Clinical Diagnosis

Cardiofaciocutaneous (CFC) syndrome is one the RASopathies: a group of syndromes having overlapping clinical features resulting from a common pathogenetic mechanism [Tidyman & Rauen 2009a].

The diagnosis of cardiofaciocutaneous (CFC) syndrome is made by clinical findings. Currently, no diagnostic criteria have been established.

Individuals with CFC syndrome display phenotypic variability and therefore not all have every finding. Phenotypic features may include the following:

Cardiac. Pulmonic stenosis; atrial septal defects; ventricular septal defects; hypertrophic cardiomyopathy; heart valve anomalies (mitral valve dysplasia, tricuspid valve dysplasia, and bicuspid aortic valve); and rhythm disturbances. These defects may be identified at birth or diagnosed later. Hypertrophic cardiomyopathy may be progressive.

Craniofacial. High forehead, relative macrocephaly, bitemporal narrowing, hypoplasia of the supraorbital ridges, ocular hypertelorism, telecanthus, downslanting palpebral fissures, epicanthal folds, ptosis, short nose with depressed bridge and anteverted nares, ear lobe creases, low-set ears that may be posteriorly rotated, deep philtrum, cupid's bow lip, high-arched palate, relative micrognathia (Figure 1). The face is broader and longer, overall more coarse, than in Noonan syndrome (a clinically similar disorder often confused with CFC syndrome), but usually not as coarse as typically seen in Costello syndrome.

Figure

Figure 1. Children with CFC syndrome who have known BRAF or MAP2K1 or MAP2K2 mutations

A. Three young children with BRAF mutations: p.Thr470del, in exon 11 (left); p.Ser467Ala, in exon 11 (middle); and p.Gln257Arg, in exon 6 (right). (more...)

Ectodermal

• Skin. Xerosis; hyperkeratosis of arms, legs, and face; ichthyosis; keratosis pilaris; ulerythema ophryogenes; eczema; hemangiomas; café-au-lait macules; erythema; pigmented moles; palmoplantar hyperkeratosis over pressure zones
• Hair. Sparse, curly, fine or thick, woolly or brittle; sparse to absent, or normal eyelashes and eyebrows
• Nails. Dystrophic with flat broad nails; nails may be fast growing.

Musculoskeletal. Short neck, pterygium colli, pectus deformity, kyphosis, and/or scoliosis, pes planus.

Lymphatic. Lymphedema, chylothorax.

Ocular. Ocular hypertelorism, strabismus, nystagmus, astigmatism, myopia and/or hyperopia. Optic nerve hypoplasia, cortical blindness, and cataracts have been described. Although most individuals with CFC syndrome have ocular manifestations, some have a normal ophthalmologic examination.

Feeding/gastrointestinal. Severe feeding problems manifest as gastroesophageal reflux (GER), aspiration, vomiting, and oral aversion. Other GI problems include dysmotility, intestinal malrotation, hernia, and/or constipation. Some individuals have splenomegaly or hepatomegaly. Most children have failure to thrive. Fatty liver and anal stenosis have also been reported.

Growth delays. Feeding issues contribute to growth delay. Growth may be normal with appropriate birth weight and length; however, weight and length may drop to below the fifth centile during early infancy while head circumference remains within the normal range (resulting in relative macrocephaly).

Endocrine abnormalities. Some individuals have growth hormone deficiency. Some may have precocious puberty.

Neurologic. Some aspect of neurologic or neurocognitive findings are present in nearly all individuals. Cognitive delay typically ranges from mild to severe, although a few individuals with CFC syndrome have IQs in the normal range. The most common neurologic findings include hypotonia and developmental delay. Other abnormalities can include seizure disorders, abnormal EEG, corticospinal tract findings, hydrocephalus, cortical atrophy versus dilated perivascular spaces, ventriculomegaly, frontal lobe hypoplasia, agenesis of the corpus callosum, abnormal myelination, Chiari malformation, and pachygyria.

Malignancy. The risk for malignancies may be increased, although at the present time this is still unclear. Individuals with a mutation in one of the four genes associated with CFC syndrome have been reported with acute lymphoblastic leukemia (ALL); immunosuppression and hepatoblastoma; non-Hodgkin lymphoma; and large B-cell lymphoma.

