Genetic causes of growth hormone insensitivity beyond GHR.

Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.

Growth and growth hormone in Turner syndrome: Looking back, looking ahead.

Short stature is the most ubiquitous feature of Turner syndrome (TS). Today, many girls with TS are treated with recombinant human growth hormone (GH) to accelerate growth in childhood and to improve adult height. Here, we will review the history of our understanding of growth in TS, reflect on the path of clinical trials ultimately leading to regulatory approval for clinical use of GH, discuss factors associated with growth outcomes and survey the current unanswered questions about growth and GH in TS.

Monitoring rhGH Safety: rhGH Registries, SAGhE and Future Needs.

The safety of growth hormone (GH) therapy in children has been studied extensively. The identification of Creutzfeldt-Jacob disease in individuals who received pituitary-derived GH led to heightened surveillance for safety issues related to recombinant human GH (rhGH). An excellent safety profile of rhGH has been demonstrated in large Phase IV registries comprising > 600,000 patient-years of rhGH exposure and long-term safety cohorts of adults treated with GH as children. Increased mortality risk has been reported but eliminated when corrected for small size at birth. Increased risk of mortality from cerebrovascular disease has been reported but interpretation of these events remains difficult due to the lack of appropriate control groups and a lack of replication of these findings in other studies. The advent of new long-acting growth hormone (LAGH) products provides an opportunity for the development of cohorts of individuals receiving LAGH replacement therapy for continued long-term safety studies.

In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone.

MOD-4023 is a novel long-acting version of human growth hormone (hGH), containing the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG). MOD-4023 is being developed as a treatment for adults and children with growth hormone deficiency (GHD), which would require fewer injections than currently available GH formulations and thus reduce patient discomfort and increase compliance. This study characterizes MOD-4023's binding affinities for the growth hormone receptor, as well as the pharmacokinetic and pharmacodynamics, toxicology, and safety profiles of repeated dosing of MOD-4023 in Sprague-Dawley rats and Rhesus monkeys. Although MOD-4023 exhibited reduced in vitro potency and lower affinity to the GH receptor than recombinant hGH (rhGH), administration of MOD-4023 every 5 days in rats and monkeys resulted in exposure comparable to daily rhGH, and the serum half-life of MOD-4023 was significantly longer. Repeated administration of MOD-4023 led to elevated levels of insulin-like growth factor 1 (IGF-1), and twice-weekly injections of MOD-4023 resulted in larger increase in weight gain with fewer injections and a lower accumulative hGH dose. Thus, the increased half-life of MOD-4023 in comparison to hGH may increase the frequency of protein-receptor interactions and compensate for its decreased in vitro potency. MOD-4023 was found to be well-tolerated in rats and monkeys, with minimal adverse events, suggesting an acceptable safety profile. These results provide a basis for the continued clinical development of MOD-4023 as a novel treatment of GHD in children and adults.

Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations.

CONTEXT AND OBJECTIVE: Titrating the dosage of growth hormone (GH) to serum levels of insulin-like growth factor-I (IGF-I) is a feasible treatment strategy in children with GH deficiency (GHD) and idiopathic short stature (ISS). The objective was to assess the dose-sparing effect and theoretical safety of IGF-I-based GH therapy. DESIGN, SETTING AND PATIENTS: This was a post hoc analysis of a previously described 2-year, multicenter, open-label, randomized, outpatient, controlled clinical trial in 172 prepubertal short children [age 7·5 ± 2·4 years; height standard deviation score (HSDS) -2·64 ± 0·61] classified by baseline peak GH levels as GHD (<7 ng/ml) or ISS (≥7 ng/ml). INTERVENTION: Conventional weight-based dosing of GH (0·04 mg/kg/day) (n = 34) or GH dosing titrated to an IGF-I target of 0 SDS (IGF0T; n = 70) or an IGF-I target of +2 SDS (IGF2T; n = 68). MAIN OUTCOME MEASURES: Change in HSDS per GH mg/kg/day dose (∆HSDS/GH dose ratio) and proportion of IGF-I levels above +2 SDS at the end of 2 years. RESULTS: GH dosing titrated to an IGF-I target of 0 SDS was the most dose-sparing treatment regimen for GHD or ISS children (mean±SE ∆HSDS/GH dose ratios 48·1 ± 4·4 and 32·5 ± 2·8, respectively) compared with conventional dosing (30·3 ± 6·6 and 21·3 ± 3·5, respectively; P = 0·02, P = 0·005) and IGF2T (32·7 ± 4·8 and 16·3 ± 2·8, respectively; P = 0·02, P < 0·0001). IGF0T also resulted in the fewest IGF-I excursions above +2 SDS (6·8% vs 30·0% for conventional dosing; P < 0·01). CONCLUSIONS: IGF-I-based GH dosing, targeted to age- and gender-adjusted means, may offer a more dose-sparing and potentially safer mode of therapy than traditional weight-based dosing.

