Cardiofaciocutaneous syndrome

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Cardiofaciocutaneous syndrome
OMIM 115150
DiseasesDB 30111

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Synonyms and Related Keywords: Cardio-facio-cutaneous syndrome, CFC syndrome

Overview

Cardiofaciocutaneous syndrome is a disorder that affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). People with this condition also have delayed development and mental retardation, usually ranging from moderate to severe.

Heart defects occur in most people with cardiofaciocutaneous syndrome. The heart problems most commonly associated with this condition include malformations of one of the heart valves (pulmonic stenosis), a hole between the two upper chambers of the heart (atrial septal defect), and a form of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy).

Cardiofaciocutaneous syndrome is also characterized by distinctive facial features. These include a high forehead that narrows at the temples, a short nose, widely spaced eyes (ocular hypertelorism), outside corners of the eyes that point downward (down-slanting palpebral fissures), droopy eyelids (ptosis), a small chin, and low-set ears. Overall, the face is broad and long, and the facial features are sometimes described as "coarse."

Skin abnormalities occur in almost everyone with cardiofaciocutaneous syndrome. Many affected people have dry, rough skin; dark-colored moles (nevi); wrinkled palms and soles; and a skin condition called keratosis pilaris, which causes small bumps to form on the arms, legs, and face. People with cardiofaciocutaneous syndrome also tend to have thin, dry, curly hair and sparse or absent eyelashes and eyebrows.

Infants with cardiofaciocutaneous syndrome typically have weak muscle tone (hypotonia), feeding difficulties, and a failure to grow and gain weight at the normal rate (failure to thrive). Additional features of this disorder in children and adults can include an unusually large head (macrocephaly), short stature, problems with vision, and seizures.

The signs and symptoms of cardiofaciocutaneous syndrome overlap significantly with those of two other genetic conditions, Costello syndrome and Noonan syndrome. The three conditions are distinguished by their genetic cause and specific patterns of signs and symptoms; however, it can be difficult to tell these conditions apart in infancy. Unlike Costello syndrome, which significantly increases a person's cancer risk, cancer does not appear to be a major feature of cardiofaciocutaneous syndrome.

Prevalance

Cardiofaciocutaneous syndrome is a very rare condition whose incidence is unknown. Researchers estimate that 200 to 300 people worldwide have this condition.

Inheritance

Cardiofaciocutaneous syndrome is considered to be an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. All reported cases have resulted from new gene mutations and have occurred in people with no history of the disorder in their family

Causes

Costello and Noonan syndrome are similar to CFC and their phenotypic overlap may be due to the biochemical relationship of the genes mutated in each syndrome to each other. Genes that are mutated in all three of these syndromes encode proteins that function in the MAP kinase pathway. Mutations that cause CFC are found in the KRAS, BRAF, MEK1 and MEK2 genes. Costello syndrome is caused by mutations in HRas. Mutations that cause Noonan Syndrome have been found in PTPN11 and SOS1. The relative severity of CFC when compared to Noonan Syndrome may reflect the position in the biochemical pathway each gene occupies. Shp2, the protein product of the PTPN11, appears to regulate the MAP kinase pathway at or above the level of SOS1. SOS1 in turn regulates the activities of RAS, RAF, MEK, ERK and p90RSK. 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 may mitigate the consequence of such mutations giving rise to the phenotypic differences seen between these syndromes[1].

The BRAF, MAP2K1, and MAP2K2 genes provide instructions for making proteins that work together to transmit chemical signals from outside the cell to the cell's nucleus. This chemical signaling pathway is essential for normal development before birth. It helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement, and the self-destruction of cells (apoptosis).

Mutations in any of these genes can result in the characteristic features of cardiofaciocutaneous syndrome. The protein made from the mutated gene is overactive, which disrupts tightly regulated chemical signaling during development. The altered signaling interferes with the development of many organs and tissues, resulting in the characteristic features of cardiofaciocutaneous syndrome.

Some people with the signs and symptoms of cardiofaciocutaneous syndrome do not have an identified mutation in the BRAF, MAP2K1, or MAP2K2 gene. In these cases, affected individuals may actually have Costello syndrome or Noonan syndrome, which are caused by mutations in related genes. The proteins produced from these genes interact with one another as part of the same chemical signaling pathway. These interactions help explain why mutations in different genes can cause conditions with overlapping signs and symptoms.

Symptoms and Signs

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 eye lashes.

  • 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)
  • Heart malformations (congenital or appearing later) especially an obstruction of the normal flow of blood from the lower right ventricle of the heart to the lungs (valvular pulmonary stenosis)
  • Delayed growth
  • Mental retardation
  • Psychomotor retardation
  • Foot abnormalities (extra toe or fusion of two or more toes)

References

  1. Bentires-Alj M, et al. Nat Med. 2006; 12:283-285

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