What Is Cardiofaciocutaneous Syndrome?

Introduction

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder that affects multiple organs like the heart, skin, and face. A person diagnosed with CFC syndrome can have the following features:

• Deformities in the head and face
• Congenital heart disease
• Dermatological (skin) abnormalities
• Growth retardation and 
• Learning disabilities

The CFC  syndrome is a member of a class of conditions called RASopathies. RASopathies are a group of diseases that occur as a result of genetic mutations in a cellular pathway called the RAS-MAPK (Ras/mitogen-activated protein kinase) pathway. The RAS-MAPK pathway plays a critical role in growth and development; hence, any dysregulations in the pathway affect normal development.² 

Other RASopathies, namely Costello syndrome and Noonan syndrome, can present very similarly to CFC syndrome, making it important that CFC syndrome is distinguished from these conditions during diagnosis. 

As CFC syndrome impacts a range of bodily systems, collaboration between different kinds of medical specialists is necessary for managing and treating the condition.^1,3

Causes of cardiofaciocutaneous syndrome

CFC syndrome results from a genetic mutation that causes dysregulation in a cellular pathway called the RAS-MAPK pathway. Due to the role the RAS-MAPK pathway plays in growth and development, this genetic mutation leads to disrupted development.^{1 2}

Several genes may be mutated in CFC syndrome:

• BRAF
• KRAS
• MAP2K1
• MAP2K2

The genetic mutation that causes CFC syndrome commonly occurs after fertilisation of the egg with the sperm. Therefore, almost all cases of CFC syndrome are not inherited.³

Signs and symptoms of cardiofaciocutaneous syndrome

CFC syndrome can present a range of signs and symptoms. There can be delayed development of gross motor skills (movements made with the large muscles of the legs, arms, and torso) and speech, especially in the early years of the child. Although the signs and symptoms can vary among individuals, CFC is characterised by abnormal development, both mentally and physically, and by deformities of the heart, face and head, and skin. As well as this, those with CFC syndrome may experience neurological (nervous system), gastrointestinal (digestive system), and musculoskeletal signs and symptoms.^{1, 3, 4}

Heart

Heart valves are commonly deformed in patients with CFC syndrome. In addition, hypertrophic cardiomyopathy can occur.¹ Both deformed heart valves and hypertrophic cardiomyopathy can cause several signs and symptoms:

• Chest pain
• Palpitations
• Shortness of breath
• Fatigue and weakness
• Light-headedness and fainting
• Swollen ankles and feet^{5, 6}

Another deformity of the heart that is common in patients with CFC syndrome is a septal defect, which is the presence of a hole between chambers of the heart, which should have closed during development shortly after birth. The hole, if large enough, can cause blood to flow in the wrong direction, impairing the heart’s function, as well as that of the lungs.⁷

Face and head

Facial deformities, as well as abnormalities of the head, with varying degrees of severity, are characteristic of CFC syndrome. Some features include:

• Sparse or completely absent eyebrows or eyelashes
• Poor growth of hair on the scalp
• Creases on the earlobe
• A large-sized head in relation to the body (macrocephaly)^1,4

Skin

Skin disorders are a common occurrence in patients with CFC syndrome. There are several ways in which the skin can be affected:

• Dry or scaly skin 
• Red rashes
• Eczema
• Moles
• Red lesions called hemangiomas or ‘strawberry marks’⁸
• Rapidly-growing nails
• Sparse hair on the arms and legs
• Odour from the armpits¹

Neurological

Neurological deficits and developmental delays can occur in patients with CFC syndrome and can commonly manifest in a range of ways:

• Delay in the development of intellectual and learning abilities
• Delay in the development of movements
• Seizures
• A buildup of fluid in the brain can cause headaches, worsen delays in the development of intellectual and learning abilities, impair vision, disrupt sleep, and cause walking abnormalities¹

Gastrointestinal

Involvement of the gastrointestinal system can lead to poor growth. A person/child with CFC syndrome can present with the following signs and symptoms:

• Difficulty sucking and swallowing
• Avoidance of eating
• Gastroesophageal reflux disease
• Constipation or infrequent passing of stools^{1, 9,10}

