Costello Syndrome
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Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a 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 chromosome abnormality. Although polygenic disorders ...
that affects many parts of the body. It is characterized by delayed development and
intellectual disabilities Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. .
Heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
abnormalities are common, including a very fast heartbeat (
tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
), structural
heart defects A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital he ...
, and overgrowth of the
heart muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
(
hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ...
). 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 refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ...
and many have reduced levels of
growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
s. It is a RASopathy. Beginning in early childhood, people with specific mutations on the Costello syndrome gene variant have an increased risk of developing certain cancerous and noncancerous tumors. Small growths called
papilloma A papilloma (plural papillomas or papillomata) ('' papillo-'' + '' -oma'') is a benign epithelial tumor growing exophytically (outwardly projecting) in nipple-like and often finger-like fronds. In this context, papilla refers to the projection cr ...
s are the most common noncancerous tumors seen with this condition. They usually develop around the nose and mouth. The most frequent cancerous tumor associated with Costello syndrome is a
soft tissue Soft tissue connective tissue, connects and surrounds or supports internal organs and bones, and includes muscle, tendons, ligaments, Adipose tissue, fat, fibrous tissue, Lymphatic vessel, lymph and blood vessels, fasciae, and synovial membranes. ...
tumor called a
rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the neoplasm, tumor are identified as rhabdomyoblasts. The four ...
. Other cancers also have been reported in children and adolescents with this disorder, including a tumor that arises in developing
nerve cells A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...
(
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the head, neck, chest, abdomen, or Vertebral column, spine. Symptoms may include ...
) and a form of
bladder cancer Bladder cancer is the abnormal growth of cells in the bladder. These cells can grow to form a tumor, which eventually spreads, damaging the bladder and other organs. Most people with bladder cancer are diagnosed after noticing blood in thei ...
(
transitional cell carcinoma Transitional cell carcinoma is a type of cancer that arises from the transitional epithelium, a tissue lining the inner surface of these hollow organs. It typically occurs in the urothelium of the urinary system; in that case, it is also called ...
). Costello syndrome was discovered by Jack Costello, a New Zealand paediatrician, in 1977. He is credited with first reporting the syndrome in the Australian Paediatric Journal, Volume 13, No.2 in 1977.


Signs and symptoms

This condition is characterized by delayed development and intellectual disability, loose folds of skin (which are especially noticeable on the hands and feet), unusually flexible joints, and distinctive facial features including a large mouth with full lips. Others also include heart abnormalities. Infants born with this condition 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 hormones.


Genetics

Costello syndrome is caused by any of at least five different mutations in the ''
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 (human), chromosome 11 at position 15.5, ...
'' gene on
chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...
. This
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
provides instructions for making a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
, H-Ras, that helps control
cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...
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 those affected to the development of
benign Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
and
malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
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 An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
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.


Diagnosis

Costello Syndrome can be difficult for doctors to immediately clinically diagnose, as there are similar conditions that resemble this syndrome. A physician will start by assessing the child's height, the size of the head, and birth weight. Full genome and Exome next generation DNA testing is the primary diagnostic tool for Costello Syndrome.


Treatments

At the 2005
American Society of Human Genetics The American Society of Human Genetics (ASHG), founded in 1948, is a professional membership organization for specialists in human genetics. As of 2009, the organization had approximately 8,000 members. The society's members include researchers, ...
meeting,
Francis Collins Francis Sellers Collins (born April 14, 1950) is an American physician-scientist who discovered the genes associated with a number of diseases and led the Human Genome Project. He served as director of the National Institutes of Health (NIH) ...
gave a presentation about a treatment he devised for children affected by
Progeria Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome or Hutchinson–Gilford progeroid syndrome (HGPS). A single gene mutation is responsible for causing progeria. The affected gene, known as lamin A ( ...
. He discussed how farnesyltransferase inhibitors (FTIs) 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 trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
with an FTI, to help them consider next steps. Another medication that affects H-Ras is
Lovastatin Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It is taken by mouth. ...
, which is planned as a treatment for
neurofibromatosis type I Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system neurocutaneous disorder caused by a subset of genetic mutations at the neurofibromin 1 (''NF1'') locus. Other conditions associated with mutation of the ...
. 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.


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 transferable 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.


Historical

That
genetic mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
s in ''HRAS'' cause Costello syndrome was first reported in 2005. These mutations, along with mutations that cause
cardiofaciocutaneous syndrome Cardiofaciocutaneous (CFC) syndrome is an extremely rare genetic disorder, 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 scal ...
, 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 (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 ...
mutation,
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 hu ...
, but did not find anything related to Costello syndrome or cardiofaciocutaneous syndrome. The first mutation that is now identified as one of the Costello syndrome
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
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 In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryo ...
that brings information from outside the cell to the nucleus. This pathway is called the Ras-MAP-kinase signal transduction pathway (Ras-MAPK Pathway).Lisa Schoyer, 2007 Costello syndrome medical symposium.


References

''Some text in this article was originally taken from http://ghr.nlm.nih.gov/condition=costellosyndrome, a
public domain The public domain (PD) consists of all the creative work to which no Exclusive exclusive intellectual property rights apply. Those rights may have expired, been forfeited, expressly Waiver, waived, or may be inapplicable. Because no one holds ...
source''


External links


GeneReviews: Costello Syndrome

GeneReviews: Daisy's battle with Costello Syndrome
{{Deficiencies of intracellular signaling peptides and proteins Genodermatoses RASopathies Autosomal dominant disorders Syndromes affecting the heart Syndromes with craniofacial abnormalities Rare syndromes