Urogenital. Some affected individuals may have renal, uterine, and/or cervical anomalies.

Molecular Genetic Testing

Genes. The four genes currently known to be associated with CFC syndrome are in the Ras/mitogen-activated protein kinase (MAPK) signaling cascade (Figure 2):

Figure

Figure 2. The mitogen-activated protein kinase (MAPK) signaling cascade, also known as the Raf/MEK/ERK (extracellular signal-related kinase)

• BRAF [Niihori et al 2006, Rodriguez-Viciana et al 2006]
• MAP2K1 [Rodriguez-Viciana et al 2006]
• MAP2K2 [Rodriguez-Viciana et al 2006]
• KRAS. Because KRAS mutations were identified in individuals clinically diagnosed with CFC syndrome or with Noonan syndrome [Niihori et al 2006, Schubbert et al 2006], the role of its protein product GTPase KRas (KRAS) in CFC syndrome has yet to be clarified.

Clinical testing

• Sequence analysis
  • BRAF. BRAF mutations are the most common in CFC syndrome. Utilizing strict diagnostic criteria for the classic CFC syndrome phenotype, initial studies by Rodriguez-Viciana et al [2006] identified BRAF mutations in 18 of 23 (78%) affected individuals and Niihori et al [2006] identified BRAF mutations in 16 of 43 (37%). However, more recent studies have determined BRAF mutations in about 75% of mutation-positive individuals with CFC syndrome [Tidyman & Rauen 2009b].
    
    At present, about 40 novel BRAF mutations affecting 28 different codons have been indentified in individuals with CFC syndrome. The exon 6 mutation p.Gln257Arg is the most common and represents about 25% of all BRAF mutations. Other exons in which mutations have been reported include exons 11, 12, 14, 15, and 17. About 80% of the mutations in BRAF occur in exons 6, 11, and 12.
    Of note, reevaluation of individuals with the clinical diagnosis of Costello syndrome but without HRAS mutations revealed BRAF missense mutations in exons 13 and 16 and a phenotype consistent with CFC syndrome [Rauen 2006]. No mosaicism has been reported to date.
  • MAP2K1 (MEK1), MAP2K2 (MEK2). MEK mutations (including MAP2K1 and MAP2K2 collectively) have been reported in approximately 25% of individuals with the clinical diagnosis of CFC syndrome [Rodriguez-Viciana et al 2006, Tidyman & Rauen 2009b]. To date, all published MAP2K1 mutations have occurred in exon 2, 3, and 6; mutations that have been indentified in MAP2K2 have occurred in exons 2, 3, and 7. Most identified mutations have been de novo missense mutations with the exception of a four-generation family with autosomal dominant transmission of a MAP2K1 p.Pro128Gln mutation [Rauen et al 2010]. No mosaicism has been reported to date.
  • KRAS. KRAS mutations have been identified in a small percentage of individuals with Noonan syndrome and fewer than 5% of individuals with CFC syndrome [Carta et al 2006, Niihori et al 2006, Schubbert et al 2006, Zenker et al 2007]. Mutations reported in coding exons 1, 2, and 4b have been de novo missense substitutions, possibly implying that classic CFC syndrome is not caused by KRAS mutations. No mosaicism has been reported to date.
• Deletion/duplication analysis. Preliminary data suggest that large deletions are rare; thus, mutation detection frequency is unknown.

Interpretation of test results. If a mutation in BRAF, MAP2K1, MAP2K2, or KRAS is not identified in an individual who has phenotypic features consistent with the clinical diagnosis of CFC syndrome, reasons may include the following:

• Presence of a mutation in another gene associated with a similar but different phenotype, such as HRAS (Costello syndrome), PTPN11, SOS1, RAF1, NRAS, or SHOC2 (Noonan syndrome)
• Presence of a mutation in a gene affecting the Ras/MAPK pathway that has yet to be identified
• Presence of low-level tissue mosaicism, which to date has not been reported for CFC syndrome
• Testing-related issues. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Clinical evaluation should include detailed family history with a three-generation pedigree and detailed prenatal history.