Musculoskeletal

Muscles, bones, and joints are also commonly affected by CFC syndrome. Common features include:

• Flat feet
• Difficulty moving the shoulders and hands
• Difficulty walking
• Stiffness in the knees
• Instability in the hip joint
• Abnormal curving of the spine
• Decreased muscle tone and bone density¹

Diagnosis of cardiofaciocutaneous syndrome

Diagnosing CFC syndrome involves ruling out other disorders that present with similar clinical features. Costello syndrome and Noonan syndrome can be particularly difficult to distinguish from CFC syndrome, so, it’s important to establish the differences between the diseases to identify and confirm the diagnosis:

Confirming a diagnosis of CFC syndrome can involve a doctor examining a newborn to look for the characteristic features of the condition. Furthermore, a range of techniques, called molecular tests, can be used to diagnose CFC syndrome.¹

Physical examination 

Signs and symptoms of CFC syndrome can commonly be observed in the newborn, so, a doctor’s examination of a newborn can aid in confirming a diagnosis of the condition. Some features of CFC can be present and observable early in the development of the foetus. So, observations made during pregnancy can also aid in diagnosing CFC syndrome. For example, there tends to be excessive amniotic fluid, that is the fluid that surrounds a foetus, during pregnancy with a child with CFC syndrome. Furthermore, about half of the babies with CFC syndrome are born prematurely.¹

Molecular tests

Molecular tests can detect the genetic abnormalities that are responsible for CFC syndrome, these being variations in one of several genes:

• BRAF gene
• KRAS gene
• MAP2K1 gene
• MAP2K2 gene

Performing a molecular test typically involves taking a sample of blood or saliva, which is then analysed to determine whether genetic abnormalities are present.^11,10

Management and treatment of cardiofaciocutaneous syndrome

CFC syndrome cannot be cured but management and treatment can address the signs and symptoms. Since the signs and symptoms of CFC syndrome can vary, management and treatment can change depending on the individual. In order to manage and treat the multiple bodily systems affected by CFC syndrome, a range of medical specialists are typically involved in the care of patients with CFC syndrome. The doctor can coordinate with other medical specialists to form a customised management and treatment plan for the individual. Interventions may include medication, surgery, and making adjustments to the patient’s environment such as their  home, school, and work, so they can function optimally.¹⁰

FAQs

How common is cardiofaciocutaneous syndrome?

Exactly how common CFC syndrome is has not been established. However, it is a rare condition.¹⁰

Is there a cure for cardiofaciocutaneous syndrome?

CFC syndrome cannot be cured. However, management and treatment can help reduce the severity of signs and symptoms.¹⁰

Can individuals with cardiofaciocutaneous syndrome have a normal life expectancy?

The life expectancy of people with CFC syndrome varies depending on their specific signs and symptoms and how severe they are. Individuals with severe deformities of the heart may face a shorter life expectancy.¹¹

How does cardiofaciocutaneous syndrome affect development and learning abilities?

People with CFC syndrome commonly face delays in development and learning abilities. Delays in development can occur intellectually, and therefore, they may need extra assistance in the educational setting and specific help with communication. Physical developmental delays may also occur, causing difficulties such as those related to feeding and moving.¹

Can genetic testing be done to determine whether someone carries the gene for cardiofaciocutaneous syndrome?

The genetic mutation that causes CFC syndrome commonly occurs after conception in the egg or sperm. Therefore, most cases of CFC syndrome are not inherited, and, as a result, genetic testing can’t always determine whether someone carries the gene for CFC syndrome. However, after birth, molecular testing can be done to determine whether a newborn has the genetic mutation responsible for CFC syndrome.^10,11

Summary

CFC syndrome is a rare genetic disease affecting the newborn. It is classified within the group of conditions called Rasopathies, It can affect a range of systems in the body but primarily affects the heart, face, and skin. Examination of a newborn by a doctor and molecular testing can help confirm a diagnosis of CFC syndrome. CFC syndrome cannot be cured, but management and treatment can help reduce the severity of signs and symptoms. Management and treatment typically require a range of medical specialists to address the different bodily systems affected.