Treatment Of Growth Disorders Research Articles

The Treatment of Growth Disorders in Childhood and Adolescence.

3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience. Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management. There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.

First results of the growth disorders related twinning programme Partners4Growth implemented at the tertiary university pediatric endocrinology clinics in Bulgaria.

Early diagnosis of childhood growth disorders, their timely and proper treatment are important for better outcomes.The aim of the present study was to assess the results of the first 18months of the growth disorders related twinning programme "Partners4Growth" implemented at all tertiary university pediatric endocrinology clinics in Bulgaria. In 2019, Partners4Growth started operation at 7 centres (4 experienced and 3 twin centres) with the main aim of aligning their practices in the shortest possible time. Education of twin centres' personnel was organized, equipment and methods for growth evaluation and follow-up were standardized. The approach was tested initially at one centre. At baseline and at the 18th month a questionnaire concerning diagnosis and management of recombinant human growth hormone (rhGH) requiring disorders was applied. A total of 104 new patients were diagnosed compared to 30 in the previous year. Of those, 91 started rhGH treatment- 65 (64 %) GH deficient, 12 (12 %) Turner syndrome, 7 (7 %) Prader-Willi syndrome patients, and 7 (7 %) born small for gestational age without postnatal catch-up, representing 35.8 % of all currently rhGH treated Bulgarian children. A better geographical coverage and more advanced diagnostic and management practices were achieved. Partners4Growth facilitated the alignment of the tertiary pediatric endocrinology centres competences thus leading to an improved diagnosis and treatment of growth disorders as well as better patients' access. For its short existence, the Programme increased significantly the number of new patients in the difficult times of COVID-19 pandemic thus justifying its continuation.

Fathers’ involvement in handling growth disorder of children family members: a systematic review

To find out fathers' involvement in the treatment of growth disorders. The systematic review comprised search on Scopus, CINAHL, ScienceDirect, SpringerLink, ProQuest and Google Scholar databases for studies published in English language between January 2017 and March 2022 and described fathers' roles in handling stunting in children. The keywords used along with Boolean operators included father, paternal, involvement, engagement, role, stunting, and growth disorder. The studies shortlisted were subjected to charting and narrative analyses. Of the 699 studies initially found, 13(1.85%) were analysed in detail. Four factors identified were economic support, instrumental support, nurturing the children, and health risk behaviour. Strategies to increase fathers' involvement related to internal and external barriers. Fathers' role is crucial in handling growth disorder in children. Growth disorder management strategies need to involve fathers and mothers by considering the identified barriers and potential facilitators.

Selective quantification of the 22-kDa isoform of human growth hormone 1 in serum and plasma by immunocapture and LC–MS/MS

The human growth hormone GH1 (22 kDa) is a commonly measured biomarker for diagnosis and during treatment of growth disorders, but its quantification by ligand binding assays may be compromised by the occurrence of a number of isoforms. These can interfere in the assays and lead to differences in results between laboratories and potentially even in the treatment of patients. We present an LC–MS/MS method that is able to distinguish the major growth hormone isoform (GH1, 22 kDa) from other isoforms and quantify it without any interference across the clinically relevant concentration range of 0.5 to 50 ng/mL. Analysis involves purification of a 100-µL serum sample by immunocapture using an anti-GH-directed antibody, tryptic digestion, and LC–MS/MS quantification of an isoform-specific signature peptide for GH1 (22 kDa). A tryptic peptide occurring in all GH isoforms is monitored in the same 16-min analytical run as a read-out for total GH. Stable-isotope-labeled forms of these two peptides are included as internal standards. Full validation of the method according to recent guidelines, against a recombinant form of the analyte in rat plasma calibrators, demonstrated intra-assay and inter-assay imprecision below 6% across the calibration range for both signature peptides and recoveries between 94 and 102%. An excellent correlation was found between nominal and measured concentrations of the WHO reference standard for GH1 (22 kDa). Addition of up to 1000 ng/mL biotin or the presence of a 100-fold excess of GH binding protein did not affect the measurement. Equivalent method performance was found for analysis of GH in serum, EDTA, and heparin plasma. Analyte stability was demonstrated during all normal sample storage conditions. Comparison with the IDS-iSYS GH immunoassay showed a good correlation with the LC–MS/MS method for the isoform-specific signature peptide, but a significant positive bias was observed for the LC–MS/MS results of the peptide representing total GH. This seems to confirm the actual occurrence of other GH isoforms in serum. Finally, in serum from pregnant individuals, no quantifiable GH1 (22 kDa) was found, but relatively high concentrations of total GH.Graphical abstract

High Engagement of Patients Monitored by a Digital Health Ecosystem Indicates Significant Improvements of Key r-hGH Treatment Metrics.