Identification of mutations in BRAF, MAP2K1, MAP2K2, or KRAS by direct gene sequencing establishes the diagnosis.

Single gene testing. Based on current published information, sequencing can be approached stepwise:

1.

Direct sequencing of the seven BRAF exons in which causative mutations have been identified (exons 6, 11-17). If no causal mutation is identified:

2.

Direct sequencing of select exons of MAP2K1 (exons 2, 3, and 6) and MAP2K2 (exons 2, 3, and 7). If no causal mutation is identified:

3.

Consider sequencing the remaining BRAF exons and remaining MAP2K1 and MAP2K2 exons in which causal mutations have not yet been reported. If no causal mutation is identified in BRAF, MAP2K1, and MAP2K2:

4.

Direct sequencing of KRAS where additional causal mutations have been demonstrated in individuals with a phenotype that overlaps CFC syndrome. If no causal mutation is identified:

5.

Direct sequencing of HRAS (all exons). Individuals who have an HRAS mutation by definition have Costello syndrome.

6.

Consider array GH genome scanning for copy number variants. Rare deletions in MEK genes (i.e., MAP2K1 and MAP2K2) may cause phenotypic features that are reminiscent of CFC syndrome [Author, personal observation].

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having CFC syndrome is use of a multi-gene panel. The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest. See Differential Diagnosis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Natural History

Cardiofaciocutaneous (CFC) syndrome affects males and females equally.

Prenatally, polyhydramnios is present in the vast majority of cases. Maternal hyperemesis gravidarum may occur and subjective decrease in fetal movement may be observed. Newborns may be premature and large for gestational age, although the majority are appropriate for gestational age.

In the neonate, distinctive craniofacial features are present. Chylothorax and lymphedema have been reported at birth. Cardiac abnormalities, when present, typically present at birth, although hypertrophic cardiomyopathy and rhythm disturbances may present later in life. Feeding difficulties may be present.

In infancy, severe feeding difficulties are common, resulting in failure to thrive. Many children require nasogastric or gastrostomy feeding, while some undergo a Nissen fundoplication procedure for severe gastroesophageal reflux. Constipation is typically reported and continues to be an issue throughout childhood and adolescence.

All children have some form of neurologic abnormalities, neurocognitive delay, or learning issues. Overall, developmental delay typically ranges from moderate to profoundly severe. Rarely, developmental delays are mild, and a few individuals have IQs in the normal range. Children have speech delays and the vast majority have hypotonia, causing motor delays.

Childhood and adolescence. At present, no longitudinal or natural history studies have been done for CFC syndrome. However, CFC syndrome does have an evolving phenotype.

Later in childhood, feeding difficulties and hypotonia improve. Oral feedings are achieved usually in early childhood.

Growth failure affects most individuals with CFC syndrome. Although the vast majority of children are not tested, some have growth hormone deficiency.

Many children have recurrent otitis media and are found to have narrow external auditory canals.

Ocular abnormalities including strabismus, nystagmus, optic nerve hypoplasia, astigmatism, myopia, and/or hyperopia are present in most individuals and may result in decreased vision and acuity.

Nearly 50% of individuals with CFC and a mutation in one of its associated genes have a seizure disorder. Most seizures begin in infancy or early childhood [Yoon et al 2007]; however, a seizure disorder may develop later in childhood as well.

With age, the dryness of the skin and the follicular hyperkeratosis tend to improve, allowing the hair to grow on the face and scalp [Roberts et al 2006]; however, palmoplantar hyperkeratosis and lymphedema may become more severe. Nevi, when present, increase in number over time [Siegel et al 2011]. Individuals with CFC syndrome have been known to develop severe skin infections.

Neurodevelopmental delay may be less obvious in mildly or moderately affected children, but speech delays and difficulty walking become apparent in those who are more severely affected.

The craniofacial appearance becomes less like that seen in Noonan syndrome.

Some young adults participate in assisted living programs.

