcome of treatment in this condition remain to be delineated. Here we report a patient who exhibited complete growth hormone deficiency who responded to hormonal treatment but with adverse effects. Horseshoe kidney was present in this patient, which is also atypical in BFLS. A heterozygous nonsense mutation c.673C>T (p.R225X) of PHF6 gene was identified in the patient, inherited from her unaffected mother. Both the patient and her mother showed highly skewed X-inactivation. We reviewed the phenotypes of all reported BFLS cases, and summarized their endocrine presentations. This first report of an Asian patient with BFLS further delineated the genetic and phenotypic spectrum of the syndrome. The adverse effect experienced by the patient suggests caution in the use of growth hormone treatment in this condition.

Restarting rhGH in adolescents with childhood-onset (CO-) GHD is usually based on GH retest, IGF-1, additional pituitary hormone deficiencies, pituitary morphology and history. Short-term changes in body composition in adolescents with CO-GHD when off rhGH may contribute to the identification of those in need of treatment continuation.This is a longitudinal single-centre study.The body composition of 90 male adolescents with low-likelihood severe GHD of adolescence was measured by DXA at the time of rhGH discontinuation and 6 months thereafter. At diagnosis, mean age was 5.4 years, height was -2.68 SDS and stimulated GH peak was 5.1 ng/mL. RhGH treatment was stopped at 16.7 years at near-final height of -0.44 SDS. The adolescents were re-examined after 3 months off rhGH using both IGF-1 and GHRH-arginine tests. Severe GHD of adolescence was defined both by stimulated GH 16 ng/mL and by IGF-1 -1.90 SDS.Males with severe GHD of adolescence (n = 8) gained more relative and absolute fat mass and lost significantly more relative lean body mass after 6 months off rhGH than healthy individuals (n = 82; P 0.001). The sum of absolute fat mass gain and lean body mass loss (=body composition changes score; BCC score) correlated highly with the GH peak (R = 0.17; P 0.001). A BCC score7.0 kg was 88% sensitive and 94% specific for detecting severe GHD of adolescence (AUC = 0.975).Short-term body composition changes when off rhGH are good clinical markers of severe GHD in male adolescents. The novel BBC score is an aggregate of these changes.

In this chapter, we want to give an overview on what we have learned from more than 30 years ago on the use of recombinant human growth hormone (rhGH) and later recombinant human IGF-1 which was introduced for the treatment of short children and what are the safety issues concerned with this treatment. However, rhGH is used not solely in conditions where short stature is the consequence of GH deficiency but also in various disorders without a proven GH deficiency. In clinical studies, growth responses to various forms of rhGH therapy were analyzed, adding to our concept about the physiology of growth. Most patients under rhGH treatment show a considerable short-term effect; however, the long-term gain of height in a child obtained by a year-long treatment until final height remains controversial in some of the growth disorders that have been treated with rhGH or IGF-1. Today the first studies on the long-term safety of rhGH treatment have been published and raising some questions whether this treatment is similarly safe for all the patient groups treated with rhGH. Although there is a long-standing safety record for these hormone replacement therapies, in the face of the considerable costs involved, the discussion about the risk to benefit ratio is continuing. Newer developments of rhGH treatment include long-term preparations, which have only to be injected once a week. Although some of these drugs already have proven their non-inferiority to conventional rhGH treatment, we have to await further results to see whether they show improvements in treatment adherence of the patients and prove their long-term safety.

Recombinant human growth hormone (rhGH) is an approved and effective treatment for short children born small for gestational age (SGA). Prevalence of children eligible for treatment as SGA is reported to be 1:1800. The latest data from the National Registry of Growth Hormone therapy (RNAOC) showed that the number of children treated with SGA indication is still small (prevalence 0.37/100,000) and these children are significantly less reported than those treated for growth hormone deficiency (GHD), although GHD prevalence is 1:4000–1:10,000. This means that many short children born SGA are still not properly identified, and therefore not treated with rhGH, or misdiagnosed as GHD. This article provides some practical tools for the identification of children eligible for rhGH treatment.