Overview 

Cardiofaciocutaneous (KAR-dee-oh-FAY-shee-oh-kyoo-TAY-nee-us) syndrome (also known as CFC syndrome) is a rare genetic condition that affects various parts of the body. This syndrome is named due to the effects it has on the heart (cardio), face (facio), and the skin and hair (cutaneous).¹ Notably, individuals with this condition also experience effects such as delayed developmental milestones and processing disabilities.² Due to the similarities of features with other syndromes, diagnosing CFC syndrome can be challenging. Doctors diagnose CFC through a systematic approach, including physical examinations, synthesising a patient’s medical history, and genetic testing.¹ This article provides a detailed yet accessible guide to how doctors diagnose CFC syndrome, from initial symptom recognition to molecular genetic testing.

What is cardiofaciocutaneous syndrome

CFC syndrome is part of a wider group of genetic conditions known as RASopathies, as the syndrome is caused by a mutation to genes involved in the RAS signalling pathway.³ This signalling pathway plays a fundamental role in cell growth, development, and differentiation. CFC syndrome mainly occurs because of a mutation to one of four genes: BRAF, MAP2K1, MAP2K2, or KRAS. When there is a mutation in one of these genes, it disrupts normal development, leading to the characteristics seen in CFC syndrome. Generally, this syndrome is described as being sporadic- this means it arises in individuals with no familial history of the condition.⁴

Research suggests that CFC is a very rare disease with only 200-300 cases reported worldwide to date. Importantly, the true incidence numbers are obscure due to possible misdiagnosis or underdiagnosis. This highlights the importance of accurate diagnoses by medical professionals such as doctors to ensure those with this condition have access to adequate and the right forms of care. 

Common signs and symptoms of CFC syndrome

Physical features (Facial and cutaneous):^1,6,7

• Macrocephaly (enlarged head size) or proportionally large head 
• Distinctive facial characteristics, including elevated forehead, hypertelorism (widely spaced eyes), shortened nose, low-positioned ears, and prominent lips 
• Curly, thin, brittle, or sparse hair 
• Dermatological (skin) issues, such as scaling or thickened skin texture

Growth and Development (Neurological):^1,8

• Progressive short stature that typically emerges during infancy or early childhood 
• Delayed motor skills and speech development (although some children may develop normally)
• Intellectual disabilities and learning challenges 
• Nutritional and feeding difficulties during early childhood years

Cardiac (Heart) Abnormalities:^1,4

• Structural heart defects affecting the heart valves (i.e., pulmonary stenosis) 
• Septum (wall separating the left and right side of the heart) structural defects (i.e., atrial septal defects)
• Hypertrophic cardiomyopathy (abnormal thickening of heart muscle tissue)

Consultation, medical history, and physical examination

CFC syndrome is often first noticed by parents or caregivers during infancy or early childhood when something seems abnormal in their child’s growth, appearance, or development when compared to the advised developmental milestones. The road to diagnosis typically starts at home and then moves into a clinical setting.

Parents may notice early concerns such as:^1,9

• Feeding difficulties: Poor suck, reflux, or failure to thrive
• Developmental delays: Slow progress in motor skills at specified milestones, as well as speech and cognition delays. Delays in rolling over, sitting, or walking
• Skin and muscle issues: Their infant’s skin may be excessively rough, dry, or have unusual spots. As well as When holding their child, they may feel floppy when held, indicating poor muscle tone
• Facial features: Unusual facial features, or sparse eyes or features

Following concerns, this is where the doctor (GP or family physician) would primarily conduct a physical examination, looking closely at:¹

• Growth measurements (height, weight, head size)
• Muscle tone and motor skills
• Facial features such as a broad forehead, wide-set eyes, and full lips
• Skin texture or unusual pigmentation
• Checking heart and lung sounds using a stethoscope 

Probing questions would likely be asked to supplement the physical examination, gathering information about developmental milestones and medical history: 

• Has the child started crawling or walking?
• Are they making sounds or saying words?
• How do they interact with toys?
• Do they have trouble breathing or experience shortness of breath?

The doctor may start to consider a genetic disorder like CFC syndrome if several uncommon signs or symptoms are present, particularly when combined with developmental delay or heart problems. They may refer the infant or child to being consulted and examined by specialist healthcare professional, such as a geneticist, cardiologist, or paediatrician, for further evaluations and testing. 