Neoplasias, such as benign papillomas or malignancies observed in the other RASopathies including Costello syndrome, Noonan syndrome, or neurofibromatosis type 1, have not been reported in CFC syndrome. However, acute lymphoblastic leukemia (ALL) has now been reported in a few individuals [Niihori et al 2006, Makita et al 2007, Rauen et al 2010], hepatoblastoma in an immunocompromised individual [Al-Rahawan et al 2007], non-Hodgkin lymphoma [Ohtake et al 2011], and large B-cell lymphoma [Rauen et al 2010].

Genotype-Phenotype Correlations

Further evaluation of more individuals with CFC syndrome is necessary to clarify genotype-phenotype correlations, thereby permitting more accurate prognoses.

Preliminary correlations include the following:

• Individuals with the BRAF p.Gln257Arg mutation, the most common CFC causing mutation, have many phenotypic features in common, including characteristic facies, cardiac defects, short stature, failure to thrive, abnormal brain imaging, musculoskeletal and ocular abnormalities, and relatively mild developmental delay [Niihori et al 2006, Rodriguez-Viciana et al 2006].
• The two individuals reported with the kinase-impaired BRAF p.Gly596Val mutation have a milder phenotype as indicated by normal growth and development, and no cardiac, GI, or brain abnormalities [Rodriguez-Viciana et al 2006].
• Individuals with a MAP2K1 or MAP2K2 mutation are more likely to have keratosis pilaris and progressive nevi formation than those with a BRAF mutation [Siegel et al 2011].

Penetrance

Penetrance is complete in CFC syndrome.

Nomenclature

Blumberg et al [1979] at the March of Dimes Birth Defects Conference reported three individuals with intellectual disability who also had characteristic craniofacial dysmorphology, ectodermal anomalies, and cardiac defects. These three persons, along with five others, were subsequently reported by Reynolds et al [1986], who designated this new disorder cardiofaciocutaneous syndrome. Also Baraitser & Patton [1986] reported on a Noonan syndrome-like short stature syndrome with ectodermal anomalies that was presumed to be the same entity.

Prevalence

More than 100 individuals with CFC syndrome have been reported in the literature. The total number of individuals worldwide with CFC syndrome is estimated to be 200 to 300, yet this may be an underestimation because of underdiagnosis of mildly affected individuals.

Evaluations Following Initial Diagnosis

The following evaluations are recommended in an individual known to have or suspected to have cardiofaciocutaneous (CFC) syndrome:

• Genetics consultation
• Complete physical examination including measurement growth parameters
• Cardiac evaluation including echocardiogram and electrocardiogram
• Neurologic evaluation
• MRI of the brain to detect any structural changes
• Electroencephalogram if seizures are suspected
• Full abdominal ultrasound examination to evaluate for renal and urogenital anomalies
• Psychomotor developmental evaluation
• Endocrine evaluation if growth delay is suspected
• Ophthalmologic examination
• Audiologic examination
• Nutrition and feeding evaluation, consider swallow study
• Dermatologic evaluation

Treatment of Manifestations

CFC syndrome affects many organ systems and, therefore, the vast majority of individuals require ongoing care by a multidisciplinary team of healthcare providers. At present, phenotypic features caused by germline mutations in BRAF, MAP2K1, MAP2K2, or KRAS are treated as in the general population.

Cardiovascular management is dictated by the abnormality, with treatment similar to that in the general population: structural defects are managed surgically as needed; hypertrophic cardiomyopathy is followed by serial echocardiograms, and cardiac arrhythmias are medically managed in an aggressive manner.

Severe feeding issues during the first years of life require management by a pediatric gastroenterologist. Many children with CFC syndrome require nasogastric or gastrostomy tube feeding because of failure to thrive. Increasing caloric intake may be of benefit. Children with severe gastroesophageal reflux may require a Nissen fundoplication. Constipation affects the majority of individuals; increased fiber in the diet, under the direction of a pediatrician, may be beneficial.

Seizures are treated as in the general population. However, seizures may be refractory to single agent therapy and may require polytherapy.

Some individuals are growth hormone deficient and may benefit from management by an endocrinologist. Hypertrophic cardiomyopathy is considered by some to be a contraindication to growth hormone therapy.

