Introduction

Different parts of the body, including the heart, face, skin, and hair, are affected by Cardiofaciocutaneous (CFC) syndrome. Individuals with this disorder may also suffer from intellectual disability and developmental delay. CFC syndrome is caused by mutations in BRAF, MAP2K1, MAP2K2 or KRAS genes. In most cases, it is not inherited; however, it is an autosomal dominant condition. Cardiofaciocutaneous (CFC) syndrome is rare. It is a kind of RASopathies, genetic conditions which affect the RAS pathway. Its features include a relatively large head (relative macrocephaly), sparse, brittle, curly hair; abnormal narrowing of the sides of the forehead, a prominent forehead, congenital heart defects, failure to thrive, intellectual disability, skin abnormalities and short stature.¹

Common signs and features of CFC syndrome

Symptoms may start to appear during pregnancy or as a newborn and can vary from mild to severe, affecting different body parts. Congenital heart defects may include abnormal heart valves affecting the flow of blood from the heart to the lungs, a weak heart muscle, a hole in the heart and a heart murmur. Skin affected by CFC syndrome can be dry and rough. Dark moles may be present. Eyebrows or eyelashes may be missing or sparse. Arms, legs and face can have small bumps (keratosis pilaris). Wrinkles are present on palms and soles. Abnormal facial features include a large head (macrocephaly), high forehead with narrow sides, broad and long face, eyes that are widely spaced and slant downward, drooping eyelids (ptosis), low-set ears, small chin and short nose. Individuals having CFC syndrome may also suffer from low levels of growth hormones, developmental delays and intellectual disability, difficulty eating, excess fluid in the brain, vision problems, trouble gaining weight, growing seizures and weak muscles (hypotonia).¹

The RAS/MAPK pathway

The Ras/Raf/MAPK pathway is a signal transduction pathway in cell biology. It functions to transduce signals to and from the cells, inducing activation of genes for cell growth, division and differentiation. Hence, the Ras/Raf/MAPK pathway is involved in cell cycle regulation, integrin signalling and cell migration, wound healing and tissue repair.²

Key genes involved in CFC syndrome

Genes encode proteins, which are needed to carry out important functions in the body, including cell communication and the smooth mechanism of molecular pathways such as the RAS/MAPK pathway. Some of the most common genes that have mutations leading to CFC syndrome are discussed below.¹

BRAF gene

It is found on chromosome seven and encodes a protein called BRAF. This protein contributes to cell growth via signalling, which induces cell division.³ About 50 % of CFC syndrome patients who have a BRAF mutation have pulmonic stenosis and experience seizures frequently.¹

MEK1 and MEK2 genes (Also called MAP2K1 and MAP2K2)

MEK1 and MEK2 genes are related and encode dual-specificity protein kinases, which play an important role in the RAS/MAPK signalling pathway. Individuals with MAP2K1-related CFC syndrome experience a greater frequency. There is a lower risk of severe neurodevelopmental delay and epilepsy among individuals with MAP2K2-related CFC syndrome compared to individuals with MAP2K1-related CFC syndrome. MEK1 and MEK2 are related protein kinases which take part in the RAS-RAF-MEK-ERK signal transduction cascade, involved in the regulation of apoptosis, cell cycle progression, cell migration, differentiation, metabolism, and proliferation.^1,4

KRAS gene (rare in CFC)

The KRAS gene encodes a protein that contributes to cell signalling pathways, cell growth and division, cell maturation, and cell death. An association exists between the KRAS T58I mutation and cardiofaciocutaneous syndrome.⁶

How are these genes related?

Mutations in various genes lead to Cardiofaciocutaneous syndrome. The BRAF gene accounts for 75 to 80 per cent of the cases. MAP2K1 and MAP2K2 are involved in 10 to 15 per cent of cases, and KRAS gene mutations account for less than 5 per cent of cases. The BRAF, MAP2K1, MAP2K2, and KRAS genes encode proteins that function together and transmit chemical signals into the cell nucleus from outside, known as the RAS/MAPK pathway. These gene variants give rise to characteristic features of cardiofaciocutaneous syndrome. The altered gene produces an overactive protein, which disrupts the regulation of chemical signalling during development, interfering with the development of many organs and tissues and leading to cardiofaciocutaneous syndrome symptoms.^1-6

