Cardiofaciocutaneous (CFC) syndrome is an extremely rare

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

, and is one of the RASopathies. It was first described in 1986. It is characterized by the following: *Distinctive facial appearance *Unusually sparse, brittle, curly scalp hair *A range of skin abnormalities from dermatitis to thick, scaly skin over the entire body (generalized

ichthyosis Ichthyosis is a family of genetic skin disorders characterized by dry, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cause and mode of inheritance (e.g., dominan ...

) *Heart malformations in over 75% of patients (

congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

or appearing later), especially an obstruction of the normal flow of blood from the lower right ventricle of the heart to the lungs (valvar

pulmonary stenosis Pulmonic stenosis, is a dynamic or fixed obstruction of flow from the right ventricle of the heart to the pulmonary artery. It is usually first diagnosed in childhood. Signs and symptoms Cause Pulmonic stenosis is usually due to isolated valvula ...

) *Growth delays *Feeding problems associated with severe

gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...

(GERD) *Foot abnormalities (extra toe or fusion of two or more toes) *Intellectual disability *

Failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

Presentation

Head

Individuals with the disorder usually have distinctive malformations of the craniofacial area including an unusually large head (macrocephaly), prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction); The nose can be upturned and short with a low nasal bridge; and large ears that are abnormally rotated toward the back of the head. In many cases, affected individuals also have downward slanting eyelid folds, widely spaced eyes, drooping of the upper eyelids, inward deviation of the eyes, and other eye abnormalities including absent eyebrows and eyelashes.

Gastrointestinal system

Genetic

Costello and

Noonan syndrome Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored ...

are similar to CFC and their phenotypic overlap may be due to the biochemical relationship of the genes mutated in each syndrome. Genes that are mutated in all three of these syndromes encode proteins that function in the

MAP kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...

pathway. * Mutations that cause CFC are found in the

KRAS ''KRAS'' (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...

, BRAF,

MEK1 Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the ''MAP2K1'' gene. Function The protein encoded by this gene is a member of the dual-specificity protein kinase family that acts as a mito ...

, and

MEK2 Dual specificity mitogen-activated protein kinase kinase 2 is an enzyme that in humans is encoded by the ''MAP2K2'' gene. It is more commonly known as MEK2, but has many alternative names including CFC4, MKK2, MAPKK2 and PRKMK2. Function The ...

genes. * Costello syndrome is caused by mutations in

HRAS GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 ...

. * Mutations that cause Noonan syndrome have been found in

PTPN11 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...

and

SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the ''SOS1'' gene. Function SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with RAS proteins to phosphorylate GDP into GTP, or from an inactive state to an ...

. The relative severity of CFC when compared to Noonan syndrome may reflect the position in the biochemical pathway occupied by the affected genes. * Shp2, the protein product of the PTPN11 gene, appears to regulate the MAP kinase pathway at or above the level of SOS1. * SOS1 in turn regulates the activities of

RAS Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...

RAF The Royal Air Force (RAF) is the United Kingdom's air and space force. It was formed towards the end of the First World War on 1 April 1918, becoming the first independent air force in the world, by regrouping the Royal Flying Corps (RFC) and ...

, MEK, ERK, and

p90RSK P9 or P-9 may refer to: * Planet Nine, a hypothetical new planet in the far outer solar system * Boeing XP-9, a prototype fighter aircraft from the 1930s * Heckler & Koch P9, a semi-automatic pistol * Springfield Armory P9, a semi-automatic pistol * ...

. * SOS1 has been demonstrated to be a target of negative feedback by ERK and p90RSK. Thus, any activating mutation downstream of SOS1 may be subject to less regulation that might mitigate the consequence of such mutations, giving rise to the phenotypic differences seen between these syndromes.

Diagnosis

Management

References

External links

CFC Syndrome at Genetics Home Reference

GeneReview/UW/NIH entry on CFC
{{DEFAULTSORT:Cardiofaciocutaneous Syndrome Genodermatoses Papulosquamous hyperkeratotic cutaneous conditions Neuro-cardio-facial-cutaneous syndromes Human appearance Syndromes affecting head size Syndromes affecting the heart Syndromes affecting the skin Syndromes with dysmelia Syndromes with craniofacial abnormalities