Costello syndrome

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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.[1]:571 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).

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[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.

The genetic mutation that causes Costello syndrome (CS), the HRAS gene, was identified in 2005. This gene, along with mutations that cause cardiofaciocutaneous syndrome (CFC), found soon after, surprised the genetics world and changed how genetic syndromes can be grouped.[citation needed] Before this, they looked for new mutations in genes with mutations that caused syndromes similar to the unknown syndrome.[citation needed] For example, researchers looked at and around the most common Noonan syndrome mutation, PTPN11, but didn't find anything related to CS or CFC syndrome.[citation needed] The mutation that is now identified as the Costello syndrome allele was found unexpectedly when Japanese researchers used children with Costello syndrome's DNA samples as a control, looking for another Noonan gene.

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: the mutations that cause Costello syndrome, Noonan syndrome and CFC (cardio-facio-cutaneous)syndromes are linked by their role in a cellular function, not by being on or close to a gene with a known mutation. (It's what they do, not where they are.) The cellular function that links them together is a common signalling pathway that brings information from outside the cell to the nucleus. This information pathway is called the Ras-MAP-kinase signal transduction pathway (Ras-MAPK Pathway).[2]

The HRAS gene is well-known to cancer researchers and cell biologists. But unlike cancer tumors, children with Costello syndrome have the HRAS mutation in every cell of their bodies (germline). Fortunately for the families raising children with Costello syndrome, the test for the mutation in cancer tumors can be used to test children for Costello syndrome as well.

[edit] Treatment ideas

At the 2005 American Society of Human Genetics (ASHG) meeting, Francis Collins made a presentation about a treatment he came up with for children affected by Progeria. He discussed how Farnesyltransferase inhibitor affects 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 Mark Kieran, who presented at the 1st International Costello Syndrome Research Symposium in 2007. 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.[citation needed]

Another medication that affects how H-Ras works is Lovastatin, which is planned to seek to help people with neurofibromatosis type I. When this made the 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 their cognition.[citation needed]

A third medication that might help children with Costello syndrome is a MEK inhibitor that helps inhibit the pathway closer to the cell nucleus.[citation needed]

[edit] Next steps

Because there are so few children in the world with Costello syndrome, researchers believe there are only enough children to test one medication at a time effectively. Researchers have to decide which medication to try first, consider any ethical dilemmas and risks involved, and raise funding for the research.[citation needed]

Spanish researchers published their development of a Costello mouse, with the G12V mutation, in early 2008. While the G12V mutation is rare among children with Costello syndrome, and the G12V mouse doesn't appear to develop tumors as anticipated, valuable information about the mouse model's heart may be transferrable to humans.[citation needed]

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.[citation needed]

[edit] References

  1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0721629210.
  2. ^ Lisa Schoyer, 2007 Costello syndrome medical symposium.

[edit] External links

Retrieved from "http://en.wikipedia.org/wiki/Costello_syndrome"
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