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

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.CFC International, Vestal, New YorkNational Institutes of HealthNational Institutes of Health (NIH)Univ Minnesota, Dept Pediat & Ophthalmol, Div Genet & Metab, Minneapolis, MN 55454 USAUniv Minnesota, Dept Pediat, Div Clin Behav Neuroscience, Minneapolis, MN 55454 USAChildrens Hosp & Clin Minnesota, St Paul, MN USATexas Childrens Hosp, Dept Mol & Human Genet, Houston, TX 77030 USABaylor Coll Med, Houston, TX 77030 USABenioff Childrens Hosp, Madison Clin Pediat Diabet, San Francisco, CA USAUniv Calif San Francisco, San Francisco, CA 94143 USAUniversidade Federal de São Paulo, Med Genet Ctr, São Paulo, BrazilCatholic Univ, A Gemelli Sch Med, Inst Med Genet, Rome, ItalyUniv Kentucky, Dept Pediat, Lexington, KY USAUniv Texas Hlth Sci Ctr San Antonio, Dept Orthoped, San Antonio, TX 78229 USABoston Childrens Hosp, Dept Cardiol, Boston, MA USABoston Childrens Hosp, Div Genet, Boston, MA USAHarvard Univ, Sch Med, Boston, MA USAEmory Univ, Sch Med, Dept Human Genet, Atlanta, GA USAEmory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USAUniv Calif San Francisco, Dept Neurol, San Francisco, CA USAYoungstown State Univ, Special Educ & Sch Psychol, Dept Counseling, Youngstown, OH 44555 USACFC Int, Vestal, NY USAUniv Calif Davis, UC Davis MIND Inst, Dept Pediat, Div Genom Med, Sacramento, CA 95817 USAUniversidade Federal de São Paulo, Med Genet Ctr, São Paulo, BrazilNational Institutes of Health: R01-AR062165Web of Scienc

My Memories of Professor Giovanni Neri: the Cardiofaciocutaneous Syndrome (CFC)

Universidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Cytogenetic and molecular studies on cardiofaciocutaneous syndrome

Objetivos: Verificar se pacientes com a sindrome Cardiofaciocutanea (CFC) apresentam microdelecoes na regiao cromossomica 12q21.2q22, se os mesmos apresentam mutacoes de sentido trocado ou delecoes intragenicas no gene PTPN11, e a presenca de rearranjos telomericos. Metodos: Foram utilizadas 12 sondas BAC, cobrindo o intervalo 12q21.2q22, para analise dessa regiap por FISH, em 17 pacientes. Para o estudo do gene PTPN11, sequenciamos toda a regiao codificante do mesmo, alem das regioes de transicao intron/exon, em 10 pacientes. Amplificamos por PCR porcoes parcialmente sobreponiveis do cDNA dos mesmos pacientes para detectar possiveis delecoes intragenicas. Utilizamos sondas subtelomericas para buscar rearranjos ou perdas cromossomicas em todos os cromossomos, em uma amostra de 10 pacientes. Resultados: Nao foram encontradas microdelecoes na regiao 12q21.2q22 nos pacientes com a sindrome CFC. Pacientes com a sindrome CFC nao apresentam mutacoes de sentido trocado no gene PTPN11, nem micro ou macro delecoes do mesmo na sua porcao codificante. Pacientes com a sindrome CFC nao apresentam rearranjos ou perdas nas regioes subtelomericas. Conclusoes: A regiao cromossomica 12q21.2q22 nao e regiao candidata para o gene da sindrome CFC. Fica molecularmente demostrado que a sindrome CFC e sindrome de Noonan sao entidades com etiologias geneticas distintas. Finalmente, a sindrome CFC nao e caracterizada por rearranjos ou perdas subteiomericasBV UNIFESP: Teses e dissertaçõe

