Decreased bone mineralization in children with Noonan syndrome: Another consequence of dysregulated RAS MAPKinase pathway?

Choudhry, Kiran S.; Grover, Monica; Tran, Alyssa A.; Smith, E. O’Brian; Ellis, Kenneth J.; Lee, Brendan

doi:10.1016/j.ymgme.2012.04.003

Cited by 30 publications

(33 citation statements)

References 32 publications

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“…In the last years, numerous studies explored the effects of the Ras/MAPK pathway deregulation on the skeletal development and bone metabolism [Yu et al, ; Stevenson et al, ; Stevenson and Yang, ; Choudhry et al, ; Petramala et al, ; Rhodes et al, ]. Low bone mineral density was reported in NF1 [Brunetti‐Pierri et al, ; Dulai et al, ; Stevenson et al, ; Yilmaz et al, ; Armstrong et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…In CS, dual energy X‐ray absorptiometry scan (DXA) showed decreased mineralization with the lumbar one predominantly compromised, a finding potentially explaining the predisposition to non‐dystrophic scoliosis [Leoni et al, ]. As concerns NS, literature data are particularly scanty [Takagi et al, ; Noordam et al, ; Stevenson et al, ; Choudhry et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…Prenatal features might include enlarged nuchal translucency, polyhydramnios, hydrothorax, cystic hygroma, and multiple effusions [Baldassarre et al, , ; Croonen et al, ; Gaudineau et al, ; Myers et al, ]. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized that the Ras pathway may regulate bone metabolism and homeostasis [Yu et al, ; Stevenson et al, ; Stevenson and Yang, ; Choudhry et al, ; Petramala et al, ; Rhodes et al, ]. However, excepting NF1 which has been largely explored both from a clinical and biochemical viewpoint, data on skeletal mineralization, bone metabolism and fracture rate are scanty in the other Rasopathies .…”

Section: Introductionmentioning

confidence: 99%

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Constitutional bone impairment in Noonan syndrome

Baldassarre

Mussa²,

Carli

et al. 2017

American J of Med Genetics Pt A

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Noonan syndrome (NS) is an autosomal dominant trait characterized by genotypic and phenotypic variability. It belongs to the Ras/MAPK pathway disorders collectively named Rasopathies or neurocardiofaciocutaneous syndromes. Phenotype is characterized by short stature, congenital heart defects, facial dysmorphisms, skeletal and ectodermal anomalies, cryptorchidism, mild to moderate developmental delay/learning disability, and tumor predisposition. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized a role for the RAS pathway in regulating bone metabolism. In this study, we investigated the bone quality assessed by phalangeal quantitative ultrasound (QUS) and the metabolic bone profiling in a group of patients with NS, to determine whether low bone mineralization is primary or secondary to NS characteristics. Thirty-five patients were enrolled, including 20 males (55.6%) and 15 females (44.5%) aged 1.0-17.8 years (mean 6.4 ± 4.5, median 4.9 years). Each patients was submitted to clinical examination, estimation of the bone age, laboratory assays, and QUS assessment. Twenty-five percent of the cohort shows reduced QUS values for their age based on bone transmission time. Bone measurement were adjusted for multiple factors frequently observed in NS patients, such as growth retardation, delayed bone age, retarded puberty, and reduced body mass index, potentially affecting bone quality or its appraisal. In spite of the correction attempts, QUS measurement indicates that bone impairment persists in nearly 15% of the cohort studied. Our results indicate that bone impairment in NS is likely primary and not secondary to any of the phenotypic traits of NS, nor consistent with metabolic disturbances. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Constitutional bone impairment in Noonan syndrome

Baldassarre

Mussa²,

Carli

et al. 2017

American J of Med Genetics Pt A

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“…This idea is based on the observation that orthopedic manifestations are a common feature of Rasopathies. In the case of NS, scoliosis and other spinal deformities are frequently encountered [49,50] and it was recently reported that NS children may have decreased bone mineralization [51], even though this study was performed on a limited number of patients. This hypothesis is also based on a recent report showing that PTPN11 disruption causes severe skeletal defects in mice [52].…”

Section: Defects In Bone Homeostasismentioning

confidence: 95%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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Short stature is a frequent feature of Noonan syndrome (NS), a disease caused by mutations of genes encoding components of the Ras/mitogen-activated protein kinases (MAPK) signalling pathway. To date numerous patients have been treated with growth hormone (GH) in various countries. However this treatment is still controversial, as its efficacy is a matter of debate. The final height gain of GH therapy represents 5 to 10 cm, at best, which is disappointing considering the length and burden of the treatment. The reasons explaining this lack of efficiency are poorly understood and they seemed to involve a waning effect after the first year of GH treatment or acceleration of bone maturation in patients on GH. Moreover, GH therapy raises questions about its safety, especially in subjects with NS who are at risk for cardiac defects and malignancies. Cases of severe adverse effects were described, yet too sporadically to conclude that they were certainly caused by GH therapy. Novels insights in understanding the dysfunction of GH-dependent processes in NS were recently reported and this manuscript aims at reviewing the latest advances. Clinical data suggested that growth retardation could be caused by a partial postreceptor resistance to GH, an impaired sensitivity to GH which could also explain the modest efficiency of GH therapy in NS patients. Similar observations were also obtained in a NS mouse model harboring a mutation in the gene encoding the tyrosine phosphatase Shp2. In the mouse, the mechanism of GH resistance is thought to involve upregulation by mutated Shp2 of GH-induced Ras/MAPK, a signaling pathway which seemed to play a negative regulatory role in the production of GH mediators involved in bone growth. Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.

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“…The skeletal deformities represent a major challenge in the life of NS patients, but their etiology is not well understood. Dual-energy X-ray absorptiometry has shown that bone mineralization is decreased in NS children (12) and analysis of collagen I fragments in urine suggests that this reflects increased bone resorption (13). However, no biopsies or histological sections of NS patients' bones have been reported.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal expression of activated K-ras yields Noonan Syndrome-like bone defects that are rescued by mid-gestational MEK inhibition

Nedelcu

Kobayashi

Stanciu

et al. 2019

Preprint

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Activating germline K-ras mutations cause Noonan syndrome (NS), which is characterized by several developmental deficits including cardiac defects, cognitive delays and skeletal abnormalities. NS patients have increased signaling through the MAPK pathway. To model NS skeletal defects and understand the effect of hyperactive K-ras signaling on normal limb development, we generated a mouse model in which activated Kras G12D was expressed specifically in mesenchymal progenitors of the limb bud. These mice display short, abnormally mineralized long bones that phenocopy those of NS patients. This defect was first apparent at E14.5, and was characterized by a delay in bone collar formation. Coincident mutation of p53 had no effect on the K-ras G12D induced bone defect, arguing that it is does not result from senescence or apoptosis. Instead, our data revealed profound defects in the development of the committed osteoblasts; their appearance is delayed, concordant with the delay in bone collar formation, and they display an aberrant localization outside of the bone shaft. Additionally, we see growth plate defects including a reduction in the hypertrophic chondrocyte layer. Most importantly, we found that in utero delivery of a MEK inhibitor between E10.5 and E14.5 is sufficient to completely suppress

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Decreased bone mineralization in children with Noonan syndrome: Another consequence of dysregulated RAS MAPKinase pathway?

Cited by 30 publications

References 32 publications

Constitutional bone impairment in Noonan syndrome

Constitutional bone impairment in Noonan syndrome

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Mesenchymal expression of activated K-ras yields Noonan Syndrome-like bone defects that are rescued by mid-gestational MEK inhibition

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