The E180splice mutation in the GHR gene causing Laron syndrome: witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?

Laron syndrome (LS) is a genetic disorder caused by mutations in the growth hormone receptor (GHR) gene. The most frequent GHR mutation is E180splice (rs121909360), which was initially found in an inbred population of Spanish descent in Ecuador and subsequently in Israel, Brazil, Chile, and the United States. The aim of the present study is to determine if the E180splice mutation arose from a common origin. We studied 22 patients with LS from Ecuador, Israel (of Moroccan origin), Brazil, Chile, and the United States (of Mexican origin) who were homozygous for the E180splice mutation and compared them to control individuals for markers surrounding the GHR, intragenic polymorphisms, and Y-chromosome STR. An identical haplotype was found in all but one of the subjects carrying the E180splice mutation: D5S665: 150/150; D5S2082: 192/192; D5S2087: 246/246; rs6179 G/G; and rs6180 C/C. One patient differed from the others only at D5S2082 (168/192). This haplotype is rare (~1%) in control individuals and confirmed that the E180splice-associated haplotype was not derived from independent origins but represented recombination from a common ancestor. The analysis of paternal lineage markers showed that 50% belong to haplogroup R1b (found in Portugal and Spain) and 40% to haplogroups J and E (typical in the Middle East and in Eastern European Jews). The germline E180Splice mutation appears to have originated from a single common ancestor. The presence of Y-chromosome markers associated with Sephardic populations in persons harboring the E180splice mutation provides genetic evidence in support of the historical tracking of the exodus of this specific population.

What Is the Role for Pediatric Endocrinologists in the Management of Skeletal Dysplasias?

Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing genetic growth disorders. Growth-altering treatments have broadened the role of the pediatric endocrinologist to manage and sometimes become primary coordinators for genetic disorders such as Turner syndrome and Prader-Willi syndrome. We illustrate how recent advances in understanding the pathophysiology of skeletal disorders and the development of targeted treatments provide an opportunity for pediatric endocrinologists to further expand their role in managing certain skeletal dysplasias, including achondroplasia.

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

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

A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor causing a mild short stature.

INTRODUCTION: Although the majority of Growth Hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include "atypical" GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects. CASE PRESENTATION: A 13-year-old pubertal boy presented with short stature (-1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/ml; reference range: 179-540). IGFBP-3 (1.3 mg/L; 3.1-9.5), and ALS (565 mU/ml; 1500-3500) were also low. GH stimulation test was normal, and GHBP markedly elevated (6300pmol/L; 240-3000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached -1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels. CONCLUSION: We describe the first synonymous heterozygous GHR splicing variant in exon 9 encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS.

Identification and management of poor response to growth-promoting therapy in children with short stature.

Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. Recombinant human (rh) insulin-like growth factor-1 (rhIGF-1) therapy is approved for severe primary IGF-I deficiency - a state of severe GH resistance. Evidence is increasing for an unacceptably high rate of poor or unsatisfactory response to growth-promoting therapy (i.e. not leading to significant catch up growth) in terms of change in height standard deviation score (SDS) and height velocity (HV) in many approved indications. Consequently, there is a need to define poor response and to prevent or correct it by optimizing treatment regimens within accepted guidelines. Recognition of a poor response is an indication for action by the treating physician, either to modify the therapy or to review the primary diagnosis leading either to discontinuation or change of therapy. This review discusses the optimal investigation of the child who is a candidate for GH or IGF-1 therapy so that a diagnosis-based choice of therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of poor response. Prevention of poor response is addressed by discussion of strategy for first-year management with GH and IGF-1. Adherence to therapy is reviewed as is the recommended action following the identification of the poorly responding patient. The awareness, recognition and management of poor response to growth-promoting therapy will lead to better patient care, greater cost-effectiveness and increased opportunities for clinical benefit.

