Clinical characteristics.

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.

Diagnosis/testing.

Diagnosis is based on clinical findings and molecular genetic testing. The four genes known to be associated with CFC syndrome are: BRAF (~75%), MAP2K1 and MAP2K2 (~25%), and KRAS (<2%).

Management.

Treatment of manifestations: Care by a multidisciplinary team; management of cardiac structural defects, hypertrophic cardiomyopathy, and arrhythmias as in the general population; increased ambient humidity or hydrating lotions for xerosis and pruritus; increased caloric intake and a nasogastric tube or gastrostomy for severe feeding problems; surgical intervention for severe gastroesophageal reflux; routine management of growth hormone deficiency, ocular abnormalities; management of seizures may require polytherapy; occupational therapy, physical therapy, and speech therapy as needed. Consensus medical management guidelines have been published.

Prevention of secondary complications: Antibiotic prophylaxis for subacute bacterial endocarditis primarily for those with valve dysplasias; evaluation for hypertrophic cardiomyopathy or a predisposition to cardiac rhythm disturbances prior to anesthesia.

Surveillance: Periodic echocardiogram (hypertrophic cardiomyopathy), electrocardiogram (rhythm disturbances), neurologic and eye examination, scoliosis check, and assessment of growth and cognitive development.

Genetic counseling.

Cardiofaciocutaneous (CFC) syndrome is inherited in an autosomal dominant manner. Most affected individuals have CFC as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting a CFC-related pathogenic variant. Prenatal testing for pregnancies at risk is possible if the BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant has been identified in an affected family member.

Suggestive Findings

Cardiofaciocutaneous (CFC) syndrome should be suspected in individuals with the following phenotypic features involving the heart, face, and ectodermal structures:

• 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 configuration of the upper 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.
• 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.

Figure 1.

Children with CFC syndrome who have known pathogenic variants in BRAF or MAP2K2 A. Three young children with BRAF pathogenic variants: p.Thr470del, in exon 11 (left); p.Ser467Ala, in exon 11 (middle); and p.Gln257Arg, in exon 6 (right). Ages are 2.5, (more...)

Additional features variably present

• 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. Growth hormone deficiency in some individuals. Some may have precocious puberty.
• Neurologic. Some aspect of neurologic or neurocognitive findings 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.
• Urogenital. Renal, uterine, and/or cervical anomalies in some individuals

Note: Individuals with CFC syndrome display phenotypic variability and therefore not all have every finding.

Establishing the Diagnosis

The diagnosis of CFC syndrome is established in a proband by the identification of a heterozygous pathogenic variant in BRAF, MAP2K1, MAP2K2, or KRAS by molecular genetic testing (see Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Consensus guidelines have been developed for a genetic testing strategy for CFC syndrome [Pierpont et al 2014]

Based on current published information, sequencing can be approached stepwise:

1.

A multigene panel for RASopathies / Noonan spectrum disorders that includes BRAF, MAP2K1, MAP2K2, and KRAS and other genes of interest (see Differential Diagnosis) is usually the preferred initial test.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

2.

If multigene panel testing is not available, serial single-gene testing is recommended, beginning with BRAF, MAP2K1, and MAP2K2, and KRAS; if no pathogenic variants are found follow with sequencing of HRAS (all exons) even though the patient appears to have a clinical diagnosis of CFC syndrome. Individuals who have an HRAS pathogenic variant by definition have Costello syndrome.

3.

If no pathogenic variant is identified in these genes using sequencing analysis, gene-targeted deletion/duplicaton analysis or array CGH can be considered. Rare deletions in MEK genes (i.e., MAP2K1 and MAP2K2) may cause phenotypic features that are reminiscent of CFC syndrome [Nowaczyk et al 2014].

More comprehensive genomic testing (when available) including exome sequencing or genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes BRAF, MAP2K1, MAP2K2, and KRAS) fails to confirm a diagnosis in an individual with features of CFC syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

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 mild to profoundly severe. 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.

