510 results on '"Rosenfeld RG"'
Search Results
2. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society
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Israel, E, Attie, Km, Bengtsson, Ba, Blethen, Sl, Blum, W, Cameron, F, Carel, Jc, Carlsson, L, Chipman, Jj, Christiansen, Js, Clayton, P, Clemmons, Dr, Cohen, P, Drop, S, Fujieda, K, Ghigo, E, Hintz, Rl, Ho, K, Ilondo, Mm, Jasper, H, Jesussek, B, Kappelgaard, Am, Laron, Z, Lippe, Bm, Malozowski, S, Mullis, Pe, DE MUNICK KEIZER SCHRAMA, S, Nishi, Y, Parks, Js, Phelps, C, Ranke, M, Robinson, I, Rosenfeld, Rg, Rose, S, Saenger, P, Saggese, Giuseppe, Savage, M, Shalet, S, Sizonenko, Pc, Strasburger, C, Tachibana, K, Tanaka, T, Thorner, Mo, Wikland, Ka, and Zadik, Z.
- Published
- 2000
3. Diagnosis and treatment of growth hormone deficiency in children and adolescents: towards a consensus. Ten years after the Availability of Recombinant Human Growth Hormone Workshop held in Pisa, Italy, 27-28 March 1998
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Saggese, Giuseppe, Ranke, Mb, Saenger, P, Rosenfeld, Rg, Tanaka, T, Chaussain, Jl, and Savage, M. O.
- Published
- 1998
4. SERUM PTROTEOLYSIS OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN (IGFBP)-3, IGFBP-4, AND IGFBP-5 IN PATIENTS UNDERGOING ABDOMINAL SURGERY
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Spagnoli, A, Torquati, A, Grande, M, and Rosenfeld, Rg
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Settore MED/18 - Chirurgia Generale - Published
- 1994
5. Insulin Resistance Is Associated With Increased Serum Concentration of IGF-Binding Protein-Related Protein 1 (IGFBP-rP1/MAC25)
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López-Bermejo A, Khosravi J, Fernández-Real JM, Hwa V, Pratt KL, Casamitjana R, Garcia-Gil MM, Rosenfeld RG, and Ricart W
- Abstract
IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [S(i)] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [K(ITT)] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased S(i) and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients (P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S(i), sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans. [ABSTRACT FROM AUTHOR]
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- 2006
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6. Growth hormone insensitivity syndromes.
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Savage, MO, Carlsson, LMS, Chatelain, PG, Ranke, MB, and Rosenfeld, RG
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- 1995
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7. Body changes in adolescent patients with growth hormone receptor deficiency receiving recombinant human insulin-like growth factor I and luteinizing hormone-releasing hormone analogue: preliminary results.
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Martinez, V, Vasconez, O, Martinez, AL, Moreno, Z, Davila, N, Rosenbloom, AL, Diamond, FB, Bachrach, L, Rosenfeld, RG, and Guevara-Aguirre, J
- Published
- 1994
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8. Effects of insulin-like growth factor I treatment on the molecular distribution of insulin-like growth factors among different binding proteins.
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Gargosky, SE, Wilson, KF, Fielder, PJ, Vaccarello, MA, Diamond, FB, Baxter, RC, Rosenbloom, AL, Guevara-Aguirre, J, and Rosenfeld, RG
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- 1994
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9. Insulin-like growth factor binding proteins and their regulation.
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Rosenfeld, RG, Pham, H, Cohen, P, Fielder, P, Gargosky, SE, Muller, H, Nonoshita, L, and Oh, Y
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- 1994
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10. Pharmacokinetics of recombinant human insulin-like growth factor I given subcutaneously to healthy volunteers and to patients with growth hormone receptor deficiency.
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Grahnén, A, Kastrup, K, Heinrich, U, Gourmelen, M, Preece, MA, Vaccarello, MA, Guevara-Aguirre, J, Rosenfeld, RG, and Sietnieks, A
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- 1993
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11. Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I.
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Fielder, PJ, Gargosky, SE, Vaccarello, M, Wilson, K, Cohen, P, Diamond, F, Guevara-Aguirre, J, Rosenbloom, AL, and Rosenfeld, RG
- Published
- 1993
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12. The use -- and misuse -- of growth hormone.
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Allen DB, Blizzard RM, and Rosenfeld RG
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Recombinant growth hormone is an effective treatment for many children with short stature. But it can be misused in some young people who don't really need it. [ABSTRACT FROM AUTHOR]
- Published
- 1995
13. Insulin-like growth factors and the basis of growth.
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Rosenfeld RG
- Published
- 2003
14. An endocrinologist's approach to the growth hormone-insulin-like growth factor axis.
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Rosenfeld, RG
- Published
- 1997
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15. Is there heterozygote expression of growth hormone receptor deficiency?
