Noonan syndrome causing-SHP2 mutants inhibit IGF-I release via GH-induced ERK1/2 hyper-activation, which contributes to short stature

2012 ◽  
Vol 73 (4) ◽  
pp. 251-252
Author(s):  
A. De Rocca Serra-Nédélec ◽  
T. Edouard ◽  
K. Tréguer ◽  
M. Tajan ◽  
T. Araki ◽  
...  
Keyword(s):  
Short Stature ◽  
Noonan Syndrome ◽  
Igf I

scholarly journals PTPN11 Mutations Are Associated with Mild Growth Hormone Resistance in Individuals with Noonan Syndrome

2005 ◽  
Vol 90 (9) ◽  
pp. 5377-5381 ◽  
Author(s):  
G. Binder ◽  
K. Neuer ◽  
M. B. Ranke ◽  
N. E. Wittekindt
Keyword(s):  
Short Stature ◽  
Noonan Syndrome ◽  
Tyrosine Phosphatase ◽  
Pcr Amplification ◽  
Heterozygous Mutation ◽  
Missense Mutations ◽  
Pulmonic Stenosis ◽  
Gh Secretion ◽  
Igf I ◽  
Igfbp 3

Abstract Context: Noonan syndrome is frequently associated with an unclear disturbance of GH secretion. Half the individuals with Noonan syndrome carry a heterozygous mutation of the nonreceptor-type protein tyrosine phosphatase, Src homology region 2-domain phosphatase-2 (SHP-2), encoded by PTPN11, which has a role in GH receptor signaling. Objective: The objective of this study was to compare GH secretion and IGF-I/IGF-binding protein-3 (IGFBP-3) levels of the SHP-2 mutation-positive (mut+ group) vs. mutation-negative individuals (mut− group). Design, Setting, and Patients: All children presenting to us with short stature plus at least three typical anomalies of Noonan syndrome or pulmonic stenosis during the last 5 yr (n = 29; 10 females and 19 males) were recruited. Auxological data, dysmorphic features, and cardiac morphology were documented. Hormone levels were measured by RIA. All coding exons of PTPN11 were sequenced after PCR amplification. Intervention: A prepubertal subgroup (n = 11) was treated with recombinant human GH (rhGH) to promote growth. Results: Sequencing yielded 11 different PTPN11 missense mutations in 16 of the 29 patients (55% mut+). Pulmonic stenosis (81 vs. 15%; P = 0.0007) and septal defects (63 vs. 15%; P = 0.02) were more frequently found in the mut+ group, whereas minor anomalies, cryptorchidism, and learning disabilities were as frequent in the mut+ group as in the mut− group. The mut+ group was younger at presentation (mean ± sd, 5.1 ± 2.7 vs. 10.3 ± 5.2 yr; P = 0.002), but not significantly shorter [−3.15 ± 0.92 vs. −3.01 ± 1.35 height sd score (SDS)]. IGF-I levels (−2.03 ± 0.69 vs. −1.13 ± 0.89 SDS; P = 0.005) and IGFBP-3 levels (−0.92 ± 1.26 vs. 0.40 ± 1.08 SDS; P = 0.006) were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation (P ≥ 0.075, not significant). The mean change in height SDS after 1 yr of rhGH therapy (0.043 mg/kg·d) was +0.66 ± 0.21 in the mut+ group (n = 8), but +1.26 ± 0.36 in the mut− group (n = 3; P = 0.007). Conclusions: Our data suggest that SHP-2 mutations in Noonan syndrome cause mild GH resistance by a postreceptor signaling defect, which seems to be partially compensated for by elevated GH secretion. This defect may contribute to the short stature phenotype in children with SHP-2 mutations and their relatively poor response to rhGH.

scholarly journals Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

2002 ◽  
pp. 319-323 ◽  
Author(s):  
Y Rakover ◽  
A Silbergeld ◽  
I Lavi ◽  
R Masalha ◽  
IB Shlomo
Keyword(s):  
Short Stature ◽  
Binding Protein ◽  
Standard Deviation Score ◽  
Bone Age ◽  
The Other ◽  
Provocative Test ◽  
Igf I ◽  
Parental Height ◽  
The Difference ◽  
Igfbp 3

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.

IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene

HORMONES ◽  
2013 ◽  
Vol 12 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Silvano Bertelloni ◽  
Giampiero I. Baroncelli ◽  
Eleonora Dati ◽  
Silvia Ghione ◽  
Fulvia Baldinotti ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Ptpn11 Gene ◽  
Prepubertal Children ◽  
Igf I ◽  
Generation Test

scholarly journals Anthropometric and biochemical correlates of PAPP-A2, free IGF-I, and IGFBP-3 in childhood

2020 ◽  
Vol 182 (3) ◽  
pp. 363-374 ◽  
Author(s):  
Masanobu Fujimoto ◽  
Jane C Khoury ◽  
Philip R Khoury ◽  
Bhanu Kalra ◽  
Ajay Kumar ◽  
...  
Keyword(s):  
Short Stature ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Single Center ◽  
Marked Rise ◽  
Cross Sectional ◽  
Igf I ◽  
Important Regulator ◽  
The Relationship ◽  
Igfbp 3

Objective Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors. Design Cross-sectional study at a single center. Methods PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3–18 years old) and an evaluation of the relationship between these proteins and anthropometric factors. Results In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = −0.58, −0.65; P < 0.0001). Conclusions This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.

Short stature with normal growth hormone and elevated IGF-I

1992 ◽  
Vol 151 (5) ◽  
pp. 321-325 ◽  
Author(s):  
T. Momoi ◽  
C. Yamanaka ◽  
M. Kobayashi ◽  
T. Haruta ◽  
H. Sasaki ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Normal Growth ◽  
Igf I

Insulin-like growth factor ternary complex components as biomarkers for the diagnosis of short stature

2021 ◽  
Vol 185 (5) ◽  
pp. 629-635
Author(s):  
Aristeidis Giannakopoulos ◽  
Alexandra Efthymiadou ◽  
Dionisios Chrysis
Keyword(s):  
Growth Factor ◽  
Short Stature ◽  
Ternary Complex ◽  
Final Height ◽  
Hormone Deficiency ◽  
Receiver Operating Curve ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Stimulation Tests ◽  
Igfbp 3

Objective The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature. Design Boys and girls (n = 429, 0.7–16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis. Results All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups. Conclusion Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

Growth hormone and insulin-like growth factor regulate insulin-like growth factor-binding protein-1 in Laron type dwarfism, growth hormone deficiency and constitutional short stature

1992 ◽  
Vol 127 (4) ◽  
pp. 351-358 ◽  
Author(s):  
Zvi Laron ◽  
Anne-Maria Suikkari ◽  
Beatrice Klinger ◽  
Aviva Silbergeld ◽  
Athalia Pertzelan ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Growth Hormone Deficiency ◽  
Short Stature ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Healthy Children ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Igf I

Insulin-like growth factors (IGFs) mediate the effects of growth hormone (GH), and the insulin-like growth factor-binding proteins (IGFBPs) modulate the actions of IGFs in tissues. We studied the circulating levels of IGFBP-1 in 6 children and 9 adults with Laron type dwarfism (LTD), in 11 children and 21 adults with growth hormone deficiency (GHD), and in 8 children with constitutional short stature. Compared with the situation in healthy children, the basal serum IGFBP-1 concentration was 5.4-fold higher in LTD children, 4.1-fold higher in GHD children, and 3.8-fold higher in children with short stature (p<0.02 vs controls in all groups). In adult patients with multiple pituitary hormone deficiency (MPHD), the IGFBP-1 concentration was 2-fold elevated, but it was normal in adult LTD patients. Intravenous (N= 10) or subcutaneous (N=9) administration ofIGF-I (75 μg·kg−1 and 150 μg·kg−1, respectively) in LTD children resulted in a rapid 50–60% fall in serum insulin (p<0.02), a decline in blood glucose and a concomitant 40–60% rise of IGFBP-1 levels (p<0.05). Treatment for seven days with IGF-I (150 μg·kg−1·d−1) resulted in a decrease by 34% and 44% of serum IGFBP-1 level in two out of three children with LTD. After prolonged GH therapy, the IGFBP-1 level fell in GHD children by 29% (p<0.05), in GHD adults by 52% (p<0.02) and in children with constitutional short stature by 17% (p<0.02). IGFBP-1 and insulin concentrations were inversely related in patients with GHD (r= −0.66, p<0.001) or with LTD (r= −0.57, p<0.05). Our data suggest that: (a) increased IGFBP-1 concentration in LTD, GHD and constitutional short children may, at least in part, be accounted for by an IGF-I deficiency; (b) both the rise in IGF-I and a fall in insulin contributed to the rise in IGFBP-1 after acute IGF-I administration; (c) prolonged IGF-I or GH treatment causes a persistent decline in IGFBP-1 concentration. In conclusion, IGF-I and GH may regulate IGFBP-1 secretion either directly or via insulin.

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