The early adoption of digital health solutions in the treatment of growth disorders has enabled the collection and analysis of more than 10 years of real-world data using the easypod™ connect platform. Using this rich dataset, we were able to study the impact of engagement on three key treatment-related outcomes: adherence, persistence of use, and growth. In total, data for 17,906 patients were available. The three features, regularity of injection (≤2h vs >2h), change of comfort setting (yes/no), and opting-in to receive injection reminders (yes/no), were used as a proxy for engagement. Patients were assigned to the low-engagement group (n=1,752) when all of their features had the low-engagement flag (>2h, no, no) and to the high-engagement group (n=1,081) when all of their features had the high-engagement flag (≤2h, yes, yes). The low-engagement group was down-sampled to 1,081 patients (subsample of n=37 for growth) using the iterative proportional fitting algorithm. Statistical tests were used to study the impact of engagement to the outcomes. The results show that all three outcomes were significantly improved by a factor varying from 1.8 up to 2.2 when the engagement level was high. These results should encourage the promotion of engagement and associated behaviors by both patients and healthcare professionals.

Growth hormone - past, present and future

Growth hormone (GH) research and its clinical application for the treatment of growth disorders span more than a century. During the first half of the 20th century, clinical observations and anatomical and biochemical studies formed the basis of the understanding of the structure of GH and its various metabolic effects in animals. The following period (1958-1985), during which pituitary-derived human GH was used, generated a wealth of information on the regulation and physiological role of GH - in conjunction with insulin-like growth factors (IGFs) - and its use in children with GH deficiency (GHD). The following era (1985 to present) of molecular genetics, recombinant technology and the generation of genetically modified biological systems has expanded our understanding of the regulation and role of the GH-IGF axis. Today, recombinant human GH is used for the treatment of GHD and various conditions of non-GHD short stature and catabolic states; however, safety concerns still accompany this therapeutic approach. In the future, new therapeutics based on various components of the GH-IGF axis might be developed to further improve the treatment of such disorders. In this Review, we describe the history of GH research and clinical use with a particular focus on disorders in childhood.

The growth hormone-insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders.

The growth hormone (GH)–insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGF-binding protein (IGFBP)-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management.

Prevalence and Correlates of Adherence in Children and Adolescents Treated with Growth Hormone: A Multicenter Italian Study

To evaluate the self-reported prevalence of poor adherence to recombinant human growth hormone (rhGH) therapy in a large, representative sample of Italian children and adolescents and to assess treatment and patient level correlates of poor adherence. The study was conducted in 46 pediatric centers throughout Italy. A questionnaire was administered to consecutive children/adolescents treated with rhGH or their parents. Eligible patients were represented by subjects aged between 6 and 16 years, of both sexes, on rhGH treatment for at least 6 months. The questionnaire was administered to the person in charge of preparing the injection. Multivariable logistic regression analysis was performed to identify factors independently associated with adherence. Overall, 1,007 children/adolescents were involved, of whom 24.4% missed 1 or more injections during a typical week and were thus considered as nonadherent. The most frequently reported reasons for missing a dose were being away from home (33.3%), forgetfulness (24.7%), not feeling well (12.9%), and pain (10.3%). Multivariable analysis indicated association between poor adherence and adolescence, low level of parent education, longer duration of treatment, need to convince the child to inject, and low level of awareness of the consequences of not properly following treatment. The likelihood of adherence markedly increased with higher levels of perceived device convenience. Poor adherence is still a major problem in the treatment of growth disorders. Increasing awareness and reassessment of treatment adherence on an annual basis should be part of clinical practice of pediatric endocrinologists involved with rhGH treatment. CI = confidence interval GH = growth hormone rhGH = recombinant human growth hormone.

Preparation of soluble isotopically labeled human growth hormone produced in Escherichia coli.

Isotopically labeled proteins have been used as internal standards for mass spectrometry (MS)-based absolute protein quantification. Although this approach can provide highly accurate analyses of proteins of interest within a complex mixture, one of the major limitations of this method is the difficulty in preparing uniformly labeled standards. Human growth hormone (hGH) is one of the most important hormones that circulate throughout the body, and its measurement is primarily of interest in the diagnosis and treatment of growth disorders. In order to provide a useful internal standard for MS-based hGH measurement, we describe an efficient strategy to produce a potentially valuable, stable isotope-labeled hGH with high purity and yield. The strategy involves the following steps: solubilization of hGH under labeling conditions, detection of stable isotope incorporation, large-scale purification, analysis of the labeled protein, and assessment of the labeling efficiency. We show that the yield of soluble hGH under selective isotopic labeling conditions can be greatly increased by optimizing protein expression and extraction. Our efficient method for generating isotopically labeled hGH does not influence the structural integrity of hGH. Finally, we assessed the efficiency of stable isotope labeling at the intact protein level, and the result was further verified by amino acid analysis. These results clearly indicate that our labeling approach allows an almost complete incorporation of 13C615N4-arginine into the hGH expressed in E.coli without detectable isotope scrambling.