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Rosenbloom, AL, Guevara-Aguirre, J, Rosenfeld, RG, and Fielder, PJ
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- 1994
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16. Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I.
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Vasconez, O, Martinez, V, Martinez, AL, Hidalgo, F, Diamond, FB, Rosenbloom, AL, Rosenfeld, RG, and Guevara-Aguirre, J
- Published
- 1994
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17. Growth hormone insensitivity: our current understanding and future directions.
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Rosenfeld, RG
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- *
SOMATOTROPIN , *PITUITARY dwarfism , *SOMATOMEDIN , *CONFERENCES & conventions , *PATIENTS , *THERAPEUTICS - Abstract
In this article author discusses different aspects of Growth Hormone (GH) Insensitivity treatment, He discusses his curiosity to know which patients should get GH treatment and which patients should get Insulin-like growth factor 1 (IGF-1) treatment. He further discussed an International workshop related to Growth Hormone (GH) Insensitivity.
- Published
- 1999
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18. Intrauterine growth retardation: our current understanding and future directions.
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Rosenfeld, RG
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- 1997
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19. Insulin-like growth factor binding proteins: a proposed superfamily.
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Hwa, V, Oh, Y, and Rosenfeld, RG
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- *
INSULIN-like growth factor-binding proteins , *PROTEINS , *PEPTIDES , *GROWTH factors , *CELLS - Abstract
Hwa V, Oh Y, Rosenfeld RG. Insulin-like growth factor binding proteins: a proposed superfamily. Acta Pzdiatr 1999; Suppl 428:37-45. Stockholm. ISSN 0803-5326 The conventional concept is that the insulin-like growth factor binding proteins (IGFBPs) are cysteine-rich proteins, with conserved N- and C-domains, that are capable of binding insulin-like growth factors (IGFs) with high affinity. This dogma was recently challenged by the discovery of a group of cysteine-rich proteins that share important structural similarities with the IGFBPs, but have demonstrably lower affinity for IGFs. It is therefore proposed that these IGFBP-related proteins (IGFBP-rPs) and the IGFBPs constitute an IGFBP superfamily. We speculate that the IGFBP superfamily is derived from an ancestral gene/protein that was critically involved in the regulation of cell growth and was capable of binding IGF peptides. Over the course of evolution, some members (IGFBPs) evolved into high-affinity IGF binders and others (IGFBP-rPs) into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means. 0 Insulin-like growth factor binding protein, insulin-like growth factor binding protein-related protein, superfamily [ABSTRACT FROM AUTHOR]
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- 1999
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20. Growth hormone insensitivity associated with a STAT5b mutation.
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Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, and Rosenfeld RG
- Published
- 2003
21. Natural history of growth hormone receptor deficiency.
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Rosenbloom, AL, Martinez, V, Kranzier, JH, Bachrach, LK, Rosenfeld, RG, and Guevara-Aguirre, J
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PITUITARY dwarfism , *EPIDEMIOLOGY , *CARDIOVASCULAR diseases , *CHOLESTEROL , *LARON dwarfism - Abstract
Rosenbloom AL, Martinez V, Kranzier JH, Bachrach LK, Rosenfeld RG, Guevara-Aguirre J. Natural history of growth hormone receptor deficiency. Acta Pædiatr 1999; Suppl 428: 153-6. Stockholm. ISSN 0803-5326 This review discusses the natural history of growth hormone receptor deficiency (GHRD) in relation to epidemiology, mortality, growth, certain aspects of body composition, and intellectual development. The majority of affected individuals are of Semitic origin and 90% come from the Indian peninsula, the Middle East, or elsewhere in the Mediterranean. There is a twofold increased mortality before the age of 7 years for children with GHRD. Affected adults may have increased cardiovascular risk resulting from increased total cholesterol and low-density lipoprotein cholesterol, unrelated to adiposity or insulin resistance. Intrauterine growth is affected minimally, if at all. Within a genetically homogeneous population in Ecuador, postnatal growth effects are as variable as in a large genetically heterogeneous population. There is no influence of parental heights. Areal bone mineral density is reduced in adults with GHRD, but estimated volumetric bone density (bone mineral apparent density) is normal. Intellectual development is unaffected by GHRD. □ Body composition, growth, growth hormone receptor deficiency, insulinlike growth factor I deficiency, intellectual development, Laron syndrome, natural history [ABSTRACT FROM AUTHOR]
- Published
- 1999
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22. Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity.
