Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders

Nyström, Anna-Maja; Ekvall, Sara; Berglund, Erna; Björkqvist, Maria; Braathen, Gunnar; Duchén, Karel; Enell, Henrik; Holmberg, Eva; Holmlund, Ulrika; Olsson-Engman, Mia; Annerén, Göran; Bondeson, Marie-Louise

doi:10.1136/jmg.2008.057653

Cited by 93 publications

(90 citation statements)

References 30 publications

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“…However, there are no sufficient histological data to rule out the possibility that early onset cardiomyopathies with hypertrophic appearances could have increased cardiomyocyte numbers. B-Raf +/LSLV600E mice do not develop other cardiovascular defects typically present in CFC patients, such as pulmonary valve stenosis, septal defects, and aortic abnormalities (12,24,25). Whether these differences are caused by the intrinsic physiological differences between the cardiovascular systems of rodents and humans or differences in the constitutive B-Raf kinase activity remains to be determined.…”

Section: B-raf +/Lslv600e Mice Display Craniofacial Dysmorphism and Dmentioning

confidence: 99%

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Urosevic

Sauzeau

Soto-Montenegro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS/RAF/MEK signaling pathway. A well-recognized RASopathy is the cardiofacio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-RAF, MEK1, MEK2, and K-RAS. B-RAF is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-Raf LSLV600E allele. This targeted allele allows low levels of expression of B-Raf V600E , a constitutively active B-Raf kinase first identified in human melanoma. B-Raf +/LSLV600E mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf +/LSLV600E mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome.

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Section: B-raf +/Lslv600e Mice Display Craniofacial Dysmorphism and Dmentioning

confidence: 99%

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Urosevic

Sauzeau

Soto-Montenegro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In our cohort, all mutations were found to affect exons 2 and 3 of both genes, confirming earlier observations indicating that the regulatory region and the adjacent N-terminal portion of the catalytic domain are mutation hot spots, possibly because of the specific perturbing effect of mutations on the autoinhibitory mechanism controlling protein activation. Nevertheless, based on the identification of rare mutations outside this region (E203Q in MEK1 18 and K273R in MEK2 3 ), MEK1 and MEK2 mutation screening should not be limited to these exons. Our data also confirmed that mutations affecting the tyrosine residue at codon 130 of MEK1 represent the most common event underlying CFCS, and that mutations involving residue F57 are the most frequent lesions occurring in MEK2.…”

Section: Discussionmentioning

confidence: 99%

Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype–phenotype correlations

et al. 2009

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Cardio-facio-cutaneous syndrome (CFCS) is a rare disease characterized by mental retardation, facial dysmorphisms, ectodermal abnormalities, heart defects and developmental delay. CFCS is genetically heterogeneous and mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes, encoding for components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway, have been identified in up to 90% of cases. Here we screened a cohort of 33 individuals with CFCS for MEK1 and MEK2 gene mutations to further explore their molecular spectrum in this disorder, and to analyze genotypephenotype correlations. Three MEK1 and two MEK2 mutations were detected in six patients. Two missense MEK1 (L42F and Y130H) changes and one in-frame MEK2 (K63_E66del) deletion had not been reported earlier. All mutations were localized within exon 2 or 3. Together with the available records, the present data document that MEK1 mutations are relatively more frequent than those in MEK2, with exons 2 and 3 being mutational hot spots in both genes. Mutational analysis of the affected MEK1 and MEK2 exons did not reveal occurrence of mutations among 75 patients with Noonan syndrome, confirming the low prevalence of MEK gene defects in this disorder. Clinical review of known individuals with MEK1/MEK2 mutations suggests that these patients show dysmorphic features, ectodermal abnormalities and cognitive deficit similar to what was observed in BRAF-mutated patients and in the general CFCS population. Conversely, congenital heart defects, particularly mitral valve and septal defects, and ocular anomalies seem to be less frequent among MEK1/MEK2 mutation-positive patients.

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“…On a related note, some studies have found that, occasionally, mutations in BRAF and MEK1 can result in a phenotype more similar to NS or NSML than to typical CFC (Nystrom et al 2008;Nishi et al 2015;Sarkozy et al 2009). This finding has resulted in some debate regarding whether these individuals can be diagnosed as having a Noonan-like syndrome or whether they simply exhibit a milder phenotype of CFC (Neri et al 2008).…”

Section: Relationship Between Genotype and Neurocognitive Outcomesmentioning

confidence: 99%

“…For example, individuals with KRAS mutations have been described as having an intermediate or ambiguous clinical phenotype that has features of both NS and CFC syndrome (Schubbert et al 2006;Nystrom et al 2008). Individuals with this mutation can be diagnosed with either one of these conditions depending on their specific clinical presentation.…”

Section: Relationship Between Genotype and Neurocognitive Outcomesmentioning

confidence: 99%

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

Pierpont

2015

J Pediatr Neuropsychol

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Noonan syndrome (NS) is a relatively common genetic syndrome with variable features including short stature, congenital heart disease, distinctive facial characteristics, skeletal anomalies, and varying degrees of developmental delay. NS is caused by gene mutations in a cellular signaling pathway that is essential for typical growth and development. Research in the past few decades has revealed that individuals with NS have highly variable neurocognitive and behavioral outcomes. To a certain extent, variability in cognitive functioning depends on the particular gene where a mutation is found; additionally, factors related to medical severity and environmental effects contribute substantially to outcomes. This article contains a systematic review of research on neuropsychological features of NS, including cognition, motor development, language, memory, attention, visual perception, adaptive behavior, social skills, and mental health concerns. Given the wide variety of possible cognitive and behavioral complications associated with NS, it is recommended that clinical neuropsychological evaluation of cognitive, adaptive, and psychological domains of functioning should be standard of care for all individuals with NS. Suggested considerations for assessment of individuals with NS are provided. The paper concludes with recommendations for educational and therapeutic interventions, as well as suggestions for future research directions.

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Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders

Cited by 93 publications

References 30 publications

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype–phenotype correlations

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

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