Overview

Cardiofaciocutaneous Syndrome (CFC) (literally heart-face-skin syndrome) is a rare, spontaneous disorder which affects approximately 1 in 800,000 individuals.¹ Caused due to genetic defects, it leads to an increase in the activity of the Ras/MAPK signalling pathway, which has downstream effects on how the cells develop. This can have widespread effects on the foetus, causing many abnormalities. The following article will dive into these in more detail, and help differentiate CFC from other Ras/MAPK disorders like Noonan syndrome, Costello syndrome and NF1.

Molecular basis of disease

The embryonic period of one’s life is when you grow from one cell to trillions, forming limbs, organ systems and your brain that will stay with you for your entire life. This is a very complicated system that still isn’t completely understood, and therefore, accurate control of the many different signalling pathways is vital to ensure that every part of the foetus develops correctly.

The Ras/ MAPK (mitogen-activated-protein-kinase) pathway controls many factors, but primarily is in control of cell multiplication, cell specialisation and cell death.

It acts like a molecular switchboard, activating the cell’s machinery due to external factors that first affect proteins in the cell membrane. Downstream effects lead to changes in how the DNA in a cell is copied and proteins produced, affecting the cell’s cell cycle through transcription factors. This is key in determining what the cell will specialise as, whether it will multiply or if it will succumb to death itself. Without this signalling being correctly controlled, the new life cannot form correctly.

MAPK also blocks apoptosis, especially when growth factors are present, permitting healing and controlling cell death in a reasonable manner that promotes controlled formation and protection.

As the new life starts off as one cell that becomes many, the Ras-MAPK pathway is vital when determining the different cell types that can form and how many of each cell type will occur. The timing of its activation, where in the body it occurs, and how much signalling occurs will decide the cell’s fate. For example, temporary activation can lead to cell duplication, whereas sustained, long-term activation of the pathway can cause differentiation of the tissue (specialisation). Naturally, where this occurs in the body during the embryonic/ foetal stage will have a lasting impact, from where the limbs grow on the body to the shape of different bones like the skull.

CFC has been identified to cause gain-of-function mutations, meaning that the Ras/ MAPK pathway becomes hyperactivated. This can be because of mutations in the following genes:

• BRAF
• MAPKK1 (MEK1)
• MAPKK2 (MEK2)
• KRAS

As a result, many parts of embryonic development can be affected, including how the cardiac progenitor cells align to produce the structure of the heart, how the neural crest cells affect the formation of the great vessels of the heart (outflow tract), how many skin keratinocytes form the skin barrier, how hair follicles develop, how neural crest cells form the face/ skull shape and how nerves form and make connections to one another (synapses). Changes from the norm in these processes can lead to CFC.

Clinical symptoms of CFC

As the mutations occur spontaneously, the type of mutation and when it occurs during gestation will determine the extent and severity of symptoms. These include:²

Heart issues

• Hole in the wall between the heart’s two top chambers (atrial septal defect)
• Hole in the wall between the heart’s two bottom chambers (ventricular septal defect)
• Abnormal blood flow from the heart to the lungs due to abnormal valves (pulmonary stenosis)
• Weak, thickened heart muscle (hypertrophic cardiomyopathy)
• Heat valve issues
• Random rhythm changes

Facial issues

• High forehead/ long face
• Very large head (macrocephaly)
• Down-slanting eyes (downslanting parapebral fissures)
• Droopy eyes (ptosis)
• Sparse, brittle hair
• Red bumps on skin with loss of eyebrows (Ulerythema ophryogenes)
• Ear lobe creases
• Relatively small lower jaw (micrognathia)
• Short nose with depressed bridge
• Low-set ears

Skin issues

• Painless bumps on the skin (keratosis pilaris)
• Eczema
• Thickened skin (hyperkeratosis)
• Very dry, scaly skin (ichthyosis, xerosis)
• Black moles (café au lait macules)
• Red patches (erythema)

Neural issues

• Seizures
• Hypotonia
• Developmental delay
• Intellectual disability

Gastric issues

• Poor feeding
• Swallowing issues that can improve as patients age
• Twisted or misaligned intestines (intestinal malrotation)
• Hernias (umbilical or inguinal)
• Abnormal/ irregular movement of food in the gastrointestinal tract (dysmotility)
• Recurrent vomiting

Due to all these issues, poor growth may also result. Cardiac issues affect 75% to 80% of patients, and skin issues are always present, so they are good indicators for CFC. Lymphedema may occur and will normally get worse with age.