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Burren, CP, Wanek, D, Mohan, S, Cohen, P, Guevara-Aguirre, J, and Rosenfeld, RG
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SOMATOMEDIN , *INSULIN-like growth factor-binding proteins , *PROTEINS , *ECUADORIANS , *HORMONES - Abstract
Burren CP, Wanek D, Mohan S, Cohen P, Guevara-Aguirre J, Rosenfeld RG. Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity. Acta Pædiatr 1999; Suppl 428: 185-91. Stockholm. ISSN 0803-5326 Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 ug/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly ( p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs. □ Growth hormone, growth hormone insensitivity, insulin-like growth factor I, insulin-like growth factor binding protein [ABSTRACT FROM AUTHOR]
- Published
- 1999
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23. Gender-specific dose-responses to GH in GHD children: Results of a 3-year randomized trial in 109 patients
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Cohen, P and Rosenfeld, RG
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- 1998
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24. Treatment of growth hormone insensitivity syndrome with insulin-like growth factor I: long-term results of the European multicentre study.
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Ranke, MB, Savage, MO, Chatelain, P, Preece, MA, Rosenfeld, RG, and Wilted, P
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SOMATOTROPIN , *SOMATOMEDIN - Abstract
An abstract of the article "Treatment of growth hormone insensitivity syndrome with insulin-like growth factor I: long-term results of the European multicentre study," by MB Ranke and colleagues is presented.
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- 1999
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25. What Is the Role for Pediatric Endocrinologists in the Management of Skeletal Dysplasias?
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Merchant N, Polgreen LE, and Rosenfeld RG
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- Child, Humans, Endocrinologists, Osteochondrodysplasias diagnosis, Osteochondrodysplasias genetics, Osteochondrodysplasias therapy, Achondroplasia genetics, Prader-Willi Syndrome
- Abstract
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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2024
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26. A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor, and Causing a Mild Short Stature.
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Giannakopoulos A, Papanastasiou AD, Zarkadis IK, Andrew SF, Rosenfeld RG, Efthymiadou A, Chrysis D, and Hwa V
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- Humans, Male, Adolescent, Heterozygote, RNA Splicing, Laron Syndrome genetics, Protein Domains, Dwarfism genetics, Mutation, Body Height genetics, Receptors, Somatotropin genetics
- Abstract
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; 1,500-3,500) were also low. GH stimulation test was normal, and GHBP was markedly elevated (6,300 pmol/L; 240-3,000). 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 the 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., (© 2023 S. Karger AG, Basel.)
- Published
- 2024
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27. The History of the Insulin-Like Growth Factor System.
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Miller BS, Rogol AD, and Rosenfeld RG
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- Animals, Humans, Peptide Hormones, Protein Processing, Post-Translational, Signal Transduction, Somatomedins deficiency, Somatomedins history, Somatomedins physiology, Insulin-Like Growth Factor I deficiency, Insulin-Like Growth Factor I history, Insulin-Like Growth Factor I physiology, Insulin-Like Growth Factor I therapeutic use, Laron Syndrome drug therapy, Laron Syndrome genetics, Laron Syndrome history, Laron Syndrome physiopathology, Insulin-Like Growth Factor II deficiency, Insulin-Like Growth Factor II history, Insulin-Like Growth Factor II physiology, Insulin-Like Growth Factor II therapeutic use
- Abstract
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., (© 2022 S. Karger AG, Basel.)
- Published
- 2022
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28. 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.
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Horikawa R, Tanaka T, Hasegawa Y, Yorifuji T, Ng D, Rosenfeld RG, Hoshino Y, Okayama A, Shima D, Gomez R, Pastrak A, and Castellanos O
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- Body Height, Child, Female, Growth Disorders drug therapy, Growth Hormone, Humans, Japan, Male, Pain drug therapy, Recombinant Proteins therapeutic use, Dwarfism, Pituitary drug therapy, Human Growth Hormone
- Abstract
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., (© 2022 S. Karger AG, Basel.)
- Published
- 2022
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29. Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease.
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Barrios V, Chowen JA, Martín-Rivada Á, Guerra-Cantera S, Pozo J, Yakar S, Rosenfeld RG, Pérez-Jurado LA, Suárez J, and Argente J
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- Animals, Disease Models, Animal, Growth Hormone metabolism, Humans, Insulin-Like Growth Factor I metabolism, Mutation genetics, Pregnancy-Associated Plasma Protein-A genetics, Disease, Physiological Phenomena, Pregnancy-Associated Plasma Protein-A metabolism
- Abstract
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.
- Published
- 2021
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30. Genetic causes of growth hormone insensitivity beyond GHR.
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Hwa V, Fujimoto M, Zhu G, Gao W, Foley C, Kumbaji M, and Rosenfeld RG
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- Growth Disorders, Growth Hormone, Humans, Insulin-Like Growth Factor I genetics, Mutation, Abnormalities, Multiple, Human Growth Hormone genetics, Laron Syndrome genetics
- Abstract
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.