Molecular genetic testing 

If clinical signs strongly suggest a RASopathy like CFC, specialist doctors will order molecular genetic testing to confirm the diagnosis. This typically happens after further patient consultations and physical examinations point toward a specific pattern of signs and symptoms synonymous with CFC syndrome.

Genetic testing can be done using a blood sample, and the sample is transported to a medical laboratory for testing. Technicians isolate the DNA from the blood sample and use advanced medical machinery to read the genetic code of the target genes, which are associated with CFC syndrome:¹⁰

• BRAF (most common)
• MAP2K1
• MAP2K2
• KRAS (less common)

Geneticists compare patients' results with typical gene sequences to identify if they have any disease-causing mutations. For CFC syndrome, a gene panel would typically examine the four main genes plus potentially other genes that cause similar conditions. This targeted approach is:¹¹

• Faster: Results usually available in 2-4 weeks
• More affordable: Costs less than comprehensive testing
• Quicker to interpret: Fewer unexpected findings to sort through
• Highly accurate: Endorsed in industry for detecting known disease-causing mutations

However, gene panels have limitations:

• It will not detect mutations in genes not included on the panel, so if someone has an unusual form of the condition caused by a different gene, it might be missed.

Whole Genome Sequencing (WGS)

Whole genome sequencing is a laboratory testing method that reads the complete DNA sequence of an individual- all 3 billion base pairs of DNA code. This comprehensive approach:¹¹

• Examines everything: Looks at all genes simultaneously, not just suspected ones
• Catches rare causes: Can identify unusual genetic causes that gene panels might miss
• Provides comprehensive analysis: May reveal additional health risks or carrier status for other conditions
• Long-term benefits: Data can be reanalysed as scientific knowledge advances on CFS syndrome

The disadvantages include:¹¹

• Higher costs: Significantly more expensive than gene panel testing
• Long wait times for results: May take 6-12 weeks for results
• Complex interpretation: Generates enormous amounts of data that require expert analysis and a long evaluation period
• Incidental findings: May discover unrelated health risks that the patient did not expect to learn about

Following analysis of the genes by the geneticist, the results will be returned to the specialist doctor to explain to the family. The outcomes presented to the family may be:¹²

• Positive: A known disease-causing mutation to one of the four genes (BRAF, MAP2K1, MAP2K, KRAS) was found, confirming the diagnosis
• Negative: No mutations were observed in the tested genes
• Variant of Uncertain Significance (VUS): A change in the DNA was found; however, it is unclear whether it relates to symptoms observed in the patient

Why genetic testing matters

Whilst genetic testing does confirm a diagnosis, the implications of the results are much greater as it has real-life benefits which can shape a patient’s care and support the entire family.

Confirms the diagnosis 

Families frequently experience a protracted time of uncertainty when an infant or child exhibits odd characteristics or developmental delays, visiting numerous doctors and undergoing numerous tests. This diagnostic process can be concluded with a definitive response from genetic testing. A confirmed diagnosis of CFC syndrome relieves families of the anxiety that comes with uncertainty and helps them better understand what to expect.

Tool to guide medical care 

Once the genetic cause is known, doctors can create a personalised care plan. Whilst all CFC-related gene mutations affect the same signalling pathway, depending on which gene is mutated, this can lead to slightly different clinical features and severity levels. For example, BRAF gene mutations are often associated with more severe developmental disabilities and heart defects. This can be valuable in setting up early medical interventions, further screening, and comprehensive management plans with a multidisciplinary team. 

Summary

Diagnosing Cardiofaciocutaneous syndrome (CFS) is a complex but systematic process. Doctors begin with a consultation, discussing observations by parents and conducting a physical examination. By carrying out a physical examination, doctors can look for characteristic signs and symptoms that are associated with CFS. The typical signs and symptoms include heart defects confirmed by listening with a stethoscope, examining for distinct facial features, the presence of skin conditions, and significant developmental delays.

This examination is supplemented with a consultation to review a child’s medical history covering their developmental milestones, motor skills, and growth. If a genetic condition like CFS is suspected, doctors often refer the child to specialists for further evaluation. Specialist healthcare professionals would typically request genetic testing as it is a valuable tool to definitively confirm CFS by identifying the mutation in genes responsible for the syndrome. There are two options for genetic testing that geneticists may conduct: a gene panel (the most common test) or whole exome sequencing (WES). Once a diagnosis is confirmed, a multidisciplinary team can use the results from the physical examination, medical history, and genetic testing together to manage the various symptoms and improve the quality of life for the patient and their families.