The History of the Insulin-Like Growth Factor System.

The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

Efficacy and Safety of Once-Weekly Somatrogon Compared with Once-Daily Somatropin (Genotropin®) in Japanese Children with Pediatric Growth Hormone Deficiency: Results from a Randomized Phase 3 Study.

INTRODUCTION: Somatrogon is a long-acting recombinant human growth hormone being developed as a once-weekly treatment for children with growth hormone deficiency (GHD). The objective of this phase 3 study (NCT03874013) was to compare the efficacy and safety of once-weekly somatrogon with once-daily Genotropin in Japanese children with GHD. METHODS: In this open-label, randomized, active-controlled study, 44 prepubertal Japanese children with GHD (boys: 3 to <11 years; girls: 3 to <10 years) were randomized 1:1 to receive once-weekly somatrogon or once-daily Genotropin (0.025 mg/kg/day) for 12 months. Dose escalation for somatrogon-treated subjects occurred in the first 6 weeks (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each) with the remaining 46 weeks at a dose of 0.66 mg/kg/week. The study's primary endpoint was annualized height velocity (HV) at 12 months. RESULTS: Baseline characteristics were similar between treatment groups. Compared with Genotropin-treated subjects, somatrogon-treated subjects had higher least-squares mean HV at 12 months (9.65 cm/year vs. 7.87 cm/year). Once-weekly somatrogon was concluded as being comparable to once-daily Genotropin as the mean treatment difference (somatrogon-Genotropin) in HV was +1.79 cm/year (95% confidence interval, 0.97-2.61), which was greater than the preestablished margin (-1.8 cm/year). For both treatment groups, most adverse events were mild to moderate in severity and a similar proportion of subjects reported injection-site pain, although the somatrogon group reported more painful injections. CONCLUSION: In prepubertal Japanese children with GHD, once-weekly somatrogon was comparable to once-daily Genotropin in terms of annualized (12-month) HV. Both treatments had similar safety and tolerability profiles.

When Is a Positive Test for Pediatric Growth Hormone Deficiency a True-Positive Test?

BACKGROUND: In most cases, the growth hormone stimulation test is a necessary component for the diagnosis of growth hormone deficiency (GHD) in children. Diagnostic testing can lead to unnecessary treatment of children with false-positive test results and omission of treatment in children with false-negative results. False-positive results are suggested by the absence of typical growth responses in treated children and false-negative results are suggested by continued growth failure in those left untreated. SUMMARY: The probability that a positive test result indicates the presence of the condition (true positive) depends on the prevalence of that condition in the test population and the false positive rate of the test. This probability has been estimated using published data on the prevalence of GHD in children and the false positive rates estimated from performance of stimulation tests in normally growing children and from repeated testing in short children. Because of the low prevalence of GHD and the substantial false positive rate of the test, the probability of a true-positive result in a child with short stature is 0.028, or about 1 in 36 cases. Key Messages: In children with short stature, most positive growth hormone stimulation test results will be false-positive results, resulting in growth hormone treatment of children misdiagnosed as growth hormone deficient. Additional information is required for accurate diagnosis and prediction of successful treatment outcomes in children. Improvements in diagnostic accuracy and treatment outcome predictions can be anticipated from the use of additional predictive enrichment markers identified and evaluated in broadly based studies of growth hormone treatment in children.

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease.

The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.

The continuum of growth hormone-IGF-I axis defects causing short stature: diagnostic and therapeutic challenges.

The growth hormone (GH)-IGF-I axis is essential for normal foetal and childhood growth. Defects at different sites in the axis frequently result in short stature which may compromise adult height. We describe a continuum of clinically relevant abnormalities from GH deficiency through to GH resistance and discuss the implementation and interpretation of investigations. We consider appropriate therapy for patients with abnormal auxology and subnormal adult height prognosis, highlighting new data to clarify therapeutic choices leading to optimal clinical outcome.

