Three novel <i>IGF1R</i> mutations in microcephalic patients with prenatal and postnatal growth impairment

Juanes, Matías; Guercio, Gabriela; Marino, Roxana; Berensztein, Esperanza; Warman, Diana M.; Ciaccio, Marta; Gil, Silvia; Bailez, Marcela; Rivarola, Marco A.; Belgorosky, Alicia

doi:10.1111/cen.12555

Cited by 41 publications

(33 citation statements)

References 34 publications

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“…[32] Microcephaly, pre-and postnatal growth retardation were found in patients with heterozygous missense mutations in three unrelated patients, de novo p.Arg1256Ser, de novo p.Asn359Tyr and p.Tyr865Cys. [33] We checked the exon 2 of the IGF1R gene for possible genetic alterations and found no alterations.…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone Treatment in Children Born Small for Gestational Age (SGA)

Janchevska

Krstevska-Konstantinova

Tasić

et al. 2018

Prilozi

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Introduction: Growth failure is a common consequence in small for gestational age (SGA) children. Patients and Methods: The growth patterns and serum insulin like growth factor 1 (IGF1) concentrations before and after the 1st year under growth hormone treatment of 32 short stature SGA born children have been evaluated. In addition, we investigated the insulin like growth factor 1 receptor (IGF1R) exon 2 as a hotspot for IGF1R genetic alterations. It is of note that no dysmorphic features were observed in this group of children. Results: The tests for pituitary reserve were within normal ranges for all 32 patients. Growth hormone (GH) treatment (0.037 mg/kg/day) was initiated at the mean age of 9.32±3.19 years. Growth velocity increased yearly from −1.80 SDS after the first year to −0.03 SDS in the sixth year of treatment. Their IGF1 serum concentrations before treatment were age and sex appropriate, while during treatment a significant increase was observed fitting in the upper third of the normal range: before the treatment IGF1 SDS was 0.84±1.78 after 1st year the concentrations increased to IGF1 SDS 0.94±2.23. No genetic alterations were found in the IGF1R exon 2 by PCR analysis. Conclusions: Herein we present 32 short stature SGA children with no dysmorphic features treated with GH. They all had increased growth velocity and entered the normal growth range on their growth charts. No side-effects were observed. GH treatment in children with no genetic alterations on the IGF1R exon 2 is safe and efficient in treating SGA children with short stature.

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Section: Discussionmentioning

confidence: 99%

Growth Hormone Treatment in Children Born Small for Gestational Age (SGA)

Janchevska

Krstevska-Konstantinova

Tasić

et al. 2018

Prilozi

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“…As reviewed in (Aleman and Torres-Aleman 2009), there are numerous studies supporting a critical role for IGF-1 in normal brain development and function. Clinical studies have shown that point mutations in both the IGF-1 and IGF-1R genes result in decreased IGF-1 signaling and lead to microcephaly and mental impairment (Abuzzahab et al 2003; Bonapace et al 2003; Gannage-Yared et al 2013; Juanes et al 2014; Netchine et al 2009; Walenkamp et al 2005; Woods et al 1996). These patients often exhibit significant delays in psychomotor function and hearing loss (Bonapace et al 2003; Walenkamp et al 2005).…”

Section: Gh/igf-1 Regulation Of Neuronal Development Structure and mentioning

confidence: 99%

Growth hormone, insulin-like growth factor-1 and the aging brain

Ashpole

Sanders

Hodges

et al. 2015

Experimental Gerontology

179

126

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Growth hormone (GH) and insulin-like growth factor (IGF)-1 regulate the development and function of cells throughout the body. Several clinical diseases that result in a decline in physical and mental function are marked by mutations that disrupt GH or IGF-1 signaling. During the lifespan there is a robust decrease in both GH and IGF-1. Because GH/IGF-1 are master regulators of cellular function, impaired GH and IGF-1 signaling in aging/disease states leads to significant alterations in tissue structure and function, especially within the brain. This review is intended to highlight the effects of the GH and IGF-1 on neuronal structure, function, and plasticity. Furthermore, we address several potential mechanisms through which the age-related reductions in GH and IGF-1 affect cognition. Together, the studies reviewed here highlight the importance of maintaining GH and IGF-1 signaling in order to sustain proper brain function throughout the lifespan.

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“…STAT5 proteins contribute to the common pathway of growth hormone and interleukin-2 cytokine family signaling, therefore mutations in STAT5B cause growth failure and immune deficiency [142]. Mutations in IGF1 or IGF1R cause intrauterine growth restriction (because IGF1 signaling is important for intrauterine growth while GH is not required), postnatal growth failure, microcephaly and other various anomalies including developmental delay [143–147]. Mutations in a gene that stabilizes IGF-1, IGFALS, forming an IGF-1-IGFBP3-ALS complex, cause growth deficiency, insulin resistance and osteoporosis [148–149].…”

Section: Genetics Of Short Staturementioning

confidence: 99%

Genetics of Short Stature

Jee¹,

Andrade

Baron³

et al. 2017

Endocrinology and Metabolism Clinics of North America

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Synopsis Short stature is a common and heterogeneous condition which is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown, but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. These genetic causes can involve not only hormonal deficiencies, including the growth hormone-IGF-1 axis, thyroid hormone or glucocorticoid and defects in hormonal receptors or subsequent signaling, but also defects in fundamental cellular processes (intracellular signaling pathways, transcriptional regulation, and DNA repair), extracellular matrix, or paracrine signaling. Especially, heterozygous and/or mild mutations in SHOX, NPR2, ACAN, IGF1, IGF1R, or FGFR3 have been associated with isolated short stature without other prominent or noticeable phenotype while homozygous and/or severe mutations in these genes cause severe short stature with bone malformation, that is, a chondrodysplasia. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, individualized management, and help avoid unnecessary testing for endocrine and other disorders.

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Three novel IGF1R mutations in microcephalic patients with prenatal and postnatal growth impairment

Abstract: These variations led to failure of the IGF1R function causing pre- and postnatal growth retardation and microcephaly. Microcephaly should be considered in the evaluation of SGA patients, because it seems to favour the frequency of detection of IGF1R mutations.

Cited by 41 publications

References 34 publications

Growth Hormone Treatment in Children Born Small for Gestational Age (SGA)

Growth Hormone Treatment in Children Born Small for Gestational Age (SGA)

Growth hormone, insulin-like growth factor-1 and the aging brain

Genetics of Short Stature

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