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1.
Horm Res Paediatr ; : 1-14, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31514194

RESUMO

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.

2.
Horm Res Paediatr ; 91(4): 241-251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31185471

RESUMO

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.

3.
Am J Med Genet C Semin Med Genet ; 181(1): 86-90, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30811776

RESUMO

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.

4.
Pediatr Endocrinol Rev ; 16(Suppl 1): 150-161, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30378793

RESUMO

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.

5.
Endocr Rev ; 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30265312

RESUMO

GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature, 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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30219920

RESUMO

Context: Safety concerns regarding premature mortality, diabetes, neoplasia and cerebrovascular disease in association with growth hormone (GH) therapy have been raised. Objective: To assess incidence of key safety outcomes. Design: Prospective, multinational, observational study (1999-2015). Setting: 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 (SMR) and incidence (SIR) ratios with 95% confidence intervals (CI) 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 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 (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 31/622 (5.0%) cancer survivors (10.7 [7.5-15.2] cases/1000 PY), and intracranial tumor recurrences in 67/823 (8.1%) tumor survivors (16.9 [13.3-21.5] cases/1000 PY). All 3 hemorrhagic stroke cases had risk factors. Conclusions: GeNeSIS data support the favourable safety profile of pediatric GH treatment. Overall risk for 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 to the general population, but most cases had diabetes risk factors.

8.
Nat Commun ; 9(1): 2105, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844444

RESUMO

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.

9.
J Endocr Soc ; 1(4): 345-358, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29188236

RESUMO

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.

10.
J Clin Endocrinol Metab ; 102(9): 3195-3205, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575299

RESUMO

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.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/mortalidade , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Intervalos de Confiança , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Transtornos do Crescimento/diagnóstico , Humanos , Internacionalidade , Estimativa de Kaplan-Meier , Masculino , Estudos Prospectivos , Valores de Referência , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
11.
Ann Endocrinol (Paris) ; 78(2): 80-82, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28495324

RESUMO

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).


Assuntos
Somatotrofos/fisiologia , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Doenças da Hipófise/genética , Doenças da Hipófise/metabolismo , Receptor IGF Tipo 1/genética , Fatores de Transcrição STAT/genética , Somatotrofos/metabolismo
12.
Horm Res Paediatr ; 87(6): 412-422, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28395282

RESUMO

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.


Assuntos
Transtornos do Crescimento/genética , Haploinsuficiência , Receptores de Somatomedina/genética , Criança , Exoma , Feminino , Transtornos do Crescimento/diagnóstico , Humanos
13.
Horm Res Paediatr ; 87(5): 324-332, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28399519

RESUMO

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.


Assuntos
Hormônio do Crescimento Humano , Fator de Crescimento Insulin-Like I/metabolismo , Modelos Biológicos , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/farmacocinética , Humanos , Masculino
14.
J Clin Endocrinol Metab ; 102(5): 1578-1587, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323965

RESUMO

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.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Criança , Pré-Escolar , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Nanismo Hipofisário/metabolismo , Europa (Continente) , Feminino , Terapia de Reposição Hormonal , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Proteínas Recombinantes
15.
J Clin Endocrinol Metab ; 101(11): 3879-3883, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27648969

RESUMO

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.


Assuntos
Mutação da Fase de Leitura , Transtornos do Crescimento/tratamento farmacológico , Fator de Crescimento Insulin-Like I/uso terapêutico , Proteína Plasmática A Associada à Gravidez/deficiência , Criança , Códon de Terminação , Éxons , Feminino , Transtornos do Crescimento/genética , Homozigoto , Humanos , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/efeitos adversos , Fator de Crescimento Insulin-Like I/genética , Masculino , Proteína Plasmática A Associada à Gravidez/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Irmãos , Resultado do Tratamento
16.
Eur J Endocrinol ; 174(6): C1-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27009113

RESUMO

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.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Hormônio do Crescimento Humano/uso terapêutico , Ensaios Clínicos como Assunto , Consenso , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Projetos de Pesquisa
17.
Eur J Endocrinol ; 174(5): 669-79, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26888628

RESUMO

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.


Assuntos
Progressão da Doença , Gonadotropinas/deficiência , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/epidemiologia , Hormônios Hipofisários/deficiência , Adolescente , Fatores Etários , Criança , Hipotireoidismo Congênito/epidemiologia , Feminino , Seguimentos , Humanos , Hipotireoidismo , Masculino , Fatores Sexuais , Tireotropina/deficiência
18.
EMBO Mol Med ; 8(4): 363-74, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26902202

RESUMO

Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs.


Assuntos
Nanismo/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Mutação , Proteína Plasmática A Associada à Gravidez/genética , Proteína Plasmática A Associada à Gravidez/metabolismo , Adolescente , Criança , Pré-Escolar , Nanismo/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Adulto Jovem
19.
Mol Pharm ; 13(2): 631-9, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26713839

RESUMO

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.


Assuntos
Hormônio do Crescimento Humano/farmacocinética , Fator de Crescimento Insulin-Like I/metabolismo , Fragmentos de Peptídeos/química , Receptores da Somatotropina/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Western Blotting , Proliferação de Células , Feminino , Meia-Vida , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/química , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Camundongos , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
20.
Growth Horm IGF Res ; 28: 43-5, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26654694

RESUMO

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.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Transtornos do Crescimento/diagnóstico , Perda Auditiva Neurossensorial/tratamento farmacológico , Hormônio do Crescimento Humano/deficiência , Humanos , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/uso terapêutico
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