- Published
- 2021
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31. When Is a Positive Test for Pediatric Growth Hormone Deficiency a True-Positive Test?
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Bright GM, Morris PA, and Rosenfeld RG
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- Biomarkers, Child, Growth Disorders diagnosis, Growth Disorders epidemiology, Growth Hormone, Humans, Dwarfism, Pituitary diagnosis, Human Growth Hormone
- Abstract
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., (© 2021 S. Karger AG, Basel.)
- Published
- 2021
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32. A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes.
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Shapiro MR, Foster TP, Perry DJ, Rosenfeld RG, Dauber A, McNichols JA, Muir A, Hwa V, Brusko TM, and Jacobsen LM
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- CD4 Lymphocyte Count, Case-Control Studies, Congenital Abnormalities immunology, Failure to Thrive genetics, Female, Humans, Infant, Newborn, Infant, Premature, Leukocytes, Mononuclear metabolism, Receptor, IGF Type 1 metabolism, Twins, Codon, Nonsense, Congenital Abnormalities genetics, Hypoglycemia genetics, Receptor, IGF Type 1 genetics
- Abstract
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., (© 2020 S. Karger AG, Basel.)
- Published
- 2020
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33. Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action.
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Storr HL, Chatterjee S, Metherell LA, Foley C, Rosenfeld RG, Backeljauw PF, Dauber A, Savage MO, and Hwa V
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Growth Disorders genetics, Growth Disorders metabolism, Growth Disorders pathology, Growth Disorders physiopathology, Human Growth Hormone genetics, Human Growth Hormone metabolism, Insulin-Like Growth Factor I administration & dosage, Insulin-Like Growth Factor I deficiency, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism
- Abstract
GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature and dysmorphic and metabolic abnormalities. In recent years, the clinical, biochemical, and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders. We review this important spectrum of defects, which present with phenotypes at the milder end of the GHI continuum. We discuss their clinical, biochemical, and genetic characteristics. The objective of this review is to clarify the definition, identification, and investigation of this clinically relevant group of growth defects. We also review the therapeutic challenges of mild GHI., (Copyright © 2019 Endocrine Society.)
- Published
- 2019
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34. Growth and growth hormone in Turner syndrome: Looking back, looking ahead.
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Los E and Rosenfeld RG
- Subjects
- Child, Female, Growth Disorders drug therapy, Humans, Human Growth Hormone therapeutic use, Turner Syndrome physiopathology
- Abstract
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., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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35. Safety Outcomes During Pediatric GH Therapy: Final Results From the Prospective GeNeSIS Observational Program.
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Child CJ, Zimmermann AG, Chrousos GP, Cummings E, Deal CL, Hasegawa T, Jia N, Lawrence S, Linglart A, Loche S, Maghnie M, Pérez Sánchez J, Polak M, Predieri B, Richter-Unruh A, Rosenfeld RG, Yeste D, Yorifuji T, and Blum WF
- Subjects
- Adolescent, Cerebral Hemorrhage chemically induced, Child, Child, Preschool, Diabetes Mellitus, Type 2 chemically induced, Female, Follow-Up Studies, Growth Disorders mortality, Humans, Incidence, Male, Neoplasms chemically induced, Prospective Studies, Recombinant Proteins adverse effects, Risk Factors, Cerebral Hemorrhage epidemiology, Diabetes Mellitus, Type 2 epidemiology, Growth Disorders drug therapy, Human Growth Hormone adverse effects, Neoplasms epidemiology
- Abstract
Context: Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy., Objective: To assess incidence of key safety outcomes., Design: Prospective, multinational, observational study (1999 to 2015)., Setting: A total of 22,311 GH-treated children from 827 investigative sites in 30 countries., Patients: Children with growth disorders., Interventions: GH treatment., Main Outcome Measures: Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries., Results: Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors., Conclusions: GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.
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- 2019
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36. Height Gain and Safety Outcomes in Growth Hormone-Treated Children with Idiopathic Short Stature: Experience from a Prospective Observational Study.
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Child CJ, Quigley CA, Cutler GB Jr, Moore WV, Wintergerst KA, Ross JL, Rosenfeld RG, and Blum WF
- Subjects
- Adolescent, Child, Dwarfism, Pituitary physiopathology, Female, Growth Disorders physiopathology, Humans, Male, Prospective Studies, Body Height drug effects, Dwarfism, Pituitary drug therapy, Growth Disorders drug therapy, Human Growth Hormone administration & dosage
- Abstract
Background/objectives: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice., Methods: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data., Results: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and -1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD - most were common childhood conditions or previously reported in GH-treated patients., Conclusions: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD., (© 2019 S. Karger AG, Basel.)