Ocular abnormalities such as myopia or hyperopia are corrected with lenses as in the general population.

Musculoskeletal abnormalities, such as scoliosis or pectus deformity, are managed as in the general population.

Xerosis and pruritus may be relieved by increasing the ambient humidity or using hydrating lotions. Hyperkeratoses are treated as in the general population.

Signs and symptoms of skin infection, especially in the presence of lymphedema, warrant thorough and immediate evaluation by a physician for the consideration of antibiotic treatment.

Recurrent otitis media may require placement of PE tubes.

Enrollment in early-intervention therapies to promote motor and intellectual development (e.g., occupational therapy, physical therapy, or speech therapy) is highly recommended.

Note: Specialized NF/Ras pathway genetics clinics are available in the US and United Kingdom.

Prevention of Secondary Complications

Cardiac. Certain congenital heart defects (notably valve dysplasias) require antibiotic prophylaxis for subacute bacterial endocarditis (SBE).

Anesthesia. Individuals with CFC syndrome may have an unrecognized hypertrophic cardiomyopathy, tracheomalacia, or a predisposition to cardiac rhythm disturbances.

Surveillance

If anomalies are identified in any organ system, lifelong periodic follow-up is warranted. At present, no guidelines for surveillance in CFC syndrome have been established. However, based on phenotypic findings and anecdotal observations, the following may apply:

• Audiologic. Annual evaluation of hearing is recommended.
• Cardiac. If the initial cardiac evaluation is normal, periodic follow-up evaluations including an echocardiogram and an electrocardiogram are necessary as hypertrophic cardiomyopathy and rhythm disturbances may develop later in life.
• Neurologic. Monitor neurologic signs and symptoms with period neurologic evaluations and MRI if indicated. Chiari malformation and later onset of seizures have been observed [Rauen, unpublished observation].
• Gastrointestinal. Monitor for signs and symptoms of gastrointestinal reflux.
• Ophthalmologic. Periodic evaluation by an ophthalmologist to monitor for ocular issues (such as myopia, hyperopia, cataracts) is recommended.
• Musculoskeletal. Periodic evaluation for scoliosis during young childhood is recommended.
• Endocrine. Monitor growth parameters to identify evidence of growth failure that may be associated with growth hormone deficiency. Monitor for signs of precocious puberty.
• Dermatologic. As affected individuals age, formation of nevi may be progressive. At present, the natural history of the nevi is unknown. Periodic and routine dermatologic evaluation of nevi may be warranted to monitor for malignant change, though no individuals with CFC syndrome have been reported to have a malignant change.
• Malignancy. At present there is no screening protocol as it is unclear if individuals with CFC syndrome are at an increased risk for malignancies.

Agents/Circumstances to Avoid

Over-exposure to heat. Individuals with CFC syndrome report heat intolerance.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Because the Ras/MAPK pathway has been studied intensively in the context of cancer, numerous therapeutics that specifically target this pathway are in development.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Cardiofaciocutaneous (CFC) syndrome is transmitted in an autosomal dominant manner [Rauen et al 2010]. However, in most cases, it is the result of a de novo dominant mutation.

Risk to Family Members

Parents of a proband

• The vast majority of individuals with CFC syndrome have the disorder as the result of a de novo mutation.
• The parents of a proband with a de novo mutation are not affected.

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the proband's parents.
• Because the vast majority of CFC syndrome occurs as a de novo mutation, the risk to the sibs of a proband is small.
• Currently, no instance of germline mosaicism has been reported, although it remains a possibility. Thus, the risk to sibs of a proband may be on the order of one in 500, as in other disorders cause by de novo dominant mutations.

