High prevalence of growth plate gene variants in children with familial short stature treated with growth hormone

2019 ◽  
Author(s):  
Plachy L ◽  
Strakova V ◽  
Elblova L ◽  
Obermannova B ◽  
Kolouskova S ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Growth Plate ◽  
Gene Variants ◽  
High Prevalence

scholarly journals High Prevalence of Growth Plate Gene Variants in Children With Familial Short Stature Treated With GH

2019 ◽  
Vol 104 (10) ◽  
pp. 4273-4281 ◽  
Author(s):  
Lukas Plachy ◽  
Veronika Strakova ◽  
Lenka Elblova ◽  
Barbora Obermannova ◽  
Stanislava Kolouskova ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Plate ◽  
Single Gene ◽  
Gene Variants ◽  
Genetic Etiology ◽  
Associated Proteins ◽  
Genetic Mechanisms ◽  
Standards And Guidelines ◽  
Minimum Height ◽  
Severe Short Stature

AbstractContextFamilial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date.ObjectivesTo identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD).Design, Settings, and PatientsOf 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height −2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines.ResultsIn 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1).ConclusionsSingle-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.

NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy

2020 ◽  
Vol 105 (3) ◽  
pp. e746-e752 ◽  
Author(s):  
Lukas Plachy ◽  
Petra Dusatkova ◽  
Klara Maratova ◽  
Lenka Petruzelkova ◽  
Dana Zemkova ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Standard Deviation ◽  
Short Stature ◽  
Treatment Response ◽  
Growth Velocity ◽  
Final Height ◽  
Standard Deviation Score ◽  
Significant Proportion ◽  
Gene Variants ◽  
Gh Treatment

Abstract Context The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. Objectives To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. Design, Settings and Patients Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ –2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. Results In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. Conclusions NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.

scholarly journals Familial Short Stature - a Novel Phenotype of Growth Plate Collagenopathies

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A723-A723
Author(s):  
Lukas Plachy ◽  
Petra Dusatkova ◽  
Klara Maratova ◽  
Lenka Petruzelkova ◽  
Stanislava Kolouskova ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Treatment Response ◽  
Growth Plate ◽  
Growth Velocity ◽  
Normal Brain ◽  
Short Term ◽  
Gh Treatment ◽  
Pre Treatment ◽  
Collagen Genes

Abstract Backround: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with asymmetric short stature (e.g. Kniest dysplasia, spondyloepiphyseal dysplasia). Less is known about nonsyndromic collagenopathies - data about their frequency and subtle phenotypic signs are sparse, the information about their response to growth hormone (GH) treatment is lacking completely. Aim: To evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. Methods: Out of 522 individuals treated in our center with GH from the indication of primary GH deficiency (GHD) or small for gestational age short stature (SGA-SS), 87 children with FSS fulfilled the inclusion criteria (pre-treatment height ≤-2 SD in both patient/their shorter parent, signed written informed consent) and were enrolled to the study. Next-generation sequencing was performed to search for variants in COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 and COL11A2 genes. The results were evaluated using ACMG guidelines. The phenotype of children with (likely) pathogenic variants was described including the short-term GH treatment response (growth velocity and body-height SDS increase over three years of treatment). For statistical evaluation, parametric tests were used, p-values <0.05 were considered significant. Results: A (likely) pathogenic variant in one of the collagen genes was found in 10/87 (11.5%) children. Their age was 12.5 years (median, range 6-17 years), their pre-treatment height was -3.1 SD (-2.4 to -4.3 SD). Their birth length (median -2.8 SD; range -0.7 to -4.1 SD) was more severely affected than birth weight (median -2.1 SD; range -1.0 to -2.7 SD). Eight children were treated with GH from SGA-SS indication, the remaining 2 were classified as mild GHD (maximal stimulated GH concentration 8.0 and 9.7 ug/l, normal brain MRI and examination of other pituitary hormones). Detailed anthropometric examination described mild asymmetry with shorter limbs and mild bone dysplasia signs (scoliosis, more pronounced lumbar lordosis, genua valga, limited elbow extension) in 2/10 and 4/10 affected children, respectively. Growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after one year of treatment (p<0.001, paired-sample T-test), height improved from a median of -3.1 SD to -2.2 SD after three years of therapy (p=0.001, ANOVA repeated measures analysis of variants). Conclusion: Nonsyndromic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising. Supported by the Ministry of Health, Czech Republic, grant number NV18- 07-00283 and by the research project of the Grant Agency of Charles University of Prague, GAUK 976718.

Growth hormone therapy in a child with severe short stature due to Miller-McKusick-Malvaux (3M) syndrome-2

2019 ◽  
Author(s):  
Sumudu Seneviratne ◽  
Deepthi de Silva ◽  
Emily Cottrell ◽  
Piumi Kuruppu ◽  
KSH de Silva ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hormone Therapy ◽  
Short Stature ◽  
Growth Hormone Therapy ◽  
Severe Short Stature

NPR2 Variants are frequent among children with familial short stature and respond well to growth hormone therapy

2020 ◽  
Author(s):  
Plachy L ◽  
Dusatkova P ◽  
Maratova K ◽  
Petruzelkova L ◽  
Zemkova D ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hormone Therapy ◽  
Short Stature ◽  
Growth Hormone Therapy
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