• Feeding issues. 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 may not be tested, some have growth hormone deficiency.
• 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. Some young adults participate in assisted living programs.
• Seizures. Nearly 50% of individuals with CFC and a pathogenic variant 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.
• Otolaryngologic problems. 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.
• Cardiac issues abnormalities occur in approximately 75%-80% of indiividuals and include hypertrophic cardiomyopathy, structural anomalies, and (more rarely) rhythm disturbances.
• Renal/ urogenital anomalies. Anomalies can occur in up to 33% of individuals, with cryptorchidism in males being the most common. Renal cysts and stones as well as hydronephrosis and hydroureter can also occur.
• Bleeding diathesis. von Willebrand disorder has been reported.
• Dermatologic. 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.
• Musculoskeletal. The vast majority of individuals have musculoskeletal findings including hypotonia with a paucity of muscle mass and lax joints. Orthopedic issues include pectus deformity, scoliosis, kyphosis, and/or gait disturbances.
• Appearance. By late adolescence to early adulthood, the craniofacial appearance becomes less like that seen in Noonan syndrome.
• Neoplasias (e.g., 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.

Ongoing correlations include the following:

• Pulmonic stenosis is present in 50% of CFC individuals with a BRAF pathogenic variant as opposed to 37% with a MEK pathogenic variant [Allanson et al 2011].
• Individuals with the BRAF p.Gln257Arg pathogenic variant, the most common CFC pathogenic variant, 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].
• Individuals with a MAP2K1 or MAP2K2 pathogenic variant are more likely to have keratosis pilaris and progressive nevi formation than those with a BRAF pathogenic variant [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 several hundred, yet this may be an underestimation because of underdiagnosis of mildly affected individuals. Overall prevalence is not known; prevalence in Japan is estimated at one in 810,000 [Abe et al 2012].

BRAF

Noonan syndrome with multiple lentigines (NSML). BRAF pathogenic variants have been reported in a few individuals who were given a clinical diagnosis of NSML (previously referred to as LEOPARD syndrome).

Noonan syndrome. BRAF pathogenic variants have been reported in a few individuals who were given a clinical diagnosis of Noonan syndrome.

Note: While individuals with a clinical diagnosis of either NSML or Noonan syndrome have been reported in the medical literature to be associated with pathogenic variants in BRAF [Sarkozy et al 2009], the author feels strongly that a pathogenic variant in BRAF molecularly defines CFC syndrome.

KRAS

Noonan syndrome. KRAS pathogenic variants have been identified in fewer than 5% of individuals with the clinical diagnosis of Noonan syndrome [Carta et al 2006, Schubbert et al 2006, Zenker et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with or suspected to have cardiofaciocutaneous (CFC) syndrome, the following evaluations are recommended. Evaluations are based on published consensus guidelines for workup at initial diagnosis or as ongoing medical management throughout an individual's life span [Pierpont et al 2014]

• Consultation with a clinical geneticist and/or genetic counselor
• Complete physical examination including measurement of growth parameters
• Nutrition and feeding evaluation; consideration of swallow study
• Endocrine evaluation
• Psychomotor developmental evaluation
• Neurologic evaluation
• MRI of the brain to detect any structural changes
• Electroencephalogram if seizures are suspected
• Audiologic examination
• Ophthalmologic examination
• Cardiac evaluation including echocardiogram and electrocardiogram
• Full abdominal ultrasound examination to evaluate for renal and urogenital anomalies
• Obtain history for possible bleeding diathesis
• Dermatologic evaluation

Treatment of Manifestations

Consensus guidelines for workup at initial diagnosis or as ongoing medical management throughout an individual's life span have been published [Pierpont et al 2014].

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 pathogenic variants in BRAF, MAP2K1, MAP2K2, or KRAS are treated as in the general population.

