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, and woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Affected individuals typically have some form of neurologic and/or cognitive delay (ranging from mild to severe). Most individuals have severe feeding issues, which can contribute to poor growth, and many require nasogastric or gastrostomy tube feeding. Many affected individuals have eye findings, including strabismus, nystagmus, refractive errors, and optic nerve hypoplasia. Seizures may be present and can be refractory to therapy.

Diagnosis/testing.

The diagnosis of CFC syndrome is established in a proband with suggestive clinical findings by the identification of a heterozygous pathogenic variant in BRAF, MAP2K1, MAP2K2, or KRAS by molecular genetic testing.

Management.

Treatment of manifestations: Consensus medical management guidelines have been published. Care by a multidisciplinary team; increased caloric intake and a nasogastric or gastrostomy tube for severe feeding issues; surgical intervention for severe gastroesophageal reflux or malrotation; management of cardiac structural defects, hypertrophic cardiomyopathy, and arrhythmias as in the general population; increased ambient humidity or hydrating lotions for xerosis and pruritus; management of seizures may require polytherapy; routine management of growth hormone deficiency; standard treatment for peripheral neuropathy, Chiari I malformation, developmental delay / intellectual disability, constipation, musculoskeletal anomalies, hypotonia, chronic/recurrent otitis media, hearing loss, cryptorchidism, hydronephrosis, bleeding disorders / thrombocytopenia, and sleep disorders.

Surveillance: At each visit: measure blood pressure; measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for GERD, constipation, generalized dysmotility; assess for new manifestations such as seizures or changes in tone; monitor developmental progress, behavior, and educational needs; monitor for signs and symptoms of thyroid and/or growth hormone deficiency. Assess for scoliosis at each visit until skeletal maturity. Monitor for signs/symptoms of precocious or delayed puberty at each visit in childhood and adolescence. Refer to endocrinologist between the ages of two to three years (or earlier if there are concerns about growth) to monitor growth velocity. Monitor for ocular issues every six to 12 months as directed by ophthalmologist. Hearing evaluation every two to three years, or as clinically indicated. Echocardiogram every two to three years up to age 20 years in those who have an initial cardiac evaluation that is normal. Echocardiogram every three to five years in individuals older than age 20 years who have no previous heart disease found. Annual dermatologic evaluation. DXA scan in early adulthood. Reassess platelet count for evidence of thrombocytopenia in those who have evidence of easy bruising or bleeding.

Agents/circumstances to avoid: Avoid overexposure to heat, strenuous activity, and dehydration. In individuals with evidence of peripheral neuropathy, avoid drugs with a neurotoxic effect.

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

Genetic counseling.

CFC syndrome is inherited in an autosomal dominant manner. The 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. However, instances of familial recurrence of CFC have been reported. Each child of an individual with CFC syndrome has a 50% chance of inheriting the BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant. Once the CFC syndrome-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CFC are possible.

Suggestive Findings

Cardiofaciocutaneous (CFC) syndrome should be suspected in individuals with the following clinical features:

• Dysmorphic facial features (see Figure 1) as outlined in Clinical Characteristics. The face is triangular in shape and overall may be more coarse than in Noonan syndrome (a clinically similar condition often confused with CFC syndrome), but usually not as coarse as is typically seen in Costello syndrome.
• Cardiac anomalies and rhythm disturbance, including pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, and heart valve anomalies
• Severe feeding issues (gastroesophageal reflux disease, aspiration, vomiting, and oral aversion) and poor growth with relative macrocephaly
• Ectodermal findings, such as xerosis; sparse, curly, and woolly or brittle hair; and dystrophic nails
• Lymphedema and/or chylothorax
• Eye anomalies, including strabismus, nystagmus, and/or optic nerve hypoplasia
• Hypotonia
• Developmental delay and cognitive impairment (mild to severe)
• Seizure disorder
• Cryptorchidism in males

Figure 1.

Children with CFC syndrome A. Three young children with BRAF pathogenic variants. Ages are 2.5, 2, and 2 years.

Establishing the Diagnosis

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

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes does not establish or rule out the diagnosis of the disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CFC syndrome or another RASopathy has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder in which individuals may have dysmorphic craniofacial features, cardiac issues, skin and hair abnormalities, hypotonia, eye abnormalities, gastrointestinal dysfunction, seizures, and varying degrees of neurocognitive delay [Pierpont et al 2014] (see Table 2). While many features have been seen in association with this condition, individuals with CFC syndrome display phenotypic variability and therefore not all have every finding.

Polyhydramnios is present in the vast majority of fetal cases diagnosed in utero. Maternal hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia may occur, and subjective decrease in fetal movement may be observed prenatally. Second- and third-trimester ultrasound abnormalities may include polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Operative delivery is not uncommon.

Neonatal outcomes of CFC individuals may include irregular heartbeat, intubation, need for feeding tube, edema, chylothorax, and hyperbilirubinemia, which may be confounded by the increased rate of prematurity [Jelin et al 2023].

Dysmorphic features (see Figure 1) are often helpful in making the diagnosis. By late adolescence to early adulthood, the craniofacial appearance becomes less like that seen in Noonan syndrome. Dysmorphic features in CFC syndrome can include:

• Relative macrocephaly
• Triangular facies
• Bitemporal narrowing
• High anterior hairline
• Hypoplasia of the supraorbital ridges
• Widely spaced eyes
• Telecanthus
• Downslanted 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

Cardiac issues occur in approximately 75%-80% of individuals. Cardiac abnormalities, when present, typically present at birth, although hypertrophic cardiomyopathy and rhythm disturbances may manifest later in life. Cardiac findings can include the following:

• Pulmonic stenosis
• Atrial septal defects and/or ventricular septal defects
• Hypertrophic cardiomyopathy
• Heart valve anomalies (mitral valve dysplasia, tricuspid valve dysplasia, and bicuspid aortic valve)
• Rhythm disturbances

Gastrointestinal/feeding issues. Most affected individuals have severe feeding issues, which can contribute to poor growth. Many children require nasogastric or gastrostomy tube feeding, while some undergo a Nissen fundoplication procedure for severe gastroesophageal reflux. Oral feedings are typically achieved in early childhood. Constipation is typically reported and continues to be an issue throughout childhood and adolescence. Later in childhood, feeding difficulties and hypotonia often improve. Other issues may include the following:

• Aspiration or swallowing problems, which may improve with age
• Recurrent vomiting, which may be association with gastroesophageal reflux disease or malrotation
• Oral aversion
• Dysmotility
• Intestinal malrotation
• Umbilical and inguinal hernia

Poor growth affects most individuals with CFC syndrome. Growth parameters may be normal at birth, with appropriate birth weight and length; however, weight and length may drop to below the fifth centile during early infancy, while head circumference typically remains within the normal range, resulting in relative macrocephaly.

Ectodermal findings. All individuals with CFC syndrome will develop dermatologic issues. With age, the dryness of the skin and the follicular hyperkeratosis tend to improve, allowing 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.

• Skin findings can include the following:
  • Xerosis
  • Hyperkeratosis of arms, legs, and face
  • Keratosis pilaris
  • Ichthyosis
  • Ulerythema ophryogenes
  • Eczema
  • Hemangiomas
  • Café au lait macules
  • Erythema, both on the face or generalized
  • Pigmented moles that may be progressive in number
  • Palmoplantar hyperkeratosis over pressure zones
• Hair may be sparse to absent, but affected individuals may have normal eyelashes and eyebrows. Hair can be curly; fine or thick; and/or woolly or brittle.
• Nails may be dystrophic; flat and broad nails; and/or fast growing.

Developmental delay (DD) and intellectual disability (ID). The vast majority of children, if not all, have some form of neurologic abnormality, neurocognitive delay, or learning issues. Overall, developmental delay typically ranges from mild to profound, although some individuals have IQs in the normal range. Developmental delay may be less obvious in mildly or moderately affected individuals, but speech and motor delays and difficulty walking become apparent in those who are more severely affected.

• The vast majority of affected individuals have hypotonia due to a skeletal muscle myopathy, causing motor delays. The average age of walking in those who become ambulatory is around three years; however, many never achieve this goal.
• A significant number of affected individuals remain nonverbal. In those who develop verbal language skills, the first word is said on average by age two years.
• Some young adults participate in assisted living programs and may have supervised employment.

