Costello syndrome

From Wikipedia, the free encyclopedia

Costello syndrome Classification and external resources
OMIM	218040
DiseasesDB	32846

Costello syndrome is a genetic disorder that affects many parts of the body. This condition is characterized by delayed development and mental retardation, distinctive facial features, loose folds of extra skin (especially on the hands and feet), and unusually flexible joints. 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 have difficulty feeding and grow more slowly than other children. Later in life, people with this condition have relatively short stature and many lack growth hormone.

Beginning in early childhood, people with Costello syndrome have an increased risk of developing certain cancerous and noncancerous tumors. Small growths called papillomas 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).

[edit] Genetics

Mutations in the HRAS gene cause Costello syndrome. The HRAS gene provides instructions for making a protein that helps control cell growth and division. Mutations that cause Costello syndrome lead to the production of an HRAS 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 to the development of benign and malignant tumors. It remains unclear how mutations in the HRAS gene cause the other features of Costello syndrome, but many of the signs and symptoms may result from cell overgrowth and abnormal cell division.

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; 200 to 300 (20/04/2007)cases have been reported worldwide.

A support group for families affected by Costello syndrome was founded in the UK in 1997. Although based in the UK, the support group runs a web site, and Listserve for families, and has formed a strong international community. The UK support group is a registered charity. In 2001 a similar not-for-profit organization for Costello syndrome was founded in the USA. The two organizations work hand in hand, providing a high level of support and information with the aim of gaining a much better understanding of this rare disorder.

The support group has a membership of 160 families world wide (05/03/2007)

COSTELLO SYNDROME RESEARCH

The Significance of the Costello Syndrome Gene Discovery

The Costello syndrome (CS) gene find in 2005 – the HRAS gene - along with mutations linked to cardio-facio-cutaneous syndrome (CFC) soon after, surprised the genetics world. Before this, they were looking at genes with known mutations that were similar to what children with a clinical costello syndrome had. For example, researchers looked at and around the most common Noonan syndrome mutation, PTPN11, and didn't find anything related to Costello syndrome. The gene mutation that would be identified as the Costello syndrome gene was found unexpectedly when Japanese researchers used children with Costello syndrome's DNA samples as a control, looking for another Noonan gene!

The HRAS gene is a well-known mutation to cancer researchers and cell biologists. But unlike cancer tumors, children with Costello syndrome have the HRAS mutation is in every cell of their bodies. Fortunately for the families raising children with Costello syndrome, researchers didn’t have to develop a test, because the test for the mutation in cancer tumors can be used for children suspected as having Costello syndrome as well.

Cell biologists are well aware of the mutated H-Ras protein (which is the result of the mutated HRAS gene “instructing” the use of the wrong amino acid), they weren't looking at what it does, if mutated, to a whole human being.

Genetic researchers started to realize that the syndromes they were grouping together clinically (by means of studying the signs and symptoms) were related in a way they never realized: it turns out that the relationship between Costello syndrome, Noonan syndrome and CFC (cardio-facio-cutaneous) syndromes is based on how they relate to a specific cell function, not a physical relationship to a known gene. The cellular function that links them together is a common pathway that brings information from outside the cell to the nucleus.

This information pathway is called the Ras-MAP-kinase (or Ras-MAPK) Pathway.

Treatment Ideas

In 2005 at American Society of Human Genetics (ASHG) meeting, Francis Collins (geneticist) made a presentation about a treatment he came up with for children affected by Progeria . He discussed how Farnesyltransferase inhibitor affect H-Ras...(!)

After his presentation members of the Costello Syndrome Family Network (CSFN) discussed the possibility of FTIs possibly helping children with Costello syndrome as well. This led to Dr. Mark Kieran, who presented at the 1st International Costello Syndrome Research Symposium in 2007.

Dr. Kieran agreed that FTIs might well help children with Costello syndrome, and shared what he'd learned in setting up and running the Progeria clinical trial with an FTI, to help Costello advocates with possible next steps.

Another medication that affects how H-Ras works was one that’s in the works to help people with Neurofibromatosis 1: Lovastatin. When this made the mainstream news, The Costello syndrome Professional Advisory Board was asked about its use in Costello Syndrome.

Reasearch into the effects of Lovastatin was linked with Dr. Alcino Silva, who very kindly agreed to present his findings at the 2007 Symposium. Dr. Alcino also believed that the medication he was studying could help children with Costello syndrome with their cognition.

A third medication that might help children with Costello syndrome is one that helps inhibit the pathway closer to teh cell nuclius - a MEK inhibitor- .

Next Steps

Because there are so few children in the world with Costello syndrome, researchers believe there are only enough children to try one medication. They have presented three key questions to answer for next steps:

1. What would the medication change in children with Costello syndrome that would show that the medication is working?

2. Which medication would be the best choice to try first?

3. What are the ethical issues we need to consider before embarking on this?

For families raising a child with Costello syndrome, weighing risks and benefits could be very complicated.

A last important requirement is funds. Based on existing clinical trials, it looks like an estimate of $2 million in funds and $2 million in in-kind donations (doctors’, researchers’ and administrators’ time, facilities overhead and other expenses over the span of 2 years) will need to be raised.

COSTELLO SYNDROME RESEARCH is based on the information presented at the 2007 costello syndrome medical symposium and was written by Lisa Schoyer