Offspring of a proband. Each child of an individual with CFC syndrome has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

The importance of determining the genetic etiology using molecular genetic testing. Noonan syndrome and CFC syndrome have phenotypic overlap; thus, determining the genetic etiology by molecular testing is important to establish the correct diagnosis in the proband as Noonan syndrome may be familial and thus inherited in an autosomal dominant manner.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk because of the possibility of germline mosaicism or for couples needing reassurance is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Molecular Genetic Pathogenesis

The MAPK signaling cascade of dual-specificity kinases (Figure 2) is highly conserved among eukaryotic organisms and is critically involved in cell proliferation, differentiation, motility, apoptosis, and senescence. The Ras/Raf/MEK/ERK signal transduction pathway is activated by extracellular stimuli. Activated Ras recruits Raf, the first kinase of the cascade, to the cell membrane. Activated Raf phosphorylates MEK1 (encoded by MAP2K1) and/or MEK2 (encoded by MAP2K2), which then phosphorylates ERK1 and/or ERK2 (aka MAPK). Noonan syndrome has been associated with mutations in PTPN11 (protein product Shp2), SOS1, RAF1, NRAS, SHOC2, and KRAS. The gene in which mutations are causative for Costello syndrome is HRAS. Cardiofaciocutaneous (CFC) syndrome is associated with mutations in BRAF, MAP2K1, and MAP2K2.

Literature Cited

1. Al-Rahawan MM, Chute DJ, Sol-Church K, Gripp KW, Stabley DL, McDaniel NL, Wilson WG, Waldron PE. Hepatoblastoma and heart transplantation in a patient with cardio-facio-cutaneous syndrome. Am J Med Genet A. 2007;143A:1481–8. [PubMed: 17567882]
2. Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37:1038–40. [PubMed: 16170316]
3. Baraitser M, Patton MA. A Noonan-like short stature syndrome with sparse hair. J Med Genet. 1986;23:161–4. [PMC free article: PMC1049573] [PubMed: 3712393]
4. Blumberg B, Shapiro L, Punnett HH, Rimoin D, Kirtenmacher M (1979) A new mental retardation syndrome with characterisitc facies, ichthyosis and abnormal hair. Paper presented at March of Dimes Birth Defects Conference. Chicago, Il.
5. Carta C, Pantaleoni F, Bocchinfuso G, Stella L, Vasta I, Sarkozy A, Digilio C, Palleschi A, Pizzuti A, Grammatico P, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. 2006;79:129–35. [PMC free article: PMC1474118] [PubMed: 16773572]
6. Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. Clin Genet. 2011;79:468–74. [PubMed: 20735442]
7. Cordeddu V, Di Schiavi E, Pennacchio LA, Ma’ayan A, Sarkozy A, Fodale V, Cecchetti S, Cardinale A, Martin J, Schackwitz W, Lipzen A, Zampino G, Mazzanti L, Digilio MC, Martinelli S, Flex E, Lepri F, Bartholdi D, Kutsche K, Ferrero GB, Anichini C, Selicorni A, Rossi C, Tenconi R, Zenker M, Merlo D, Dallapiccola B, Iyengar R, Bazzicalupo P, Gelb BD, Tartaglia M. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41:1022–6. [PMC free article: PMC2765465] [PubMed: 19684605]
8. Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, Roberts AE, Lepri F, Merbitz-Zahradnik T, König R, Kratz CP, Pantaleoni F, Dentici ML, Joshi VA, Kucherlapati RS, Mazzanti L, Mundlos S, Patton MA, Silengo MC, Rossi C, Zampino G, Digilio C, Stuppia L, Seemanova E, Pennacchio LA, Gelb BD, Dallapiccola B, Wittinghofer A, Ahmadian MR, Tartaglia M, Zenker M. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42:27–9. [PMC free article: PMC3118669] [PubMed: 19966803]
9. Estep AL, Palmer C, McCormick F, Rauen KA. Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PLoS One. 2007;2:e1279. [PMC free article: PMC2093994] [PubMed: 18060073]
10. Makita Y, Narumi Y, Yoshida M, Niihori T, Kure S, Fujieda K, Matsubara Y, Aoki Y. Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. J Pediatr Hematol Oncol. 2007;29:287–90. [PubMed: 17483702]
11. Marks JL, Gong Y, Chitale D, Golas B, McLellan MD, Kasai Y, Ding L, Mardis ER, Wilson RK, Solit D, Levine R, Michel K, Thomas RK, Rusch VW, Ladanyi M, Pao W. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res. 2008;68:5524–8. [PMC free article: PMC2586155] [PubMed: 18632602]
12. Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006;38:294–6. [PubMed: 16474404]
13. Ohtake A, Aoki Y, Saito Y, Niihori T, Shibuya A, Kure S, Matsubara Y. Non-Hodgkin lymphoma in a patient with cardiofaciocutaneous syndrome. J Pediatr Hematol Oncol. 2011;33:e342–6. [PubMed: 20523244]
14. Rauen KA. Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. Am J Med Genet A. 2006;140:1681–3. [PubMed: 16804887]
15. Rauen KA, Tidyman WE, Estep AL, Sampath S, Peltier HM, Bale SJ, Lacassie Y. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. Am J Med Genet A. 2010;152A:807–14. [PubMed: 20358587]
16. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz JM. New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome. Am J Med Genet. 1986;25:413–27. [PubMed: 3789005]
17. Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, Young T, Neri G. The cardiofaciocutaneous syndrome. J Med Genet. 2006;43:833–42. [PMC free article: PMC2563180] [PubMed: 16825433]
18. Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F, Rauen KA. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006;311:1287–90. [PubMed: 16439621]
19. Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38:331–6. [PubMed: 16474405]
20. Siegel DH, McKenzie J, Freiden I, Rauen KA. Dermatological findings in 61 mutation-positive individuals with cardio-facio-cutaneous syndrome. Br J Dermatol. 2011;164:521–9. [PubMed: 21062266]
21. Sol-Church K, Stabley DL, Demmer LA, Agbulos A, Lin AE, Smoot L, Nicholson L, Gripp KW. Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism. Am J Med Genet A. 2009;149A:315–21. [PMC free article: PMC2653086] [PubMed: 19206176]
22. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29:465–8. [PubMed: 11704759]
23. Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, Gelb BD. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39:75–9. [PubMed: 17143282]
24. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009a;19:230–6. [PMC free article: PMC2743116] [PubMed: 19467855]
25. Tidyman WE, Rauen KA. Molecular causes of cardio-facio-cutaneous syndrome. In: Zenker M, eds. Monographs in Human Genetics: Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling. Vol 17. Basel, Switzerland: Karger; 2009b:73-82.
26. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5:875–85. [PubMed: 15520807]
27. Yoon G, Rosenberg J, Blaser S, Rauen KA. Neurological complications of cardio-facio-cutaneous syndrome. Dev Med Child Neurol. 2007;49:894–9. [PubMed: 18039235]
28. Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S, Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP, Horn D, Kutsche K. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007;44:131–5. [PMC free article: PMC2598066] [PubMed: 17056636]

