Costello syndrome
Encyclopedia
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, especially on the hands and feet. Heart
abnormalities are common, including a very fast heartbeat (tachycardia
), structural heart defects
, and overgrowth of the heart muscle (hypertrophic cardiomyopathy
). Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature
and many have reduced levels of growth hormone
s. It is a RASopathy
.
Beginning in early childhood, people with Costello syndrome have an increased risk of developing certain cancerous and noncancerous tumors. Small growths called papilloma
s are the most common noncancerous tumors seen with this condition. They usually develop around the nose and mouth or near the anus. The most frequent cancerous tumor associated with Costello syndrome is a soft tissue
tumor called a rhabdomyosarcoma
. Other cancers also have been reported in children and adolescents with this disorder, including a tumor that arises in developing nerve cells
(neuroblastoma
) and a form of bladder cancer
(transitional cell carcinoma
).
Costello Syndrome was discovered by Dr Patrick Costello, a British Paediatrician in 1977. He is credited with first reporting the syndrome in the Australian Paediatric Journal, Volume 13, No.2 in 1977.
gene. This gene
provides instructions for making a protein
, H-Ras, that helps control cell growth
and division
. Mutations that cause Costello syndrome lead to the production of an H-Ras protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This unchecked cell division may predispose sufferers to the development of benign and malignant
tumors. It remains unclear how mutations in HRAS cause other features of Costello syndrome, but many of the signs and symptoms may result from cell overgrowth and abnormal cell division.
HRAS is a proto-oncogene in which somatic mutations in healthy people can contribute to cancer. Whereas children with Costello syndrome typically have a mutation in HRAS in every cell of their bodies, an otherwise healthy person with a tumor caused in part by HRAS mutation will only have mutant HRAS within the tumor. The test for the mutation in cancer tumors can also be used to test children for Costello syndrome.
Costello syndrome is inherited in an autosomal dominant manner, which means one copy of the altered gene is sufficient to cause the disorder. Almost all cases have resulted from new mutations, and occur in people with no history of the disorder in their family. This condition is rare; as of 20 April 2007, 200 to 300 cases have been reported worldwide.
s in HRAS cause Costello syndrome was first reported in 2005. These mutations, along with mutations that cause cardiofaciocutaneous syndrome
, found soon after, surprised geneticists and changed how genetic syndromes can be grouped. Before this, geneticists looked for new mutations in genes with mutations that caused syndromes similar to the unknown syndrome. For example, researchers looked at and around the most common Noonan syndrome
mutation, PTPN11
, but did not find anything related to Costello syndrome or cardiofaciocutaneous syndrome syndrome. The first mutation that is now identified as one of the Costello syndrome allele
s was found unexpectedly when Japanese researchers used the DNA of children with Costello syndrome as a control, looking for another Noonan gene
Geneticists realized that the syndromes they were grouping together clinically according to their signs and symptoms were related in a way they had never realized: the mutations that cause Costello syndrome, Noonan syndrome and cardiofaciocutaneous syndromes are linked by their cellular function, not by being on or close to a gene with a known mutation. The cellular function that links them is a common signalling pathway
that brings information from outside the cell to the nucleus. This pathway is called the Ras-MAP-kinase
signal transduction pathway (Ras-MAPK Pathway).
meeting, Francis Collins
gave a presentation about a treatment he devised for children affected by Progeria
. He discussed how farnesyltransferase inhibitor
(FTI) affects H-Ras. After his presentation, members of the Costello Syndrome Family Network discussed the possibility of FTIs helping children with Costello syndrome. Mark Kieran, who presented at the 1st International Costello Syndrome Research Symposium in 2007, agreed that FTIs might help children with Costello syndrome. He discussed with Costello advocates what he had learned in establishing and running the Progeria clinical trial
with an FTI, to help them consider next steps.
Another medication that affects H-Ras is Lovastatin
, which is planned as a treatment for neurofibromatosis type I
. When this was reported in mainstream news, the Costello Syndrome Professional Advisory Board was asked about its use in Costello Syndrome. Research into the effects of Lovastatin was linked with Alcino Silva
, who presented his findings at the 2007 symposium. Silva also believed that the medication he was studying could help children with Costello syndrome with cognition.