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- 2019
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37. Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.
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Collett-Solberg PF, Ambler G, Backeljauw PF, Bidlingmaier M, Biller BMK, Boguszewski MCS, Cheung PT, Choong CSY, Cohen LE, Cohen P, Dauber A, Deal CL, Gong C, Hasegawa Y, Hoffman AR, Hofman PL, Horikawa R, Jorge AAL, Juul A, Kamenický P, Khadilkar V, Kopchick JJ, Kriström B, Lopes MLA, Luo X, Miller BS, Misra M, Netchine I, Radovick S, Ranke MB, Rogol AD, Rosenfeld RG, Saenger P, Wit JM, and Woelfle J
- Subjects
- Child, Humans, Growth Disorders diagnosis, Growth Disorders genetics, Growth Disorders pathology, Growth Disorders therapy, Human Growth Hormone deficiency, Human Growth Hormone therapeutic use
- Abstract
The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency., (© 2019 The Author(s)Published by S. Karger AG, Basel.)
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- 2019
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38. Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes.
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Blum WF, Klammt J, Amselem S, Pfäffle HM, Legendre M, Sobrier ML, Luton MP, Child CJ, Jones C, Zimmermann AG, Quigley CA, Cutler GB Jr, Deal CL, Lebl J, Rosenfeld RG, Parks JS, and Pfäffle RW
- Subjects
- Adolescent, Child, Child, Preschool, DNA Mutational Analysis, Dwarfism, Pituitary metabolism, Dwarfism, Pituitary physiopathology, Female, Homeodomain Proteins genetics, Human Growth Hormone genetics, Humans, LIM-Homeodomain Proteins genetics, Male, Nuclear Proteins genetics, Phenotype, Pituitary Gland growth & development, Prospective Studies, Receptors, Neuropeptide, Receptors, Pituitary Hormone-Regulating Hormone, SOXB1 Transcription Factors genetics, Transcription Factor Pit-1 genetics, Transcription Factors genetics, Young Adult, Zinc Finger Protein Gli2 genetics, Dwarfism, Pituitary genetics, Mutation, Pituitary Gland metabolism
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- 2018
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39. Monitoring rhGH Safety: rhGH Registries, SAGhE and Future Needs.
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Miller BS and Rosenfeld RG
- Subjects
- Hormone Replacement Therapy, Human Growth Hormone, Humans, Recombinant Proteins, Registries
- Abstract
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., (Copyright© of YS Medical Media ltd.)
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- 2018
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40. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation.
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Klammt J, Neumann D, Gevers EF, Andrew SF, Schwartz ID, Rockstroh D, Colombo R, Sanchez MA, Vokurkova D, Kowalczyk J, Metherell LA, Rosenfeld RG, Pfäffle R, Dattani MT, Dauber A, and Hwa V
- Subjects
- Adolescent, Cell Line, Child, Eczema genetics, Female, HEK293 Cells, Humans, Immunoglobulin E blood, Infant, Insulin-Like Growth Factor I biosynthesis, Male, Mutation, Missense genetics, Response Elements genetics, Genetic Predisposition to Disease genetics, Germ-Line Mutation genetics, Human Growth Hormone metabolism, Laron Syndrome genetics, STAT5 Transcription Factor genetics
- Abstract
Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.
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- 2018
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41. Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders: Data From the Genetics and Neuroendocrinology of Short Stature International Study.
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Quigley CA, Child CJ, Zimmermann AG, Rosenfeld RG, Robison LL, and Blum WF
- Subjects
- Adolescent, Body Height drug effects, Child, Child, Preschool, Cohort Studies, Confidence Intervals, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Growth Disorders diagnosis, Humans, Internationality, Kaplan-Meier Estimate, Male, Prospective Studies, Reference Values, Risk Assessment, Survival Analysis, Treatment Outcome, Growth Disorders drug therapy, Growth Disorders mortality, Human Growth Hormone adverse effects, Human Growth Hormone therapeutic use
- Abstract
Context: Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood., Objective: To assess mortality in children receiving GH., Design: Prospective, multinational, observational study., Setting: Eight hundred twenty-seven study sites in 30 countries., Patients: Children with growth disorders., Interventions: GH treatment during childhood., Main Outcome Measure: Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population., Results: Among 9504 GH-treated patients followed for ≥4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non-GH-deficient conditions (2.47; 95% CI, 0.99-5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox-containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65)., Conclusions: No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non-GH-deficient medical conditions., (Copyright © 2017 Endocrine Society)
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- 2017
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42. Biology of the somatotroph axis (after the pituitary).
