A Comprehensive Cohort Analysis Comparing Growth and GH Therapy Response in IGF1R Mutation Carriers and SGA Children

Göpel, Eric; Rockstroh, Denise; Pfäffle, Heike; Schlicke, Marina; Pozza, Susanne Bechtold‐Dalla; Gannagé‐Yared, Marie‐Hélène; Gucev, Zoran; Mohn, Angelika; Harmel, Eva-Maria; Volkmann, Julia; Weihrauch‐Blüher, Susann; Gausche, Ruth; Bogatsch, Holger; Beger, Christoph; Klammt, J; Pfäffle, Roland

doi:10.1210/clinem/dgz165

Cited by 14 publications

(10 citation statements)

References 48 publications

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“…As previously argued, rhIGF1 therapy in SPIGFD is unable to compensate for IGF1 independent actions of GH on growth ( 13 ). Furthermore, a similar cut-off was suggested for patients with a genetic defect in the IGF1 receptor treated with rhGH, a condition expected to have lower responsiveness than approved GH indications ( 14 , 15 ).…”

Section: Discussionmentioning

confidence: 99%

“…1 ). The cut-off was based on the previously reported mean change in height of the registry population at year 1, and suggested cut-offs in patients with GH insensitivity ( 13 , 14 , 15 ). A univariate analysis used the following potential factors: sex, mid-parental adult height, birth height; and the following baseline parameters: age, height SDS, weight SDS, IGF1 level, IGF binding protein-3 and rhIGF1 therapy initial dose and dose during year 1.…”

Section: Methodsmentioning

confidence: 99%

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Effectiveness and safety of rhIGF1 therapy in patients with or without Laron syndrome

Bang

Woelfle²,

Perrot

et al. 2021

European Journal of Endocrinology

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Objective The European Increlex® Growth Forum Database Registry monitors effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF-1; mecasermin, Increlex®) therapy in patients with severe primary IGF-1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design Ongoing, open-label, observational registry (NCT00903110). Methods Children and adolescents receiving rhIGF-1 therapy from 10 European countries were enrolled 2008-2017 (N = 242). The treatment-naïve/prepubertal (NPP) cohort (N = 138) was divided into subgroups based on reported genetic diagnosis of Laron syndrome (LS, N = 21 or non-LS, N = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score [SDS] gain ≥0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years’ treatment (P<0.05). Among the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P<0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 versus 7.00 years) at baseline and height SDS gain in year 1 (0.64 versus 0.70), although, NPP-non-LS-responders were taller (P<0.001) at baseline. Body mass index SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions In most NPP children with SPIGFD, with or without LS, rhIGF-1 therapy promotes linear growth. The safety profile was consistent with previous studies.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effectiveness and safety of rhIGF1 therapy in patients with or without Laron syndrome

Bang

Woelfle²,

Perrot

et al. 2021

European Journal of Endocrinology

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“…Homozygous mutations are extremely rare and possibly not compatible with life, although one case was reported with severe pre- and postnatal growth failure (< −4.5 SDS) and congenital malformation) ( 144 ). The response to recombinant GH treatment is usually moderate and associated with high IGF-I concentrations ( 145 , 146 ).…”

Section: Clinical Management Of Children Born Sgamentioning

confidence: 99%

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood

et al. 2023

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This International Consensus Guideline was developed by experts in the field of SGA of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Besides, it presents long-term consequences of SGA birth and new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, and the metabolic and cardiovascular health of young adults born SGA after cessation of childhood-GH-treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardio-metabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at age of 3-4 years, should be referred for diagnostic work-up. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033–0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3-4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

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“…Distinct growth response patterns to rhGH therapy among individuals with IGF-1R mutations compared to typical SGA cases (8,34,35).…”

Section: Growth and Rhgh Therapy Response Analysismentioning

confidence: 99%

Insight into Insulin-like Growth Factor-1 Receptor (IGF-1R) gene mutations: Implications for growth disorders and treatment: A review of the literature and case report

Ashraf Soliman,

Fawzia Alyafei,

Vincenzo De Sanctis

et al. 2024

World J. Adv. Res. Rev.

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Background: Insulin-like Growth Factor -1 Receptor (IGF-1R) and its ligand, IGF-1, are crucial for human tissue growth and development. Mutations in IGF-1R and, to a lesser extent, IGF-1 genes lead to diverse growth disorders, characterized by intrauterine growth retardation and postnatal growth challenges. Case report: We present a case of a 6-year-old girl with speech and mild cognitive delays, exhibiting normal motor skills, no neurological issues, and standard vital signs. Her growth parameters indicated significant retardation, with a height standard deviation score (Ht-SDS) of -2 and an IGF-1 level of +1.8 SDS, normal thyroid function and delayed bone age. Genetic analysis identified a 3335 mbp interstitial loss in 15q26.1, encompassing the IGF-1R gene, critical for growth and development. Literature review: Analysis of 34 papers provided insight into the genetic complexities of IGF-1R and IGF-1 mutations. Studies ranged from familial cases to cohort studies, uncovering mutations including missense mutations, deletions, and copy number variations (CNVs), each associated with unique growth disorder phenotypes. Advances in diagnostic techniques like multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES) have been pivotal in identifying these mutations, facilitating more targeted management approaches. Conclusions: This case and review of literature underscore the importance of an integrated genetic, endocrine, and developmental approach in managing growth hormone deficiency (GHD) and IGF-1 resistance. The variability in growth disorders and response to therapy highlights the need for personalized treatment plans, informed by genetic insights, to optimize outcomes for patients with these complex conditions.

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A Comprehensive Cohort Analysis Comparing Growth and GH Therapy Response in IGF1R Mutation Carriers and SGA Children

Cited by 14 publications

References 48 publications

Effectiveness and safety of rhIGF1 therapy in patients with or without Laron syndrome

Effectiveness and safety of rhIGF1 therapy in patients with or without Laron syndrome

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood

Insight into Insulin-like Growth Factor-1 Receptor (IGF-1R) gene mutations: Implications for growth disorders and treatment: A review of the literature and case report

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