Other neurologic/neurodevelopmental features

• Hypotonia. Global hypotonia is typically evident in the newborn period. Delayed motor skills, muscle weakness, and decreased muscle bulk is commonly present. As children grow older, muscle weakness appears to gradually improve, although individuals still may have gross motor delays.
• Seizures. More than 50% of individuals with CFC syndrome develop a seizure disorder. Seizure types may include complex partial seizures, generalized tonic-clonic seizures, absence seizures, and/or infantile spasms. Most seizures begin in infancy or early childhood [Yoon et al 2007, Pierpont et al 2022]; however, a seizure disorder may develop later in childhood as well. Seizures may require polytherapy and can be refractory to therapy (see Treatment of Manifestations).
• Head MRI findings may include Chiari I malformation, ventriculomegaly, hydrocephalus, prominent Virchow-Robin spaces, abnormal myelination, and structural anomalies.
• Neuropathy may occur and is typically underreported. Musculoskeletal pain is not uncommon and may be acute or chronic [Leoni et al 2019].
• Neurobehavioral issues are common and may include irritability, short attention span, stubbornness, and obsessive and/or aggressive behaviors. Anxiety is commonly reported. Autism may also be seen in individuals with CFC syndrome.

Eye abnormalities are present in most individuals and may result in decreased vision and acuity. Findings may include the following:

• Strabismus
• Nystagmus
• Optic nerve hypoplasia
• Astigmatism
• Myopia
• Hyperopia

Musculoskeletal. The vast majority of affected individuals have musculoskeletal findings including a paucity of muscle mass, skeletal myopathy, and lax joints [Tidyman et al 2011]. Orthopedic issues can include pectus deformity, pes planus, hip dysplasia, scoliosis, kyphosis, gait disturbances, and/or joint contractures of the elbow, knee, and/or hip. Contractures may be progressive and require surgical intervention. Many affected individuals require ambulatory assistance. Bone mineral density may also be reduced [Stevenson et al 2011].

Neonatal lymphatic issues. Chylothorax and lymphedema have been reported at birth, although the natural history of these findings has not been reported. Peripheral edema in older individuals may occur.

Otolaryngologic issues. Many affected children experience recurrent otitis media and are found to have narrow external auditory canals. Many require pressure equalization tubes.

Hyperacusis and hearing loss have been reported.

Renal/urogenital anomalies 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. Bladder, uterine, and cervical abnormalities, though rare, have been reported.

Less common features

• Endocrinology. Although the vast majority of affected children have not been formally tested, some have true growth hormone deficiency. Affected individuals are also at risk for the development of growth hormone resistance. Both delayed puberty and precocious puberty may occur in males and females. Hypothyroidism has also been reported.
• Respiratory/sleep. Laryngotracheal abnormalities such as laryngotracheomalacia and laryngeal clefts have been reported. Sleep issues are common and may include poor sleeping patterns, night sweating, sleep apnea, and/or night terrors.
• Bleeding diathesis has rarely been reported, including a case of von Willebrand disorder as well as a rare case of transient thrombocytopenia in a newborn.
• Malignancy. Acute lymphoblastic leukemia has been reported in a few individuals [Niihori et al 2006, Makita et al 2007, Rauen et al 2010]. Hepatoblastoma was reported in an immunocompromised individual [Al-Rahawan et al 2007]. Other reported malignancies include non-Hodgkin lymphoma in one individual [Ohtake et al 2011] and large B cell lymphoma in one individual [Rauen et al 2010].

Phenotype Correlations by Gene

BRAF

• Pulmonic stenosis is more common in individuals with CFC syndrome due to a pathogenic variant in BRAF. Approximately 50% of individuals with BRAF-related CFC syndrome have pulmonic stenosis [Allanson et al 2011].
• The frequency of seizures is higher among individuals with BRAF-related CFC syndrome compared to those with MAP2K2-related CFC syndrome [Pierpont et al 2022].

MAP2K1. The frequency of seizures is higher among individuals with MAP2K1-related CFC syndrome comparted to those with MAP2K2-related CFC syndrome [Pierpont et al 2022].