Inheritance and diagnosis

Inheritance is when disease disease-causing genetic mutation is passed on from parents to children. Hence, family history is vital for investigating many diseases. A disease can be inherited through different patterns, like autosomal dominance, which means that one copy of the altered gene can express the condition in an individual. There is a 50% chance of inheriting an autosomal dominant condition. CFC is usually not inherited. It is caused by de novo (new) mutations. These mutations can happen by chance in the sperm or egg. Genetic testing can help in diagnosing CFC accurately and understanding prognosis and treatment options. Cardiofaciocutaneous syndrome can be diagnosed before birth through a prenatal ultrasound. Some of the early signs are extra amniotic fluid or an enlarged head and body. However, the majority of cases are diagnosed during infancy.¹

Different clinical tests may be conducted to confirm the condition. The heart function is assessed by echocardiogram, Electrocardiogram or cardiac catheterisation. Genetic mutations are identified with the help of molecular genetic testing. Abnormal formation of the brain, heart or other organs of an infant can be examined via ultrasound, X-ray, MRI or CT-scan. Stereo electroencephalography is done to examine brain waves and seizure activity. Ophthalmoscopy is done for vision tests. CFC syndrome is inherited in an autosomal dominant manner. Prenatal testing and preimplantation genetic testing can be done for a pregnancy which has an increased risk for CFC. Molecular genetic testing involves a combination of gene-targeted testing and comprehensive genomic testing, depending on the phenotype.⁷ 

CFC in everyday life: support and expectations

CFC syndrome cannot be cured. It requires a team of specialists, and treatment may vary as on the severity of the disease. For infants, nasogastric or gastrostomy feeding may be needed. If heart surgery is considered to repair specific defects, cardiologists may closely monitor the condition. Seizures are treated by neurologists. For vision, ophthalmology exams are done on a regular basis. Also, surgery or corrective lenses may improve vision. Standard treatment is carried out for skin conditions. Occupational, physical and/or speech therapy helps in motor and speech development. Children having CFC syndrome must have regular check-ups to monitor growth and development. Growth hormone therapy is given for developmental delay. Skin issues are treated with hydrating lotions and other skin treatments. As CFC syndrome is a lifelong disorder, life expectancy depends on the severity of symptoms and medical complications.^1,6

CFC syndrome is a variable and genetically heterogeneous disorder. It is caused by mutations of genes in the RAS/MAPK pathway. Signs and symptoms include congenital heart disease, facial features, and short stature. It also involves neurological and cutaneous conditions. Hence, a multidisciplinary approach is required for the treatment. CFC syndrome may be treated by medicines, surgery, growth hormone and physical therapy.  Feeding problems in infants may be treated by tubes through the nose (NG tube) or through the skin over the stomach (gastrostomy or G-tube). Children with CFC syndrome mostly need lifelong help and care, and they do well with good support.⁷

Summary

Cardiofaciocutaneous (CFC) syndrome is a rare genetic condition affecting the heart, facial features, skin, hair, and development. It is caused by mutations in genes BRAF, MEK1, MEK2 and KRAS. These genes are linked to the RAS/MAPK signalling pathway, which contributes to cell growth and development. Individuals having CFC may have different symptoms that may vary in severity. These include heart defects, distinctive facial traits, skin and hair abnormalities, and developmental delays that arise due to disruption of cell communication due by gene mutations. BRAF mutations account for about 75% of cases, while MEK1 and MEK2 make up about 25%, and KRAS is very rare. In most cases, CFC is not inherited. However, it is an autosomal dominant disease. Genetic testing is usually done to confirm the diagnosis and to identify the specific mutation. This helps in managing the condition and following appropriate treatment. Living with CFC involves medical care, early developmental therapies, educational support, and access to social resources. With early intervention and support, individuals with CFC can lead decent lives. 

Frequently asked questions (FAQs)

What is the life expectancy of someone with CFC syndrome?

Life expectancy for individuals having Cardiofaciocutaneous (CFC) syndrome varies. It depends on the severity of the condition. Milder forms may have almost normal lifespan, while individuals with severe heart defects or neurological issues may have reduced life expectancy. However, proper diagnosis and management may result in a normal life span.

What is cardiofaciocutaneous syndrome epilepsy?

Cardio-facio-cutaneous syndrome is a genetic disorder that often causes prolonged seizures.

How common is CFC?

It is considered as a rare condition. About 200 to 300 people worldwide have been diagnosed with it.

What is the cardiofaciocutaneous syndrome support group?

One of the most well-known support groups is CFC International. It is a nonprofit patient support and advocacy group founded in 1999. This organisation has provided support to more than 900 families, over 36 countries.

How is CFC syndrome different from Noonan or Costello syndromes?

These diseases are categorised as RASopathies and have overlapping features. However, each syndrome is caused by different gene mutations. Genetic testing can be done to distinguish between them.