A third medication that might help children with Costello syndrome is a MEK inhibitor that helps inhibit the pathway closer to the cell nucleus.
and risks involved, and raise funding for the research.
Spanish researchers reported the development of a Costello mouse, with the G12V mutation, in early 2008. Although the G12V mutation is rare among children with Costello syndrome, and the G12V mouse does not appear to develop tumors as expected, information about the mouse model's heart may be transferrable to humans.
Italian and Japanese researchers published their development of a Costello zebrafish in late 2008, also with the G12V mutation. The advent of animal models may accelerate identification of treatment options.
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....
that affects many parts of the body. It is characterized by delayed development and mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet. Heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
abnormalities are common, including a very fast heartbeat (tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
), structural heart defects
Congenital heart defect
A congenital heart defect is a defect in the structure of the heart and great vessels which is present at birth. Many types of heart defects exist, most of which either obstruct blood flow in the heart or vessels near it, or cause blood to flow through the heart in an abnormal pattern. Other...
, and overgrowth of the heart muscle (hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy is a disease of the myocardium in which a portion of the myocardium is hypertrophied without any obvious cause...
). Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature
Short stature
Short stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...
and many have reduced levels of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
s. It is a RASopathy
RASopathy
The RASopathies are developmental syndromes caused by germline mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinase that control Signal transduction, including:*Capillary malformation-AV malformation syndrome...
.
Beginning in early childhood, people with Costello syndrome have an increased risk of developing certain cancerous and noncancerous tumors. Small growths called papilloma
Papilloma
Papilloma refers to a benign epithelial tumor growing exophytically in finger-like fronds. In this context papilla refers to the projection created by the tumor, not a tumor on an already existing papilla . When used without context, it frequently refers to infections caused by human...
s are the most common noncancerous tumors seen with this condition. They usually develop around the nose and mouth or near the anus. The most frequent cancerous tumor associated with Costello syndrome is a soft tissue
Soft tissue
In anatomy, the term soft tissue refers to tissues that connect, support, or surround other structures and organs of the body, not being bone. Soft tissue includes tendons, ligaments, fascia, skin, fibrous tissues, fat, and synovial membranes , and muscles, nerves and blood vessels .It is sometimes...
tumor called a rhabdomyosarcoma
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
. Other cancers also have been reported in children and adolescents with this disorder, including a tumor that arises in developing nerve cells
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
(neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
) and a form of bladder cancer
Bladder cancer
Bladder cancer is any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis...
(transitional cell carcinoma
Transitional cell carcinoma
Transitional cell carcinoma is a type of cancer that typically occurs in the urinary system: the kidney, urinary bladder, and accessory organs. It is the most common type of bladder cancer and cancer of the ureter, urethra, and urachus...
).
Costello Syndrome was discovered by Dr Patrick Costello, a British Paediatrician in 1977. He is credited with first reporting the syndrome in the Australian Paediatric Journal, Volume 13, No.2 in 1977.
Genetics
Costello syndrome is caused by any of at least five different mutations in the HRASHRAS
GTPase 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 :...
gene. This gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
provides instructions for making a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, H-Ras, that helps control cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
and division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
. Mutations that cause Costello syndrome lead to the production of an H-Ras protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This unchecked cell division may predispose sufferers to the development of benign and malignant
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
tumors. It remains unclear how mutations in HRAS cause other features of Costello syndrome, but many of the signs and symptoms may result from cell overgrowth and abnormal cell division.
HRAS is a proto-oncogene in which somatic mutations in healthy people can contribute to cancer. Whereas children with Costello syndrome typically have a mutation in HRAS in every cell of their bodies, an otherwise healthy person with a tumor caused in part by HRAS mutation will only have mutant HRAS within the tumor. The test for the mutation in cancer tumors can also be used to test children for Costello syndrome.
Costello syndrome is inherited in an autosomal dominant manner, which means one copy of the altered gene is sufficient to cause the disorder. Almost all cases have resulted from new mutations, and occur in people with no history of the disorder in their family. This condition is rare; as of 20 April 2007, 200 to 300 cases have been reported worldwide.
Historical significance
That genetic mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in HRAS cause Costello syndrome was first reported in 2005. These mutations, along with mutations that cause cardiofaciocutaneous syndrome
Cardiofaciocutaneous syndrome
Cardiofaciocutaneous Syndrome is an extremely rare and serious genetic disorder.It is characterized by the following:*Distinctive facial appearance*Unusually sparse, brittle, curly scalp hair...