Diagnosis and management of growth disorders in Gulf Cooperation Council (GCC) countries: Current procedures and key recommendations for best practice.

Diagnosis and management of growth disorders comprises an important area of pediatric practice. Current procedures in the different stages of the identification, referral, investigation, and treatment of growth disorders in the Gulf Cooperation Council (GCC) countries have been summarized. Evidence-based procedures, relating specifically to height screening for identification of short stature, auxological criteria for patient referral from primary to secondary pediatric care, and general and endocrine investigations and diagnosis have been discussed and outlined. The management issues related to key disorders that are licensed for growth hormone (hGH) therapy, namely GH deficiency, Turner syndrome, short stature related to birth size small for gestational age (SGA), and idiopathic short stature are discussed with recommendations described for best practice. Finally, two key components of short stature management, namely transitional care for the transfer of patients from pediatric to adult endocrinology services and adherence to recommended therapy with hGH, have been addressed with current practice outlines and recommendations presented.

Stimulant Use and Its Impact on Growth in Children Receiving Growth Hormone Therapy: An Analysis of the KIGS® International Growth Database

Background: Children receiving stimulants for attention deficit hyperactivity disorder (ADHD) frequently present to pediatric endocrinology clinics for evaluation and treatment of growth disorders. The worldwide prevalence of stimulant use in children with ADHD also receiving recombinant human growth hormone (rhGH) and the impact on response to rhGH are unknown. Methods: Data on children enrolled in the KIGS® (Pfizer International Growth Study) registry were evaluated for the associated diagnosis of ADHD prior to initiation of Genotropin® rhGH. Concomitant stimulant medications and auxological information were captured. Response to rhGH was evaluated using established growth prediction models. Results: The prevalence of ADHD in KIGS was 2.3% (1,748/75,251), with stimulants used in 1.8% (1,326/75,251). Children with idiopathic growth hormone deficiency (IGHD) who received stimulants grew significantly less (1.1 cm) in the first year of rhGH therapy than expected for rhGH-treated non-ADHD IGHD children. After one year of rhGH, idiopathic short stature (ISS) children with ADHD were significantly shorter [0.74 cm (with stimulants) and 0.69 cm (without stimulants)] than non-ADHD ISS children. Conclusions: We demonstrated an impaired response to rhGH in IGHD and ISS children with ADHD. Our findings suggest that the ADHD phenotype, alone or in conjunction with stimulant therapy, may impair the short-term growth response to rhGH.

The Development of an Evidence-Based Clinical Practice Guideline on Linear Growth Measurement of Children

The Development of an Evidence-Based Clinical Practice Guideline on Linear Growth Measurement of Children

IGF-I Abuse in Sport

It is widely believed that growth hormone (GH) is abused by athletes for its anabolic and lipolytic effects. Many of the physiological effects of GH are mediated by the production of insulin-like growth factor-I (IGF-I). Both GH and IGF-I appear on the World Anti-Doping Agency list of prohibited substances. Little is known, however, about the prevalence of abuse with exogenous IGF-I. IGF-I has effects on carbohydrate, lipid and protein metabolism and some of these actions could prove beneficial to competitive athletes. No studies have demonstrated a positive effect of IGF-I on physical performance in healthy individuals but this has not yet been studied in appropriately designed trials. Two pharmaceutical preparations of IGF-I have recently become available for the treatment of growth disorders in children. This availability is likely to increase the prevalence of IGF-I abuse. Combining IGF-I with its binding protein IGFBP-3 in one preparation has the potential to reduce the side-effect profile but the adverse effects of long term IGF-I abuse are currently unknown. Detection of abuse with IGF-I is a major challenge for anti-doping authorities. It is extremely difficult to distinguish the exogenous recombinant form of the hormone from endogenously-produced IGF-I. One approach currently being investigated is based on measuring markers of GH and IGF-I action. This has already proved successful in the fight against GH abuse and, it is hoped, will subsequently lead to a similar test for detection of IGF-I abuse.

The recognition and treatment of growth disorders – A 50-year retrospective

The past 50 years have seen great progress in the understanding and treatment of classic growth disorders. Advances such as the recognition of hormone receptor defects, the development of recombinant growth hormone, and the expanding awareness of epigenetic phenomena affecting growth are among these great achievements. Yet growth failure remains a pervasive problem among children with complex health conditions, such as survivors of childhood cancers, premature infants, organ transplant recipients, and children with cystic fibrosis. The significant increases in life expectancy among these groups underscores the potential consequences of poor growth, whether due to the underlying conditions or medical treatments, as they may have long-lasting effects into adulthood. The ongoing contributions of human biologists to the study of human growth remain essential in the recognition and treatment of growth disorders, by defining normal patterns of growth and body composition, the interplay of growth and maturation, the role of environmental, behavioral and genetic factors, and the long-term consequences of growth patterns. Examples will be given based on two common genetic disorders, cystic fibrosis and sickle-cell anemia, to highlight the relationships between growth failure, survival, and malnutrition. Also, a study of bone mineral accretion in children with cystic fibrosis will illustrate the importance of understanding patterns of growth in healthy children, and their application in the diagnosis and management of children with chronic disease. These examples accentuate the need for continued participation of human biologists in the study of growth and development and the care of children.