Cardiofaciocutaneous syndrome: phenotype aspects

Descrevemos seis pacientes (5 masculinos: 1 feminina), com idades que variam de 5 a 24 anos, acompanhados no Centro de Genetica Medica da UNIFESP - EPM, com diagnostico da Sindrome Cardiofaciocutanea (CFC), que e caracterizada por baixa estatura, face tipica (macrocefalia relativa, ptose palpebral, fendas palpebrais com orientacao antimongoloide, pregas eoicanticas, orelhas com rotacao posterior e implantacao baixa, nariz curto, com narinas antevertidas e raiz deprimida, fronte alta, hipoplasia supaorbital e constricao bitemporal), defeito cardiaco congenito, retardo mental e anormalidades ectodermicas. Esses pacientes apresentavam a maioria das caracteristicas referidas na literatura como marcadores fenotipicos da sindrome, mas assim como nos pacientes relatados na literatura, nem todos apresentavam defeito cardiaco congenito, e/ou lesoes hiperqueratosicas na pele, caracteristicas algumas vezes consideradas fundamentais para o estabelecimento do diagnostico. A ausencia de consenso sobre quais seriam os criterios para o diagnostico da CFC e para sua separacao da Sindrome de Noonan (SN), principal diagnostico diferencial, motivou a criacao de um metodo objetivo para o estabelecimento desse diagnostico. Para tanto, foram revisados 54 pacientes referidos na literatura com o diagnostico da CFC, nos quais 82 caracteristicas da sindrome foram identificadas. A comprovacao matematica da independencia entre as caracteristicas permitiu que se criasse um unico indice (Indice CFC) indicando a intensidade da presenca da sindrome em cada um dos pacientes. Os Indices obtidos dos 54 pacientes referidos na literatura apresentam uma distribuicao com padrao de curva normal, de acordo com o teste de normalidade de Bowman-Shelton. Assim, as propriedades da distribuicao normal podem ser usadas para a interpretacao do significado do indice. Dessa forma demonstramos que os pacientes da amostra brasileira tem alta probabilidade de fazer parte da populacao da CFC, e que um paciente hipotetico com a SN, que tivesse o maior numero de caracteristicas da CFC ja descritas nesses pacientes, teria uma probabilidade muito baixa (entre 1 e 5(por cento)) de fazer parte da populacao da CFC. Com relacao a etiologia da sindrome, acrescentamos evidencias que a media das idades paternas e significativamenmte maior que na populacao geral, e que nao apresenta diferenca estatisticamente significativa quando comparada a media das idades paternas de...(au)BV UNIFESP: Teses e dissertaçõe

CFC syndrome

Univ Cattolica Sacro Cuore, Ist Genet Med, I-00168 Rome, ItalyUniversidade Federal de São Paulo, Ctr Med Genet, Escola Paulista Med, São Paulo, BrazilUniv Utah, Salt Lake City, UT USAUniversidade Federal de São Paulo, Ctr Med Genet, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

The cardiofaciocutaneous syndrome

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward- slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. the cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. the developmental delay usually is moderate to severe. the syndrome is caused by gain-offunction mutations in four different genes BRAF, KRAS, mitogen- activated protein/ extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS extracellular signal- regulated kinase ( ERK) pathway that regulates cell differentiation, proliferation and apoptosis. the CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP- 2 gene ( PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. the protein products of these genes also belong to the RAS - ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.Univ Sacred Heart, Inst Med Genet, Fac Med, I-00168 Rome, ItalyDuke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27705 USADuke Univ, Med Ctr, Dept Pediat, Durham, NC 27705 USAUniv Utah, Sch Med, Dept Pediat, Salt Lake City, UT USAUniv Kentucky, Dept Pediat, Lexington, KY USAUniversidade Federal de São Paulo, São Paulo, BrazilUniv Penn, Sch Med, Philadelphia, PA 19104 USAUniv Ottawa, Ottawa, ON, CanadaChildrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, CanadaHarvard Univ, Sch Med, Partners Healthcare Syst, Ctr Genet & Genom, Boston, MA 02115 USAUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome

Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. in 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.Tohoku Univ, Sch Med, Dept Med Genet, Sendai, Miyagi, JapanCatholic Univ, Ist Genet Med, Rome, ItalyHop Robert Debre, APHP, Dept Genet, Paris, FranceOsaka Med Ctr, Dept Planning & Res, Osaka, JapanRes Inst Maternal & Child Hlth, Osaka, JapanInst Child Hlth, Clin & Mol Genet Unit, London, EnglandAcad Med Ctr, Dept Pediat, Amsterdam, NetherlandsUniv Essen Gesamthsch, Inst Human Genet, Essen, GermanyUNIFESP, Ctr Med Genet, São Paulo, BrazilKanagawa Childrens Med Ctr, Div Med Genet, Yokohama, Kanagawa, JapanSaitama Childrens Med Ctr, Div Med Genet, Saitama, JapanGreat Ormond St Hosp Sick Children, London, EnglandPitie Salpetriere Univ Hosp, Dept Genet, Paris, FranceUniv Hosp, Dept Genet, Angers, FranceAzienda Osped Univ G Martino, Dipartimento Sci Pediat Med & Chirurg, Unita Operat Complessa Patol Neonatale & Terapia, Messina, ItalyUniv Ryukyus, Sch Med, Dept Med Genet, Okinawa, JapanYokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Kanagawa, JapanTohoku Univ, Comprehens Res & Educ Ctr Planning Drug Dev & Cli, Cent COE Program 21, Sendai, Miyagi, JapanUNIFESP, Ctr Med Genet, São Paulo, BrazilWeb of Scienc

Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype–phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects