Cardiofaciocutaneous Syndrome – Definition
Cardiofaciocutaneous syndrome (CFC syndrome) belongs to the group of RASopathies and is caused by genetic mutations in four different genes: BRAF (CFC1, OMIM #115150), KRAS (CFC2, OMIM #615278), MAP2K1 (CFC3, OMIM #615279) and MAP2K2 (CFC4, OMIM #615280). Clinically, it is characterized by various heart defects, characteristic facies, cutaneous abnormalities, musculoskeletal and neurological anomalies, and developmental delay.
Synonym:
CFC-Syndrome
Gene products:
Serin/Threonine-Protein Kinase B-Raf (BRAF)
GTPase KRas (KRAS)
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)
Function:
Parts of the RAS/MAPK signaling pathway
Pattern of inheritance:
autosomal dominant, but often de novo mutations
Prevalence:
The general prevalence is not known. There are probably several hundred people affected with CFC syndrome worldwide. In Japan, the prevalence is around 1:810,000.
Genotype-phenotype correlation:
- 50% of CFC patients with BRAF mutations have pulmonary stenosis (compared to only 37% of CFC patients with MAP2K1/MAP2K2 mutations).
- Patients with the BRAF mutation p.Gln257Arg (the most common mutation in CFC syndrome) show a very pronounced phenotypic picture.
- Patients with MAP2K1and MAP2K2 mutations tend to develop keratosis pilaris and more progressive nevi than patients with BRAF mutations.
Penetrance:
complete
Cardiofaciocutaneous Syndrome – Diagnosis
To date, there are no diagnostic criteria for CFC syndrome, so that a suspected diagnosis is usually made based on conspicuous clinical findings and confirmed by genetic diagnostics.
Suspected Diagnosis
CFC syndrome is suspected if the following findings are present:
Cardial:
- Pulmonary stenosis
- Atrial septal defect
- Ventricular septal defect
- Hypertrophic cardiomyopathy
- Heart valve defects (mitral or tricuspid valve dysplasia, bicuspid aortic valve)
- Rhythm disturbances
Craniofacial:
- Macrocephaly
- High and broad forehead and bitemporal impressions
- Hypoplasia of the arcus supraorbitalis (supraorbital bulge)
- Sparse or missing eyebrows
- Hypertelorism and drooping palpebral fissures
- Ocular anomalies: strabismus, nystagmus, myopia, hyperopia, ptosis, astigmatism)
- Short nose with sunken nasal root and anteverted nostrils
- Prominent and broad philtrum, Gothic palate
- Deep-set, backward-rotated ears
Ectodermal:
- Skin: xerosis, hyperkeratosis palmoplantar as well as on arms, legs, and face, ichthyosis, keratosis pilaris, eczema, hemangiomas, café-au-lait spots, erythema, pigment spots
- Hair: sparse, frizzy, thin or thick, woolly or brittle hair; sparse or missing eyebrows and eyelashes
- Nails: dystrophic, flat, broad nails; rapid nail growth
Other Prominent Characteristics:
- Musculoskeletal: short neck, pterygium colli, deformed rib cage, kyphosis, scoliosis, pes planus
- Neurology: mainly mild to severe psychomotor retardation and muscular hypotonia
- Gastroenterology: failure to thrive, gastroesophageal reflux, vomiting, oral aversion and constipation
- Short stature
Genetic Diagnostics
The diagnosis of “CFC syndrome” is confirmed by the detection of a heterozygous germline mutation in the BRAF, KRAS, MAP2K1, or MAP2K2 gene. Panel examinations (RASopathies/Noonan spectrum) should be used first. If these are unavailable, serial single-gene testing with sequence analysis can be performed in the order BRAF, MAP2K1, MAP2K2, and KRAS. A targeted deletion/duplication analysis or a CGH array can be performed if this does not reveal a mutation. Exome or genome sequencing can also be considered.
Differential Diagnoses
- Costello syndrome
- Noonan syndrome
Clinical Presentation
CFC syndrome occurs equally in males and females.
Prenatal and Neonatal Period
Polyhydramnios is most often present in the prenatal period. In newborns, the characteristic facies (see “Diagnosis”) is already noticeable, and cardiac anomalies are usually apparent at birth. Feeding difficulties can also be a problem in the neonatal period.
Infancy
In infants, major difficulties with food intake may still exist, which may require feeding via a nasogastric tube or a gastrostomy. Gastroesophageal reflux and constipation may also occur. Overall, this can result in failure to thrive.
All children with CFC syndrome have a neurological abnormality in the form of a psychomotor developmental delay with muscular hypotonia and delayed speech development or learning disabilities. The intensity can range from mild to extremely severe, with some patients having a normal IQ.
Childhood and Adolescence
The following manifestations can occur at this age:
- Difficulties with food intake
- Short stature: in almost all children and adolescents with CFC syndrome
- Psychomotor developmental delay of varying degrees from mild to very severe, mainly affecting motor skills and speech
- Seizures: About 50% of CFC patients suffer from seizures, which usually first occur in infancy or early childhood but can also develop in later childhood.
- ENT: recurrent otitis and narrowed external auditory canal
- Eye: Strabismus, nystagmus, hypoplasia of the optic nerve, astigmatism, myopia or hyperopia
- Heart: 75-80% of CFC patients have cardiac manifestations such as hypertrophic cardiomyopathy, structural abnormalities, and, more rarely, arrhythmias.
- Kidney/genitourinary tract: in up to 33% of CFC patients as cryptorchidism in male patients as well as renal cysts and stones, hydronephrosis, and hydroureter
- Blood: Von Willebrand syndrome has been described.
- Skin: Xerosis and follicular hyperkeratosis improve with increasing age, making hair growth increasingly possible. Palmoplantar hyperkeratosis and lymphoedema also increase with age. Nevi becomes more numerous in the course of the disease. There is also a tendency to severe skin infections.
- Musculoskeletal: In the majority of CFC patients, muscular involvement is present in the form of hypotonia, reduced muscle mass, and hyperelastic joints. Skeletal changes may include thoracic deformities, scoliosis, kyphosis, or restricted gait.
- Appearance: The characteristic facies (see “Diagnosis”) become less noticeable with age.
- Neoplasms: These rarely occur in the context of CFC syndrome. To date, acute lymphoblastic leukemia (ALL), hepatoblastoma, lymphoma, and rhabdomyosarcoma have been reported.
Special Features of Treatment
Given the many possible manifestations, treatment should always be symptom-oriented and interdisciplinary with the involvement of the relevant specialist discipline.
The manifestations of a CFC syndrome are usually treated the same way as those that occur sporadically.
Diagnosis of Cardiofaciocutaneous Syndrome- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of Cardiofaciocutaneous Syndrome- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Regular clinical examinations should be carried out to record gastroenterological abnormalities, growth, cognitive development, and musculoskeletal changes.
In addition, regular cardiologic, neurologic, ENT, ophthalmologic, and dermatologic examinations should be performed.
Patients should be made aware of a possible increased risk of neoplasia. Targeted cancer screening is not recommended.