• 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.
• Some individuals are growth hormone- and or thyroid hormone-deficient and may benefit from management by an endocrinologist. Individuals with a diagnosis of hypertrophic cardiomyopathy must be monitored closely while on growth hormone therapy.
• Enrollment in early-intervention therapies to promote motor and intellectual development (e.g., occupational therapy, physical therapy, or speech therapy) is highly recommended.
• Seizures are treated as in the general population. However, seizures may be refractory to single-agent therapy and may require polytherapy.
• Recurrent otitis media may require placement of PE tubes.
• Ocular abnormalities such as myopia or hyperopia are corrected with lenses 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.
• 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.
• Musculoskeletal abnormalities, such as scoliosis or pectus deformity, are managed as in the general population.

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 and should be evaluated for these issues prior to anesthetic administration.

Surveillance

If anomalies are identified in any organ system, lifelong periodic follow up is warranted. Consensus guidelines for surveillance in CFC syndrome have been established [Pierpont et al 2014].

• Gastrointestinal. Monitor for signs and symptoms of gastrointestinal reflux, constipation, and generalized dysmotility.
• Endocrine. Monitor growth parameters to identify evidence of growth failure that may be associated with growth hormone deficiency. Monitor for signs of precocious puberty.
• Cognitive development. Assess periodically to be certain that school programs or other supports are addressing learning needs.
• Neurologic. Monitor neurologic signs and symptoms with period neurologic evaluations and MRI if indicated. Chiari malformation and later onset of seizures have been observed.
• Audiologic. Annual evaluation of hearing is recommended.
• Ophthalmologic. Periodic evaluation by an ophthalmologist to monitor for ocular issues (such as myopia, hyperopia, cataracts) 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.
• 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, although no individuals with CFC syndrome have been reported to have a malignant change.
• Musculoskeletal. Periodic evaluation for scoliosis during young childhood is recommended.
• Malignancy. No screening protocol exists at present, 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.

Pregnancy Management

A pregnant female suspected of having CFC syndrome warrants obstetric care from a trained maternal-fetal-medicine physician due to possible polyhydramnios, cardiac issues, and/or hypertension.

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 in the US and EU Clinical Trials Register in Europe 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]. Most affected individuals reported to date have had a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• The vast majority of individuals with CFC syndrome reported to date have the disorder as the result of a de novo BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant.
• In rare cases, individuals diagnosed with CFC have an affected parent. Autosomal dominant inheritance of MAP2K2 and KRAS-related CFC has been reported in several families [Rauen et al 2010, Stark et al 2012].
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing for the pathogenic variant identified in the proband or, if a pathogenic variant has not been identified in the proband, a detailed medical history as well as physical examination of the parents to identify phenotypic features of CFC.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported, it remains a possibility).

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the proband's parents.
• As most affected individuals reported to date have had a de novo BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant, risk to sibs is presumed to be low. However, because of the possibility of germline mosaicism in a parent, the risk may be greater than in the general population.

Offspring of a proband. Each child of an individual with CFC syndrome has a 50% chance of inheriting the BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant.

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 couples if one of the two has CFC syndrome or if they have had an affected child.

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 and allow for accurate genetic counseling.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the BRAF, KRAS, MAP2K2, or MAP2K1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CFC are possible.

Molecular Pathogenesis

The four genes currently known to be associated with cardiofaciocutaneous (CFC) syndrome are in the Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The MAPK signaling cascade of dual-specificity kinases [Rauen et al 2011] (see Figure 1) 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 pathogenic variants in PTPN11 (protein product SHP2), SOS1, SOS2, RAF1 (protein product CRAF), NRAS, RIT1, LZTR1, RRAS and KRAS. Pathogenic variants in HRAS are causative for Costello syndrome. CFC syndrome is associated with pathogenic variants in BRAF, MAP2K1, and MAP2K2. Because KRAS pathogenic variants 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.

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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. She also is a member of the RASopathies Network Scientific Advisory Board and the Global Genes Advisory Board.

Dr Rauen is the Director of the UC Davis NF/Ras Pathway Genetics Clinic.

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

• 3 March 2016 (ha) Comprehensive update posted live
• 6 September 2012 (cd) Revision: multigene 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 live
• 14 September 2006 (kar) Original submission