Chronic pain in Noonan Syndrome: A previously unreported but common symptom

Vegunta, Sravanthi; Cotugno, Richard; Williamson, Amber; Grebe, Theresa A.

doi:10.1002/ajmg.a.37337

Cited by 16 publications

(20 citation statements)

References 40 publications

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“…This also applies to individuals with RASopathies. Anecdotal reports about individuals affected by these disorders experiencing joint and neuropathic pain are available in the literature (Croonen et al, ; Maridet et al, ; Reinker et al, ; Smpokou et al, ; Spatola et al, ; Vegunta et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…RASopathies are multisystemic disorders characterized by peculiar facial gestalt, growth failure, congenital heart disease, skin/muscle‐skeletal anomalies, a different level of cognitive abilities, and predisposition to malignancies (Cesarini et al, ; Tartaglia & Gelb, ). Pain in individuals affected by RASopathies is an underreported clinical problem and anecdotal reports about individuals experiencing joint and neuropathic pain have been published (Croonen et al, ; Maridet, Sole, Morice‐Picard, & Taieb, ; Reinker, Stevenson, & Tsung, ; Smpokou, Tworog‐Dube, Kucherlapati, & Roberts, ; Spatola, Wider, Kuntzer, & Croquelois, ; Vegunta, Cotugno, Williamson, & Grebe, ). However, an objective evaluation of pain in terms of prevalence and characteristics in individuals with RASopathies, is still lacking.…”

Section: Introductionmentioning

confidence: 99%

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Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

Leoni

Vollono

Onesimo

et al. 2019

American J of Med Genetics Pt A

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Pain in individuals with RASopathies is a neglected topic in literature. In this article, we assessed prevalence and profile of pain in a sample of 80 individuals affected by RASopathies. The study sample included individuals with Noonan syndrome (N = 42), Costello syndrome (N = 17), and cardio-facio-cutaneous syndrome (N = 21). A set of standardized questionnaires and scales were administered (VAS/numeric scale, r-FLACC, Wang-Baker scale, NPSI, BPI, NCCPC-R) to detect and characterize acute and chronic pain and to study the influence of pain on quality of life (PEDs-QL, SF-36) and sleeping patterns (SDSC); revision of past medical history and multisystemic evaluation was provided. Available clinical data were correlated to the presence of pain. High prevalence of acute (44%) and chronic (61%) pain was documented in the examined sample. Due to age and intellectual disability, acute pain was localized in 18/35 individuals and chronic pain in 33/49. Muscleskeletal and abdominal pain was more frequently reported. The intensity of acute and chronic pain interfered with daily activities in 1/3 of the sample. Pain negatively impacted on QoL and sleeping patterns. This work documents that pain is highly prevalent in RASopathies. Future studies including subjective and objective measures of pain are required to discriminate a somatosensory abnormality from an abnormal elaboration of painful stimuli at a central level. K E Y W O R D S cardiofaciocutaneous syndrome, costello syndrome, Noonan syndrome, pain, RASopathies

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

Leoni

Vollono

Onesimo

et al. 2019

American J of Med Genetics Pt A

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“…O’Brien et al (2015) identified ERK2 as a crucial mediator of cold nociception in the Nav1.8-expressing subpopulation of nociceptive sensory neurons. In Rasopathies patients, whose conditions are caused by various germline mutations that affect RAS downstream signaling, chronic pain is a common symptom (Vegunta et al , 2015). …”

Section: Raf – Mek – Erk Signaling In Sensory Neuron Specification Anmentioning

confidence: 99%

RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction

Zhong

2016

Biological Chemistry

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In postmitotic neurons, the activation of RAS family small GTPases regulates survival, growth and differentiation. Dysregulation of RAS or its major effector pathway, the cascade of RAF-, mitogen-activated and extracellular-signal regulated kinase kinases (MEK), and extracellular-signal regulated kinases (ERK) causes the Rasopathies, a group of neurodevelopmental disorders whose pathogenic mechanisms are the subject of intense research. I here summarize the functions of RAS – RAF – MEK – ERK signaling in neurons in vivo, and discuss perspectives for harnessing this pathway to enable novel treatments for nervous system injury, the Rasopathies, and possibly other neurological conditions.

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“…fibromyalgia) cannot be linked to an injury or disease, being assumed instead to be caused by genetic factors. 45,46 In fact several transgenic mouse lines have been generated, which show lifetime symptoms of constitutively increased nociceptive sensitivity. 25,47,48 It is interesting to note that all the genes found so far to play a role in the regulation of nociceptive sensitivity are also coincidentally involved in the regulation of neuronal differentiation.…”

Section: Genetic Variations That Interfere With Neuronal Maturation Mmentioning

confidence: 99%

“…25,47,48 It is interesting to note that all the genes found so far to play a role in the regulation of nociceptive sensitivity are also coincidentally involved in the regulation of neuronal differentiation. Such genes include ALDH2, 48 Shp2, 46 Notch3 25 and c-kit, 47 which are part of signal transduction pathways that stimulate neuronal differentiation. This coincidence supports the idea that genetic variations that interfere with neuronal differentiation will maintain an excess of highly excitable spinal cord immature neurons into adulthood.…”

Section: Genetic Variations That Interfere With Neuronal Maturation Mmentioning

confidence: 99%

Adult spinal cord neurogenesis: A regulator of nociception

Rusanescu

2016

Neurogenesis

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Adult spinal cord neurogenesis occurs at low, constant rate under normal conditions and can be amplified by pathologic conditions such as injury or disease. The immature neurons produced through adult neurogenesis have increased excitability and migrate preferentially to the superficial dorsal horn layers responsible for nociceptive signaling. Under normal conditions, this process may be responsible for maintaining a steady-state, but adaptable level of nociceptive sensitivity, thus representing an experience-dependent mechanism of regulation similar to other neurogenic niches. Under pathologic conditions, adult spinal cord neurogenesis is greatly amplified and may therefore account for the observed changes in general spinal cord excitability and nociceptive sensitivity. This mechanism also explains many types of chronic pain present in the absence of injury or disease, which may be the result of impaired neuronal differentiation due to a variety of genetic variations. This suggests the possibility of using promoters of neuronal differentiation for the long-term treatment of the causes of chronic pain, unlike current medication which is palliative and effective only for the duration of treatment. The presence of this spinal cord neurogenic niche may also lead to new approaches in spinal cord regeneration.

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Chronic pain in Noonan Syndrome: A previously unreported but common symptom

Cited by 16 publications

References 40 publications

Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction

Adult spinal cord neurogenesis: A regulator of nociception

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