What is Cardiofaciocutaneous Syndrome?

By Syed S. A.Reviewed by Danielle Ellis, B.Sc.

Causes and symptoms
RASopathies
Diagnosis and treatment
References
Further reading

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder marked by congenital heart disease, distinctive craniofacial appearance, musculoskeletal, dermatologic, and gastrointestinal abnormalities.

CFC belongs to RASopathies, a family of clinically related genetic disorders. It is caused by heterozygous mutations in the RAS/MAPK pathway genes BRAF, MAP2K1, MAP2K2, and KRAS. The cardiofaciocutaneous syndrome (CFCS) is inherited as an autosomal dominant trait.

Causes and symptoms

Mutations in four distinct genes cause CFCS. BRAF accounts for roughly 75% of patients with a known mutation, MEK1 and MEK2 together for 20–25 %, and KRAS for fewer than 5% of cases with a known mutation.

Facial dysmorphism, dermatologic abnormalities, and growth retardation are characteristic features of CFCS. Congenital heart disease, including pulmonary stenosis, other valve dysplasia, septal defects, and/or hypertrophic cardiomyopathy are also hallmarks of CFCS.

Nonexistent or sparse eyelashes and eyebrows, sparse curly hair, ear lobe creases, a high forehead, relative macrocephaly, and bitemporal constriction are signs of facial dysmorphism.

It also involves hypoplastic supraorbital ridges, hypertelorism with down-slanting palpebral fissures, ptosis, anteverted nares, deep philtrum, and low-set posteriorly rotated ears. Malignancies (acute lymphoblastic leukemia, lymphoma) appear to be slightly more common.

Many people with CFC have major neurological symptoms, such as seizures, macrocephaly, hypotonia, ocular-motor difficulties, hydrocephalus, or abnormal brain imaging. Sleep problems, such as poor sleeping patterns, sleep apnea, and night terrors, are widespread, according to parent surveys. The severity of the intellectual disability is estimated to range from low to severe.

Individuals with proven CFC-associated mutations have occasionally been reported to have IQs in the low average to the average range, although many of these individuals were first clinically classified with another RASopathy, such as Noonan syndrome.

Gross motor deficits are especially common in children with CFC. According to parent surveys, children with CFC begin to walk independently at the age of three, while roughly 18 % of those with CFC are unable to do so. The rate at which a language develops is tremendously variable. By school age, the majority of children can talk in phrases or whole sentences, although 9–31% of children remain nonverbal throughout their childhood. Although longitudinal evidence is lacking, cross-sectional research suggests that children and adolescents with CFC continue to develop adaptive skills throughout time but may have more substantial delays as they get older in comparison to their peers.

There is a scarcity of knowledge about specific behavioral characteristics of CFC, such as personality traits and mental health difficulties. Individuals with CFC were found to have a higher likelihood of symptoms of autism spectrum disorder (ASD), such as difficulties with social communication and restricted or repetitive interests and behaviors, in two investigations using parent rating measures.

Symptoms of attention deficit hyperactivity disorder (ADHD) are also quite common in this category of disorders, according to research on other RASopathies. Irritability, continuous crying, stubbornness, aggressive behaviors, and a decreased attention span have all been documented in CFC. Still, there has been little research to date to uncover the underlying reasons that may be driving these behaviors.

RASopathies

CFC is one of a set of disorders known as RASopathies, which are caused by mutations in the RAS-mitogen activated protein kinase (RAS-MAPK) signaling pathway. Noonan syndrome, Costello syndrome, and neurofibromatosis type 1 are among the RASopathies, in addition to CFC. RASopathies are a group of clinically linked genetic illnesses caused by a dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway (which usually results in enhanced or persistent activity). The control of the cell cycle and differentiation is dependent on this route.

Diagnosis and treatment

Clinical signs lead to a suspicion of CFC syndrome, which is verified by molecular testing. Individuals with phenotypic traits involving the heart (Pulmonic stenosis, ventricular septal defects, rhythm disturbances), face (High forehead, relative macrocephaly, bitemporal narrowing, epicanthal folds), and ectodermal tissues (keratosis pilaris, dystrophic with flat broad nails, sparse, curly, fine or thick hair) should be suspected of having cardiofaciocutaneous (CFC) syndrome.

CFC syndrome is diagnosed in a proband when a heterozygous pathogenic variation in BRAF, MAP2K1, MAP2K2, or KRAS is discovered using molecular genetic testing. Serial single-gene testing, the use of a multigene panel, and more complete genomic testing are all options for molecular testing.

As CFC syndrome affects so many organ systems, the vast majority of people might need continuing care from a multidisciplinary team of healthcare professionals. A pediatric gastroenterologist should be seen if a child's eating problems are severe within the first year of life. A Nissen fundoplication may be required in children with severe gastroesophageal reflux.

Some people lack growth hormone or thyroid hormone and may benefit from treatment by an endocrinologist. It is strongly advised that children participate in early intervention programs to boost motor and cognitive development. Seizures are treated in the same way they are in the general population but may require polytherapy.

Genetic counseling is highly recommended for patients and their families to help them understand the complexities of the disorder. Because the Ras/MAPK pathway has been extensively investigated in the context of cancer, various therapies targeting this system are now being developed.

References

1. Leoni, C., Viscogliosi, G., Onesimo, R., Bisanti, C., Massese, M., Giorgio, V., Corbo, F., Tedesco, M., Acampora, A., Cipolla, C., Dell'Atti, C., Flex, E., Gervasoni, J., Primiano, A., Rigante, D., Tartaglia, M., & Zampino, G. (2021). Characterization of bone homeostasis in individuals affected by cardio-facio-cutaneous syndrome. American journal of medical genetics. Part A, 10.1002/ajmg.a.62588. Advance online publication. https://doi.org/10.1002/ajmg.a.62588
2. Pierpont, E. I., & Wolford, M. (2016). Behavioral functioning in cardiofaciocutaneous syndrome: Risk factors and impact on parenting experience. American journal of medical genetics. Part A, 170(8), 1974–1988. https://doi.org/10.1002/ajmg.a.37725
3. Rauen KA. Cardiofaciocutaneous Syndrome. 2007 Jan 18 [Updated 2016 Mar 3]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/sites/books/NBK1186/
4. Templin, L., Baumann, C., Busa, T., Heckenroth, H., Pouvreau, N., Toutain, A., Cave, H., Verloes, A., Sigaudy, S., & Philip, N. (2016). Prenatal findings in cardio-facio-cutaneous syndrome. American journal of medical genetics. Part A, 170A(2), 441–445. https://doi.org/10.1002/ajmg.a.37420
5. Joyce, S., Gordon, K., Brice, G., Ostergaard, P., Nagaraja, R., Short, J., Moore, S., Mortimer, P., & Mansour, S. (2016). The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. European journal of human genetics: EJHG, 24(5), 690–696. https://doi.org/10.1038/ejhg.2015.175

Further Reading

• All Rare Disease Content
• What is a Rare Disease?
• Importance of Research into Rare Disease
• Teaching old drugs new tricks – drug repurposing for rare diseases
• What is Adenomyosis?