Differentiating CFC from other disorders

CFC is not the only disorder that results from Ras/MAPK issues. Consequently, other disorders also caused by similar issues have similar symptoms. Misdiagnosis can lead to treatment issues, which is why differentiating between similar disorders is important, like Noonan syndrome, Costello syndrome, and Neurofibromatosis type 1 (NF1).

Noonan syndrome and CFC³

Since congenital heart disease (especially pulmonary valve stenosis), short stature, and distinctive craniofacial features are common to both conditions, Noonan syndrome is frequently the first condition evaluated in infants with suspected CFC. The primary distinction is found in the dermatological and neurological findings. While many people with Noonan syndrome have normal intelligence and a mild developmental delay, children with CFC typically have more severe cognitive and motor difficulties. Anomalies of the skin and hair, such as dry, thickened skin and brittle or sparse hair, are noticeable in CFC but uncommon in Noonan syndrome. The initial indicators of CFC are frequently found in this variation in skin involvement and neurodevelopmental severity.

Costello syndrome and CFC⁴

Costello syndrome, which arises from mutations in the HRAS gene, shares some similarities with CFC, such as coarse facial features, feeding challenges, and heart issues. However, it also has its own unique characteristics. Infants with Costello syndrome often face severe feeding difficulties that necessitate long-term tube feeding, even more so than those with CFC. Their skin tends to be loose and velvety instead of thickened, and a distinctive trait is the presence of warts around the nose, mouth, or perianal area. Another significant difference is the risk of cancer: while both conditions involve hyperactivation of certain pathways, individuals with Costello syndrome have a much higher chance of developing cancers, particularly rhabdomyosarcoma and bladder cancer. This increased cancer risk is not typically associated with CFC.

Neurofibromatosis Type 1 and CFC⁵

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that make it stop working, a gene that usually helps keep Ras activity in check. Similar to CFC, NF1 can show up with learning challenges and some distinct facial features, but its skin symptoms are much more pronounced. The classic signs of NF1 include café-au-lait spots, freckling in the armpits and groin, and benign tumours called neurofibromas, which you won’t find in CFC. Additionally, eye-related symptoms like Lisch nodules on the iris can help confirm the diagnosis. It's also important to note that NF1 comes with a significant risk of tumour development, a characteristic that doesn’t apply to CFC.

Key differences

When you look at the bigger picture, the differences really come down to how involved each condition is and the intensity of that involvement. For instance, significant developmental delays along with noticeable skin and hair issues are strong indicators of CFC. On the other hand, the presence of warts and a higher risk of tumours points towards Costello syndrome. Mild cognitive challenges and mostly normal skin lean towards Noonan syndrome, while pigmented skin spots and neurofibromas are key signs of NF1.

Even though genetic testing can confirm a diagnosis these days, being able to recognise these clinical patterns is still incredibly important. A clinician's skill in distinguishing these differences plays a crucial role in guiding early treatment, anticipating potential complications, and providing families with reliable information.

Summary

Cardiofaciocutaneous syndrome is one of multiple congenital syndromes that occur due to a disruption in the Ras/MAPK pathway. Over-activation of this pathway leads to problems with cell multiplication, specialisation and cell death. Consequently, many different severe health issues can result, which need multi-disciplinary care. However, due to similarities, it can sometimes be confused with Costello syndrome, Noonan syndrome or NF1 syndrome. Although genetic testing to identify the mutations involved is the best way to differentiate between the syndromes, differences in skin conditions, e.g. dry and scaly in CFC vs loose and velvety in Costello syndrome, can be good differentiators between the different syndromes, especially when so many other symptoms are similar.