Cardiofaciocutaneous syndrome
Encyclopedia
Cardiofaciocutaneous Syndrome (CFC) is an extremely rare and serious genetic disorder
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It is characterized by the following:
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.
The relative severity of CFC when compared to Noonan Syndrome may reflect the position in the biochemical pathway each gene occupies.
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.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
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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 ichthyosisIchthyosisIchthyosis is a heterogeneous family of at least 28, generalized, mostly genetic skin disorders. All types of ichthyosis have dry, thickened, scaly or flaky skin...
) - Heart malformations (congenital or appearing later) especially an obstruction of the normal flow of blood from the lower right ventricleVentricle (heart)In the heart, a ventricle is one of two large chambers that collect and expel blood received from an atrium towards the peripheral beds within the body and lungs. The Atria primes the Pump...
of the heart to the lungs (valvar pulmonary stenosis) - Delayed growth
- Mental retardation
- Psychomotor retardation
- Foot abnormalities (extra toe or fusion of two or more toes)
Malformations of face and 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.Genetic causes of CFC
CostelloCostello syndrome
Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and mental retardation, distinctive facial features, unusually flexible joints, and loose folds of extra skin,...
and Noonan syndrome
Noonan syndrome
Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner 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 KRASKRASGTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...
, BRAFBRAFBRAF can refer to* Baton Rouge Area Foundation* The BRAF gene...
, MEK1 and MEK2 genes. - Costello syndrome is caused by mutations in HRASHRASGTPase HRas also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549.- Function :...
. - Mutations that cause Noonan Syndrome have been found in PTPN11PTPN11Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
and SOS1SOS1Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes...
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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, RAFC-RafRAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, MEK, ERKMitogen-activated protein kinaseMitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
and p90RSKRibosomal s6 kinaseIn molecular biology, ribosomal s6 kinase is a family of protein kinases involved in signal transduction. There are two subfamilies of rsk, p90rsk, also known as MAPK-activated protein kinase-1 , and p70rsk, also known as S6-H1 Kinase or simply S6 Kinase. There are three variants of p90rsk in...
. - 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.