Suggested Reading

1. Hancock JF. Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol. 2003;4:373–84. [PubMed: 12728271]
2. Tidyman WE, Rauen KA. Clinical and molecular overview of Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome: Dysregulation of the Ras/MAPK pathway. Expert Rev Mol Med. 2008;10:e37. [PubMed: 19063751]
3. van Den Berg H, Hennekam RC. Acute lymphoblastic leukaemia in a patient with cardiofaciocutaneous syndrome. J Med Genet. 1999;36:799–800. [PMC free article: PMC1734231] [PubMed: 10528867]

Author Notes

Dr. Rauen serves on the Medical Advisory Board for CFC International, Inc and is co-director and member of the Professional Advisory Board for The Costello Syndrome Family Network.

Dr Rauen is the Director of the UCSF NF/Ras Pathway Genetics Clinic (www.ucsfhealth.org/clinics/nf_ras_pathway).

Acknowledgments

Special thanks to Brenda Conger, President, and Molly Santa Cruz, Vice President, of CFC International and all the families of CFC International and the Costello syndrome Family Network for their ongoing support of research in genetic medicine. This work was supported in part by NIH grant HD048502.

Revision History

• 6 September 2012 (cd) Revision: multi-gene panels for Noonan / Costello / LEOPARD / cardiofaciocutaneous syndrome(s) (RAS/MAPK pathway) available clinically
• 23 December 2010 (me) Comprehensive update posted live
• 18 January 2007 (me) Review posted to live Web site
• 14 September 2006 (kar) Original submission