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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).
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 web-based support group for families affected by Costello syndrome in the UK started in 1997 and incorporated in 2003. 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 the Costello Syndrome Family Network was incorporated as a 501(c)(3) non-profit organization 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 worldwide (05/03/2007)
The genetic mutation that causes Costello syndrome (CS), the HRAS gene, was identified in 2005. This gene, along with mutations that cause cardio-facio-cutaneous syndrome (CFC), found soon after, surprised the genetics world and changed how genetic syndromes can be grouped. Before this, they looked for new mutations on 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 didn’t find anything related to CS or CFC syndrome. The gene mutation that is now 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.
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