CFC index for the diagnosis of cardiofaciocutaneous syndrome

Kavamura, Maria Inês; Peres, C.; Alchorne, Maurício Mota de Avelar; Brunoni, Décio

doi:10.1002/ajmg.10681

Cited by 68 publications

(74 citation statements)

References 35 publications

(26 reference statements)

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“…To delineate more precisely the phenotypic features of patients with MEK1 and MEK2 mutations and to explore possible genotype -phenotype correlations, the clinical data of the present cohort were compared with those referred to patients with MEK or BRAF gene mutations recently provided by Armour and Allanson [21] and the CFCS cohort originally described by Kavamura et al 23 . From the analysis it is apparent that MEK1 and MEK2 mutationpositive patients from the present cohort show a 'classical' CFCS phenotype, particularly regarding presence of dysmorphisms, short stature, ectodermal features and cognitive deficits (Table 2, Figure 2).…”

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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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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“…In 2002, a CFC index was developed based on 82 clinical traits to assist with diagnosis. 30 However, at present, there are no pathognomonic or obligatory features uniquely associated with CFC that can aid in making a definitive clinical diagnosis.…”

Section: Clinical Description With Differential Diagnosismentioning

confidence: 99%

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

et al. 2014

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Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. The major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care.

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“…Additional evidence that the Ras3 Erk pathway is critical for brain development comes from the recent discovery that cardio-facio-cutaneous syndrome, characterized in part by mental retardation and macrocephaly (Kavamura et al, 2002), is caused by mutations in either B-Raf, MEK1, or MEK2 (Rodriguez-Ficiana et al, 2006). These mutations lead to increased activity of the Ras/Raf/MEK/ERK pathway when transfected in vitro.…”

Section: Shca Functions In Neural Progenitor Survival Signalingmentioning

confidence: 99%

Neural-Specific Inactivation of ShcA Results in Increased Embryonic Neural Progenitor Apoptosis and Microencephaly

et al. 2006

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Brain size is precisely regulated during development and involves coordination of neural progenitor cell proliferation, differentiation, and survival. The adapter protein ShcA transmits signals from receptor tyrosine kinases via MAPK (mitogen-activated protein kinase)/ ERK (extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)/Akt signaling pathways. In the CNS, ShcA expression is high during embryonic development but diminishes as cells differentiate and switches to ShcB/Sck/Sli and ShcC/N-Shc/Rai. To directly test ShcA function in brain development, we used Cre/lox technology to express a dominant-negative form of ShcA (ShcFFF) in nestin-expressing neural progenitors. ShcFFF-expressing mice display microencephaly with brain weights reduced to 50% of littermate controls throughout postnatal and adult life. The cerebrum appeared most severely affected, but the gross architecture of the brain is normal. Body weight was mildly affected with a delay in reaching mature weight. At a mechanistic level, the ShcFFF microencephaly phenotype appears to be primarily attributable to elevated apoptosis levels throughout the brain from embryonic day 10.5 (E10.5) to E12, which declined by E14.5. Apoptosis remained at normal basal levels throughout postnatal development. Proliferation indices were not significantly altered in the embryonic neuroepithelium or within the postnatal subventricular zone. In another approach with the same nestin-Cre transgene, conditional deletion of ShcA in mice with a homozygous floxed shc1 locus also showed a similar microencephaly phenotype. Together, these data suggest a critical role for ShcA in neural progenitor survival signaling and in regulating brain size.

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CFC index for the diagnosis of cardiofaciocutaneous syndrome

Cited by 68 publications

References 35 publications

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

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

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

Neural-Specific Inactivation of ShcA Results in Increased Embryonic Neural Progenitor Apoptosis and Microencephaly

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