First-year response to rhGH therapy in children with CKD: a National Cooperative Growth Study Report.

A clear definition of the appropriate growth response during recombinant human growth hormone (rhGH) treatment has never been established in the pediatric chronic kidney disease (CKD) population. We present here data from Genentech's National Cooperative Growth Study (NCGS) on the first-year growth response in prepubertal children with CKD. Using NCGS data, we constructed response curves for the first year of rhGH therapy in 270 (186 males, 84 females) naïve-to-treatment, prepubertal children with CKD prior to transplant or dialysis. Data from both genders were combined because gender was not significantly related to height velocity (p = 0.51). Response to rhGH was expressed as height velocity (HV) in cm/year. Mean, mean + or - 1SD, and mean - 2SD for HV during the first year of rhGH treatment as well as pretreatment HV were plotted versus age. Age-specific HV plots for rhGH-treated children with CKD are presented. At all ages, the first-year mean HV was greater than the mean pretreatment HV. The mean - 2SD for HV in children on rhGH treatment was similar to the mean pretreatment HV. These growth plots will be useful to clinicians for assessing a patient's first-year growth response. We propose that a HV below the mean - 1SD is an inadequate response. These curves may help identify patients with a suboptimal growth response due to confounding medical factors and/or non-compliance.

A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes.

INTRODUCTION: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery. CASE PRESENTATION: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4+ Th-cell lineage commitment. DISCUSSION: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.

The future of research into growth hormone responsiveness.

Decades of experience with growth hormone (GH) therapy have indicated considerable variability in responsiveness to therapy, even within single diagnostic categories, such as GH deficiency, Turner syndrome, intrauterine growth retardation and idiopathic short stature. It is likely that the major explanation for such variability lies in the genetic composition of the patient, including mutations of genes participating in the GH-insulin growth factor I cascade and genetic polymorphisms. Future studies of pharmacogenomic and pharmacoproteomic markers may allow us to better predict and categorize responsiveness to therapy.

The growth hormone cascade and its role in mammalian growth.

The myriad actions of growth hormone (GH) are still incompletely understood, despite decades of research. Although it is a major regulator of post-natal growth in mammals, much of its effects on skeletal growth are recognized to be mediated indirectly, through the stimulation of production of insulin-like growth factor (IGF)-I, as well as some of the major serum carrier proteins for IGF-I and -II, such as IGF-binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). The regulation of IGF-I production by GH appears to be mediated entirely by signalling through the Janus kinase (JAK) 2 pathway, via the phosphorylation of the transcription factor, signal transducer and activator of transcription (STAT) 5b. GH also signals, however, through additional pathways that are likely to be critical to the metabolic actions of GH.

Extreme elevation of serum growth hormone-binding protein concentrations resulting from a novel heterozygous splice site mutation of the growth hormone receptor gene.

BACKGROUND/AIMS: Circulating growth hormone-binding protein (GHBP), in humans, is the proteolytic product of the growth hormone receptor (GHR). We investigated a prepubertal male subject who was of short stature, but who had a markedly elevated serum level of GHBP. METHODS: Serum and DNA from the patient and his mother were analyzed. RESULTS: Both the patient and mother had serum GHBP concentrations over 100-fold higher than normal, by assays, and Western and ligand blot analysis. Sequencing of the GHR gene revealed a novel heterozygous C>A transversion at position 785-3 in the acceptor splice site of intron 7. CONCLUSION: In silico analysis of the altered sequence suggested that 785-3(C>A) is a splicing mutation, with either retention of intron 7 or the skipping of exon 8. The consequence is a truncated GHR lacking the transmembrane domain (encoded by exon 8) and the cytoplasmic domain. We hypothesize that this GHR variant cannot anchor to the cell membrane, and the continual secretion into the circulation explains the elevated levels of serum GHBP detected in the patient and his mother. Despite this mutation, the presence of the wild-type GHR allele, presumably, permits some normality in GH-induced action.