, found soon after, surprised geneticists and changed how genetic syndromes can be grouped. Before this, geneticists looked for new mutations in genes with mutations that caused syndromes similar to the unknown syndrome. For example, researchers looked at and around the most common 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...
mutation, PTPN11
PTPN11
Tyrosine-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 ...
, but did not find anything related to Costello syndrome or cardiofaciocutaneous syndrome syndrome. The first mutation that is now identified as one of the Costello syndrome allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s was found unexpectedly when Japanese researchers used the DNA of children with Costello syndrome as a control, looking for another Noonan gene
Geneticists realized that the syndromes they were grouping together clinically according to their signs and symptoms were related in a way they had never realized: the mutations that cause Costello syndrome, Noonan syndrome and cardiofaciocutaneous syndromes are linked by their cellular function, not by being on or close to a gene with a known mutation. The cellular function that links them is a common signalling pathway
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
that brings information from outside the cell to the nucleus. This pathway is called the Ras-MAP-kinase
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
signal transduction pathway (Ras-MAPK Pathway).
Possible treatments
At the 2005 American Society of Human GeneticsAmerican Society of Human Genetics
The American Society of Human Genetics , founded in 1948, is the primary professional membership organization for specialists in human genetics worldwide. As of 2009, the organization had approximately 8,000 members...
meeting, Francis Collins
Francis Collins (geneticist)
Francis Sellers Collins , is an American physician-geneticist, noted for his discoveries of disease genes and his leadership of the Human Genome Project . He currently serves as Director of the National Institutes of Health in Bethesda, Maryland. Prior to being appointed Director, he founded and...
gave a presentation about a treatment he devised for children affected by Progeria
Progeria
Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
. He discussed how farnesyltransferase inhibitor
Farnesyltransferase inhibitor
The farnesyltransferase inhibitors are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras , which is commonly abnormally active in cancer....
(FTI) affects H-Ras. After his presentation, members of the Costello Syndrome Family Network discussed the possibility of FTIs helping children with Costello syndrome. Mark Kieran, who presented at the 1st International Costello Syndrome Research Symposium in 2007, agreed that FTIs might help children with Costello syndrome. He discussed with Costello advocates what he had learned in establishing and running the Progeria clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
with an FTI, to help them consider next steps.
Another medication that affects H-Ras is Lovastatin
Lovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
, which is planned as a treatment for neurofibromatosis type I
Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
. When this was reported in mainstream news, the Costello Syndrome Professional Advisory Board was asked about its use in Costello Syndrome. Research into the effects of Lovastatin was linked with Alcino Silva
Alcino Silva
Alcino Silva is a sprint canoer from São Tomé and Príncipe who competed in the late 2000s. At the 2008 Summer Olympics in Beijing, he was eliminated in the semifinals of the K-1 500 m event and the heats of the K-1 1000 m events....
, who presented his findings at the 2007 symposium. Silva also believed that the medication he was studying could help children with Costello syndrome with cognition.
A third medication that might help children with Costello syndrome is a MEK inhibitor that helps inhibit the pathway closer to the cell nucleus.
Next steps
Researchers believe there are only enough children with Costello syndrome to test one medication at a time effectively. Researchers have to decide which medication to try first, consider any ethical dilemmasMedical ethics
Medical ethics is a system of moral principles that apply values and judgments to the practice of medicine. As a scholarly discipline, medical ethics encompasses its practical application in clinical settings as well as work on its history, philosophy, theology, and sociology.-History:Historically,...
and risks involved, and raise funding for the research.
Spanish researchers reported the development of a Costello mouse, with the G12V mutation, in early 2008. Although the G12V mutation is rare among children with Costello syndrome, and the G12V mouse does not appear to develop tumors as expected, information about the mouse model's heart may be transferrable to humans.
Italian and Japanese researchers published their development of a Costello zebrafish in late 2008, also with the G12V mutation. The advent of animal models may accelerate identification of treatment options.
External links
- The Costellokids web site for information and support
- GeneReviews: Costello Syndrome
- GeneReviews: Daisy's battle with Costello Syndrome