Costello syndrome is an autosomal dominant disorder that affects many parts of the body. This condition is characterized by delayed development and intellectual disability, loose folds of skin, unusually flexible joints, and distinctive facial features including a large mouth. Heart problems are common, including an abnormal heartbeat, structural heart defects, and a type of heart disease that enlarges and weakens the heart muscle. Infants with Costello syndrome may be larger than average at birth, but most have difficulty feeding and grow more slowly than other children. People with this condition have relatively short stature and may have reduced growth hormone levels. Other signs and symptoms of Costello syndrome can include tight Achilles tendons, weak muscle tone , a structural abnormality of the brain called a Chiari I malformation, skeletal abnormalities, dental problems, and problems with vision.
Beginning in early childhood, people with Costello syndrome are at an increased risk of developing certain cancerous and noncancerous tumors. The most common noncancerous tumors associated with this condition are papillomas, which are small, wart-like growths that usually develop around the nose and mouth or near the anus. The most common cancerous tumor associated with Costello syndrome is a childhood cancer called rhabdomyosarcoma, which begins in muscle tissue. Neuroblastoma, a tumor that arises in developing nerve cells, also has been reported in children and adolescents with this syndrome. In addition, some teenagers with Costello syndrome have developed transitional cell carcinoma, a form of bladder cancer that is usually seen in older adults.
The signs and symptoms of Costello syndrome overlap significantly with those of two other genetic conditions, cardiofaciocutaneous syndrome (CFC syndrome) and Noonan syndrome. In affected infants, it can be difficult to tell the three conditions apart based on their physical features. However, the conditions can be distinguished by their genetic cause and by specific patterns of signs and symptoms that develop later in childhood.
Mutations in the HRAS gene cause Costello syndrome. The HRAS gene provides instructions for making proteins that help 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 a patient to the development of benign and malignant 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.
Methodology: Sequencing of entire coding region
Purpose: Confirmation of Clinical Diagnosis
ICD-10 Code Q99.9
Test Requisition: Sequencing Requisition
CPT Code: 81404 Cost: $620.00
Turn-around-time: 3-4 weeks
1. Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. (2005) “Germline mutations in HRAS proto-oncogene cause Costello syndrome”. Nat Genet. 37(10):1038-40.
2. Axelrad ME, Schwartz DD, Fehlis JE, Hopkins E, Stabley DL, Sol-Church K, Gripp KW. (2009) “Longitudinal course of cognitive, adaptive, and behavioral characteristics in Costello syndrome”. Am J Med Genet A.149A(12):2666-72.
3. Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI Jr, Doyle D, Aoki Y, Matsubara Y, Zackai EH, Lapunzina P, Gonzalez-Meneses A, Holbrook J, Agresta CA, Gonzalez IL, Sol-Church K. (2006) “HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation”. Am J Med Genet A. 140(1):1-7.
4. Rauen KA. (2007) “HRAS and the Costello syndrome”. Clin Genet.71(2):101-8. Review.