MAP2K2. Individuals with MAP2K2-related CFC syndrome have a lower risk of severe neurodevelopmental delay and epilepsy than individuals with MAP2K1-related CFC syndrome [Pierpont et al 2022].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified for specific pathogenic variants in BRAF, KRAS, MAP2K1, or MAP2K2.

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

Hundreds of individuals with CFC syndrome have been reported in the literature. Overall prevalence is not known; prevalence in Japan is estimated at one in 810,000 [Abe et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CFC syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Consensus clinical management guidelines have been published [Pierpont et al 2014] (full text).

There is no cure for CFC syndrome.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5). Specialized NF/Ras pathway genetics clinics are available in the United States, United Kingdom, and European Union.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 6 are recommended. Lifelong periodic follow up is warranted.

Agents/Circumstances to Avoid

Individuals with CFC syndrome report heat intolerance; therefore, overexposure to heat and strenuous activity should be avoided. Hydrate as needed.

In individuals with evidence of peripheral neuropathy, drugs with a neurotoxic effect should be avoided, per standard supportive treatment according to the individual's neurologist or rehabilitation medicine specialist.

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 high-risk obstetric care from a trained maternal-fetal medicine physician due to possible polyhydramnios, maternal cardiac issues, and/or maternal hypertension.

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Cardiofaciocutaneous (CFC) syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The 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.
• Individuals diagnosed with CFC syndrome may have an affected parent; instances of familial recurrence of CFC are increasingly reported in the medical literature [Rauen et al 2010, Stark et al 2012, Rauen et al 2021]. Therefore, it is critical that the parents of the proband are examined for signs of CFC syndrome and the medical history of the parents obtained.
• Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Geoghegan et al 2018]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with CFC syndrome may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the CFC-causing pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Geoghegan et al 2018].

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 has the CFC syndrome-causing pathogenic variant identified in the proband, the parent's 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/preimplantation genetic 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 and to the parents of an affected child.

Prenatal Testing and Preimplantation Genetic Testing

Once the CFC syndrome-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CFC are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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, RRAS2, KRAS, and other rarer genes. 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 warrants further study.

Mechanism of disease causation. The vast majority of pathogenic variants are missense or small in-frame deletions that cause a gain-of-function activation of the protein product BRAF, MEK1, MEK2, or KRAS that leads to activation of the Ras/MAPK pathway. This results in increased phosphorylation and, thus, activation of ERK1 and/or ERK2.

Cancer and Benign Tumors

BRAF. Somatic pathogenic variants in BRAF have been reported in approximately 8% of tumors, most frequently in melanoma, thyroid, colorectal, and ovarian cancers, and have also been found in benign nevi and premalignant colon polyps. BRAF pathogenic variants have also been seen in Langerhans cell histiocytosis and non-Langerhans cell histiocytoses [Badalian-Very et al 2010, Diamond et al 2016, Durham et al 2019].

KRAS. Single-nucleotide variants in KRAS account for approximately 85% of pathogenic variants in the Ras gene family. KRAS oncogenic variants are common in pancreatic cancer, colon cancer, small intestinal cancer, biliary cancer, and lung cancer. The vast majority of oncogenic pathogenic variants occur in hot spots in codons 12, 13, or 61. These are not the same pathogenic variants that are found in CFC syndrome [Schubbert et al 2006]. Somatic activating KRAS variants have been identified in arteriovenous malformations of the brain [Nikolaev et al 2018].

MAP2K1/MAP2K2. Somatic pathogenic variants in MAP2K1 and MAP2K2 have been reported in various tumors, including ovarian cancer and non-small cell lung carcinoma [Estep et al 2007, Marks et al 2008]. MAP2K1 and MAP2K2 pathogenic variants also occur in Langerhans cell histiocytosis and non-Langerhans cell histiocytoses [Diamond et al 2016, Durham et al 2019]. Somatic MAP2K1 pathogenic variants are associated with extracranial arteriovenous malformation [Couto et al 2017].

Author Notes

Dr Rauen serves on the Medical Advisory Board for CFC International, Inc, and is codirector 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.

Acknowledgments

Special thanks to CFC International, the Costello Syndrome Family Network, and RASopathiesNet for their ongoing support of research in genomic medicine.

Revision History

• 9 February 2023 (ma) Comprehensive update posted live
• 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

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