Stature and skeletal maturation of two cohorts of Australian children and young adults over the past two decades

Abstract Background Assessment of growth and maturation in humans has implications in the diagnosis and treatment of growth disorders and in determining timing of orthopaedic interventions. Aims Our aims were to investigate whether there was evidence of recent secular changes in stature and skeletal maturation in Australians, and to report any association between these parameters. Methods The cross-sectional study sample comprised 5,122 South Australian children and young adults, including 2,601 males and 2,521 females aged between 9 and 18 years. Records obtained from 1987 to 2005 included chronological age, stature and skeletal age in these individuals. Centiles for stature were calculated using the National Health and Medical Research Council of Australia (NHMRC) growth references published in 1975. Stature was measured to the nearest 0.1 cm and the developmental stages of strategic ossification centres on hand-wrist radiographs were evaluated using the Greulich and Pyle (1959) atlas method. Results Average values for stature were consistently greater in the 1995–2005 cohort compared with the 1987–94 cohort for both sexes, although secular increases in females were less prominent compared with males. Males in the 1995–2005 cohort were also skeletally advanced when compared with their counterparts in the 1987–94 cohort, but this trend was not evident in females. There were significant associations between stature and skeletal maturation, with the strongest associations being noted around puberty in both sexes and progressively weaker associations in older age groups. Conclusion Our findings indicate secular increases in stature in Australian children and young adults of both sexes over the past few decades, and acceleration of skeletal maturation in males.

Computation of Time-Specified Tolerance Intervals for Hybrid Time Series with Nonequidistant Sampling, Illustrated for Plasma Growth Hormone

The ideal reference interval for a variable of clinical interest would be specific for all deterministic factors affecting that variable, including the time of sampling in relation to biological rhythms. In particular, growth hormone is characterized in children by circadian and ultradian variability, with high peaks of secretion occurring mainly during sleep. For clinical applications, the use of tolerance intervals has been recommended, and they should substitute, whenever possible, for prediction limits. In the case of hybrid data (time series of data collected from a group of subjects), such a tolerance interval could be very difficult to determine following a parametric approach similar to the procedure used for the computation of prediction intervals, especially when consideration of both within-subjects and among-subjects variances is wanted. Accordingly, we have developed a nonparametric method for the computation of such tolerance intervals. Because the method is based on bootstrap techniques, it does not require the assumption of normality or symmetry in the data and is also more appropriate when dealing with small samples. The method was used to establish time-qualified reference limits for a series of growth hormone sampled around the clock in groups of prepubertal children differentiated according to stature. The use of these tolerance intervals may eliminate many false-positive and false-negative diagnoses that might be obtained when relying on time-unspecified single samples. The provision of such tolerance limits introduces time-specification and time-structure evaluation into prevention, diagnosis, and treatment of growth disorders. (Chronobiology International, 14(4), 409–425, 1997)

Treatment of growth disorders in childhood

Treatment of growth disorders in childhood

URINARY GALACTOSYL-HYDROXYLYSINE - A MARKER OF HEIGHT VELOCITY

In practical pediatric endocrinology assessment of current height velocity (HV) plays an important role for diagnosis and treatment of growth disorders. However, to date, there is no quick and simple method to determine HV. Urinary excretion of Galactosyl-hydroxylysine (GHLy), a marker of osteoclast activity, has been shown to closely reflect the activity of bone metabolism in adults. In this study we tested the hypothesis that GHLy can also be used to evaluate skeletal growth in children. GHLy was measured in 24h-urines of 74 healthy children, 21 girls with Turner's syndrome (TU) and 15 children with growth hormone deficiency (GHD). HV was calculated from two measurements of body height 6 to 12 months apart. When related to body weight, the 24h excretion of GHLy showed a highly significant correlation to HV in normal children (r=0.75, p 0.05). Data for weight-adjusted daily excretion of GHLy were transformed to standard deviation scores (SDS) to allow for comparison in different age groups. The mean SDS of both GHD and TU were significantly below zero (−1.31 and −1.83 respectively; p<0.05). None of the values in these two disorders was above the mean for healthy children of the same age. Thus, GHLy might be a useful indicator of HV for the evaluation of growth disorders. Further studies arc needed to test if GHLy excretion can be used to predict the changes of HV during growth-promoting therapies.