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Rosenfeld RG and Hwa V
- Subjects
- Human Growth Hormone genetics, Human Growth Hormone metabolism, Humans, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Pituitary Diseases genetics, Pituitary Diseases metabolism, Receptor, IGF Type 1 genetics, STAT Transcription Factors genetics, Somatotrophs metabolism, Somatotrophs physiology
- Abstract
Normal growth requires that pituitary-secreted growth hormone (GH) bind to its specific receptor and activate a complex signaling cascade, leaving to production of insulin-like growth factor-I (IGF-I), which, in turn, activates its own receptor (IGF1R). The GH receptor (GHR) is preformed as a dimer and is transported in a nonligand bound state to the cell surface. Binding of GH to the GHR dimer, results in a conformational change of the dimer, activation of the intracellular Janus Kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 5B. Phosphorylated STAT5B dimers are then translocated to the nucleus, where they transcriptionally activate multiple genes, including those for IGF-I, IGF binding protein-3 and the acid-labile subunit (ALS)., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
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- 2017
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43. Long-Acting C-Terminal Peptide-Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children.
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Zelinska N, Iotova V, Skorodok J, Malievsky O, Peterkova V, Samsonova L, Rosenfeld RG, Zadik Z, Jaron-Mendelson M, Koren R, Amitzi L, Raduk D, Hershkovitz O, and Hart G
- Subjects
- Child, Child, Preschool, Delayed-Action Preparations, Dose-Response Relationship, Drug, Dwarfism, Pituitary metabolism, Europe, Female, Hormone Replacement Therapy, Humans, Insulin-Like Growth Factor Binding Protein 3 metabolism, Insulin-Like Growth Factor I metabolism, Male, Recombinant Proteins, Dwarfism, Pituitary drug therapy, Human Growth Hormone administration & dosage
- Abstract
Context: Daily injections are required for growth hormone (GH) replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients., Objective: C-terminal peptide-modified human GH (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children., Design: A multicenter, open-label, randomized, controlled phase 2 study in children with GHD, evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of three different weekly MOD-4023 doses, compared with daily recombinant human GH (r-hGH)., Setting: The trial was conducted in 14 endocrinology centers in Europe., Patients: Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 (N = 42) or r-hGH (N = 11)., Interventions: C-terminal peptide-modified hGH (MOD-4023) was administered weekly at a dose of either 0.25, 0.48, or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk., Results: MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH. Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment. IGF-I standard deviation score for MOD-4023 did not exceed +2. All MOD-4023 cohorts demonstrated adequate catch-up growth. The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH. No serious adverse events were observed during MOD-4023 treatment, and its tolerability was consistent with known properties of r-hGH., Conclusions: This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile. This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023., (Copyright © 2017 by the Endocrine Society)
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- 2017
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44. Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency.
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Vairamani K, Merjaneh L, Casano-Sancho P, Sanli ME, David A, Metherell LA, Savage MO, Del Pozo JS, Backeljauw PF, Rosenfeld RG, Aisenberg J, Dauber A, and Hwa V
- Abstract
Context: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype., Objective: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients., Results: All three mutations (c .964dupG , c.920_921insTCTCAAAGATTACA, and c.945+2T >C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c .964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR ( c.899dupC ) mutation., Conclusion: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.
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- 2017
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45. Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies.
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Ocaranza P, Golekoh MC, Andrew SF, Guo MH, Kaplowitz P, Saal H, Rosenfeld RG, Dauber A, Cassorla F, Backeljauw PF, and Hwa V
- Subjects
- Child, Exome, Female, Growth Disorders diagnosis, Humans, Receptor, IGF Type 1, Growth Disorders genetics, Haploinsufficiency, Receptors, Somatomedin genetics
- Abstract
Background: The growth-promoting effects of IGF-I is mediated through the IGF-I receptor (IGF1R), a widely expressed cell-surface tyrosine kinase receptor. IGF1R copy number variants (CNV) can cause pre- and postnatal growth restriction or overgrowth., Methods: Whole exome sequence (WES), chromosomal microarray, and targeted IGF1R gene analyses were performed on 3 unrelated children who share features of small for gestational age, short stature, and elevated serum IGF-I, but otherwise had clinical heterogeneity. Fluorescence-activated cell sorting (FACS) analysis of cell-surface IGF1R was performed on live primary cells derived from the patients., Results: Two novel IGF1R CNV and a heterozygous IGF1R nonsense variant were identified in the 3 patients. One CNV (4.492 Mb) was successfully called from WES, utilizing eXome-Hidden Markov Model (XHMM) analysis. FACS analysis of cell-surface IGF1R on live primary cells derived from the patients demonstrated a ∼50% reduction in IGF1R availability associated with the haploinsufficiency state., Conclusion: In addition to conventional methods, IGF1R CNV can be identified from WES data. FACS analysis of live primary cells is a promising method for efficiently evaluating and screening for IGF1R haploinsufficiency. Further investigations are necessary to delineate how comparable IGF1R availability leads to the wide spectrum of clinical phenotypes and variable responsiveness to rhGH therapy., (© 2017 S. Karger AG, Basel.)
