Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Background/Aims: In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing GH1, GHR, STAT5B, IGF1, and IGFALS in children with GH insensitivity. Subjects and Methods: Patients were divided into three groups: group 1 (height SDS <–2.5, IGF-I <–2 SDS, n = 9), group 2 (height SDS –2.5 to –1.9, IGF-I <–2 SDS, n = 6) and group 3 (height SDS <–1.9, IGF-I –2 to 0 SDS, n = 21). An IGF-I generation test was performed in 11 patients. Genomic DNA was used for direct sequencing, multiplex ligation-dependent probe amplification and whole-genome SNP array analysis. Results: Three patients in group 1 had two novel heterozygous STAT5B mutations, in two combined with novel IGFALS variants. In groups 2 and 3 the association between genetic variants and short stature was uncertain. The IGF-I generation test was not predictive for the growth response to GH treatment. Conclusion: In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous STAT5B mutations, with or without heterozygous IGFALS defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare.

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“…We have not been able to test for GHSR variants, but the prevalence of abnormalities in this gene appears to be low [6,38,39,40]. …”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

Wit

Duyvenvoorde²,

Scheltinga³

et al. 2012

Horm Res Paediatr

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“…The variability of clinical phenotypes (GHD, idiopathic short stature (ISS) and constitutional delay of growth and puberty (CDGP)) and incomplete segregation of the mutations with the phenotype still cast doubt on the role of GHSR mutations in causing short stature, although functional studies do suggest that GHSR mutations may decrease GH secretion (40,41,42), implying that GHSR mutations may GHI and decreased expression or biologic activity of IGF1or IGF2 Table 2 shows the various syndromes presenting with insensitivity to GH or IGF1. The first discovered cause of GHI was Laron syndrome, usually caused by a homozygous mutation of the gene encoding the GH receptor (GHR) (43,44,45 (48,49,50) or by heterozygous GHR mutations causing a dominant negative effect (51,52,53).…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

148

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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“…A homozygous partial loss-of-function mutation in GNRHR was found in 2 brothers, 1 with self-limited DP and 1 with idiopathic HH [26], and a further heterozygous mutation was found in 1 male with self-limited DP [27]. A small cohort of 31 patients was analysed for mutations in GHSR, and 5 patients were found to have point mutations in this gene [28]. Additionally, mutations in HS6ST1, FGFR1, and newly in KLB have been found in a small number of kindreds of HH patients and their relatives with DP [29][30][31].…”

Section: Genetics Of Gnrh Deficiency or Signallingmentioning

confidence: 99%

The Genetic Basis of Delayed Puberty

Howard

2017

Neuroendocrinology

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The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty “brake.” These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.

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Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Cited by 54 publications

References 44 publications

Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

The Genetic Basis of Delayed Puberty

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