The Noonan‐CFC controversy

Neri, Giovanni; Zollino, Marcella; Reynolds, James F.

doi:10.1002/ajmg.1320390323

Cited by 59 publications

(37 citation statements)

References 18 publications

(10 reference statements)

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“…16 Because of the overlapping clinical features there is an ongoing discussion whether CFC syndrome and NS are allelic, or whether CFC is a contiguous gene syndrome. 17,18 Although two patients with CFC were reported to have an interstitial deletion of 12q21-22, 19,20 no deletions could be found in a further seven CFC patients investigated by Zollino et al, 21 using the same probe employed by Rauen et al 19 Familial occurrence has been reported in two families. 22,23 In a family with both CFC and NS, Schollen et al 24 most recently identified a mutation in the PTPN11 gene.…”

Section: Noonan-ptpn11 L Musante Et Al 204mentioning

confidence: 95%

Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

et al. 2003

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Noonan syndrome (NS) is a relatively common, but genetically heterogeneous autosomal dominant malformation syndrome. Characteristic features are proportionate short stature, dysmorphic face, and congenital heart defects. Only recently, a gene involved in NS could be identified. It encodes the nonreceptor protein tyrosine phosphatase SHP-2, which is an important molecule in several intracellular signal transduction pathways that control diverse developmental processes, most importantly cardiac semilunar valvulogenesis. We have screened this gene for mutations in 96 familial and sporadic, wellcharacterised NS patients and identified 15 different missense mutations in a total of 32 patients (33%), including 23 index patients. Most changes clustered in one exon which encodes parts of the N-SH2 domain. Five of the mutations were recurrent. Interestingly, no mutations in the PTPN11 gene were detected in five additional patients with cardio-facio-cutaneous (CFC) syndrome, which shows clinical similarities to NS.

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Section: Noonan-ptpn11 L Musante Et Al 204mentioning

confidence: 95%

Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

et al. 2003

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“…5 In 2001, PTPN11 was found to be one of the causal genes of NS, and it was possible to demonstrate that well-characterized individuals with CFC did not have a mutation in PTPN11. [6][7][8] Furthermore, individuals with CFC did not carry mutations in the HRAS gene, which causes CS, another phenotypically similar condition.…”

Section: Neurologicmentioning

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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“…CFCS has a considerable clinical overlap with NS, and 'borderline' cases are commonly observed, which justified the long debated question of whether it was a separate nosologic entity or an extreme phenotype/ variant of NS [Fryer et al, 1991;Neri et al, 1991;Wieczorek et al, 1997].…”

Section: Cardiofaciocutaneous Syndromementioning

confidence: 99%

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

2010

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Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

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The Noonan‐CFC controversy

Cited by 59 publications

References 18 publications

Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

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

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

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