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- 2017
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46. Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children.
- Author
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Fisher DM, Rosenfeld RG, Jaron-Mendelson M, Amitzi L, Koren R, and Hart G
- Subjects
- Child, Child, Preschool, Female, Humans, Male, Human Growth Hormone administration & dosage, Human Growth Hormone deficiency, Human Growth Hormone pharmacokinetics, Insulin-Like Growth Factor I metabolism, Models, Biological
- Abstract
Background/aims: MOD-4023 is a long-acting human growth hormone (hGH) in clinical trials for the treatment of growth hormone deficiency (GHD). A key goal is maintenance of serum concentrations of insulin-like growth factor (IGF) 1 within normal range throughout GH dosing. The study aimed to develop a pharmacokinetic model for MOD-4023 and a pharmacodynamic model for the effect of MOD-4023 on IGF-1 to allow estimation of peak and mean IGF-1 and to identify the optimal IGF-1 sampling day., Methods: MOD-4023 (0.25, 0.48, or 0.66 mg/kg) was administered weekly for 12 months to 41 GH-naive GHD children (age 3-11 years). The control group (n = 11, age 4-9 years) received daily recombinant human growth hormone (r-hGH; 34 µg/kg). Sparse samples (4/subject) were obtained to determine serum concentrations of MOD-4023 or r-hGH and IGF-1., Results: A 2-compartment pharmacokinetic model with first-order absorption fit MOD-4023 data well; a 1-compartment model was appropriate for r-hGH. For both, weight-normalized systemic parameters were preferred over allometric scaling. For MOD-4023, an indirect model fit IGF-1 SDS data well; baseline IGF-1 increased over time. At steady state, samples obtained 4 days following dose administration predicted mean IGF-1 SDS during the dosing interval well., Conclusion: The IGF-1 profile is consistent with the weekly dosing interval. Sampling 4 days following dose administration allows estimation of mean IGF-1 SDS during the dosing interval in GHD patients., (© 2017 The Author(s). Published by S. Karger AG, Basel.)
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- 2017
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47. Treatment With Recombinant Human Insulin-Like Growth Factor-1 Improves Growth in Patients With PAPP-A2 Deficiency.
- Author
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Muñoz-Calvo MT, Barrios V, Pozo J, Chowen JA, Martos-Moreno GÁ, Hawkins F, Dauber A, Domené HM, Yakar S, Rosenfeld RG, Pérez-Jurado LA, Oxvig C, Frystyk J, and Argente J
- Subjects
- Child, Codon, Terminator, Exons, Female, Growth Disorders genetics, Homozygote, Humans, Insulin-Like Growth Factor I administration & dosage, Insulin-Like Growth Factor I adverse effects, Insulin-Like Growth Factor I genetics, Male, Pregnancy-Associated Plasma Protein-A genetics, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Siblings, Treatment Outcome, Frameshift Mutation, Growth Disorders drug therapy, Insulin-Like Growth Factor I therapeutic use, Pregnancy-Associated Plasma Protein-A deficiency
- Abstract
Context: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that specifically cleaves IGFBP-3 and IGFBP-5. Mutations in the PAPP-A2 gene have recently been shown to cause postnatal growth failure in humans, with specific skeletal features, due to the resulting decrease in IGF-1 bioavailability. However, a pharmacological treatment of this entity is yet to be established., Case Description: A 10.5-year-old girl and a 6-year-old boy, siblings from a Spanish family, with short stature due to a homozygous loss-of-function mutation in the PAPP-A2 gene (p.D643fs25*) and undetectable PAPP-A2 activity, were treated with progressive doses (40, 80, 100, and 120 μg/kg) of recombinant human IGF-1 (rhIGF-1) twice daily for 1 year. There was a clear increase in growth velocity and height in both siblings. Bioactive IGF-1 was increased, and spontaneous GH secretion was diminished after acute administration of rhIGF-1, whereas serum total IGF-1 and IGFBP-3 levels remained elevated. No episodes of hypoglycemia or any other secondary effects were observed during treatment., Conclusion: Short-term treatment with rhIGF-1 improves growth in patients with PAPP-A2 deficiency.
- Published
- 2016
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48. Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations.
- Author
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Christiansen JS, Backeljauw PF, Bidlingmaier M, Biller BM, Boguszewski MC, Casanueva FF, Chanson P, Chatelain P, Choong CS, Clemmons DR, Cohen LE, Cohen P, Frystyk J, Grimberg A, Hasegawa Y, Haymond MW, Ho K, Hoffman AR, Holly JM, Horikawa R, Höybye C, Jorgensen JO, Johannsson G, Juul A, Katznelson L, Kopchick JJ, Lee KO, Lee KW, Luo X, Melmed S, Miller BS, Misra M, Popovic V, Rosenfeld RG, Ross J, Ross RJ, Saenger P, Strasburger CJ, Thorner MO, Werner H, and Yuen K
- Subjects
- Clinical Trials as Topic, Consensus, Hormone Replacement Therapy adverse effects, Human Growth Hormone adverse effects, Humans, Research Design, Dwarfism, Pituitary drug therapy, Hormone Replacement Therapy methods, Human Growth Hormone therapeutic use
- Abstract
Objective: The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH)., Participants: A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry., Evidence: Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues., Consensus Process: Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors., Conclusions: LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations., (© 2016 The authors.)
- Published
- 2016
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49. The future of growth-promoting therapy.
- Author
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Rosenfeld RG
- Subjects
- Growth Disorders diagnosis, Hearing Loss, Sensorineural drug therapy, Human Growth Hormone deficiency, Humans, Insulin-Like Growth Factor I deficiency, Insulin-Like Growth Factor I therapeutic use, Growth Disorders drug therapy, Human Growth Hormone therapeutic use
- Abstract
Growth hormone (GH) has been in use for 50 years in children with short stature. Recent developments suggest that our traditional approaches to growth-promoting therapy will be challenged in the following areas:1)Diagnostic: The diagnosis of GH deficiency has always been problematic, largely due to limitations inherent in GH stimulation tests and related biochemical measures. The development of new tools for diagnosis of genetic etiologies of hormonal deficiencies and insensitivity, as well as the growing availability of such methodologies, will greatly strengthen existing diagnostic strategies. 2)Therapeutic: Long-acting GH preparations are already in clinical trials. IGF-I therapy is approved for treatment of IGF deficiency. Novel approaches to select skeletal dysplasias show promise and will potentially expand our therapeutic armamentarium. 3) Monitoring: Traditional weight-based dosing of GH will be supplemented by IGF-based and auxology-based strategies, allowing greater individualization of therapy. 4) Safety: Growth-promoting therapies will continue to require careful monitoring of safety. Recent consensus workshops have advocated life-time surveillance programs. 5) Ethics: Questions will continue to be raised concerning ethical issues related to growth-promoting therapy in children. The availability of new tools for diagnosis and monitoring will address some, but not all, of these issues., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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50. Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with isolated growth hormone deficiency due to organic causes.
- Author
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Child CJ, Blum WF, Deal C, Zimmermann AG, Quigley CA, Drop SL, Cutler GB Jr, and Rosenfeld RG
- Subjects
- Adolescent, Age Factors, Child, Congenital Hypothyroidism epidemiology, Female, Follow-Up Studies, Humans, Hypothyroidism, Male, Sex Factors, Thyrotropin deficiency, Disease Progression, Gonadotropins deficiency, Human Growth Hormone deficiency, Hypopituitarism epidemiology, Pituitary Hormones deficiency
- Abstract
Objective: To determine characteristics of children initially diagnosed with isolated growth hormone deficiency (IGHD) of organic aetiology, who later developed multiple pituitary hormone deficiencies (MPHD)., Design: Data were analysed for 716 growth hormone-treated children with organic IGHD, who were growth hormone-naïve at baseline in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study., Methods: Development of MPHD was ascertained from investigator-provided diagnoses, adverse events and concomitant medications. Analyses were performed for all patients and separately for those who developed MPHD within 4.5 years or had >3.5 years follow-up and continued to have IGHD (4-year cohort)., Results: MPHD developed in 71/716 (9.9%) children overall, and in 60/290 (20.7%) in the 4-year cohort. The most frequent additional deficiencies were thyroid-stimulating hormone (47 patients) and gonadotropins (23 patients). Compared with those who remained with IGHD, children who developed MPHD had more severe GHD at study entry, significantly lower baseline insulin-like growth factor1, peak stimulated growth hormone, and more frequent diagnosis of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Multivariate logistic regression analyses identified female gender, longer follow-up, higher baseline age and lower peak stimulated growth hormone as predictors of MPHD development., Conclusions: MPHD is more likely to develop in patients with severe organic IGHD, especially those with history of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Older baseline age, female gender and longer follow-up duration were also associated with higher incidence of MPHD. Long-term monitoring of pituitary function is recommended, irrespective of the aetiology of GHD., (© 2016 European Society of Endocrinology.)
- Published
- 2016
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