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Genetics Home Reference: your guide to understanding genetic conditions
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Costello syndrome

Reviewed July 2012

What is Costello syndrome?

Costello syndrome is a disorder that affects many parts of the body. 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. Heart problems are common, including an abnormal heartbeat (arrhythmia), structural heart defects, and a type of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy). 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 (which connect the calf muscles to the heel), weak muscle tone (hypotonia), 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.

How common is Costello syndrome?

This condition is very rare; it probably affects 200 to 300 people worldwide. Reported estimates of Costello syndrome prevalence range from 1 in 300,000 to 1 in 1.25 million people.

What genes are related to Costello syndrome?

Mutations in the HRAS gene cause Costello syndrome. This gene provides instructions for making a protein called H-Ras, which is part of a pathway that helps control cell growth and division. Mutations that cause Costello syndrome lead to the production of an H-Ras protein that is abnormally turned on (active). The overactive protein directs cells to grow and divide constantly, which can lead to the development of cancerous and noncancerous tumors. It is unclear how mutations in the HRAS gene cause the other features of Costello syndrome, but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division.

Some people with signs and symptoms of Costello syndrome do not have an identified mutation in the HRAS gene. These individuals may actually have CFC syndrome or Noonan syndrome, which are caused by mutations in related genes. The proteins produced from these genes interact with one another and with the H-Ras protein as part of the same cell growth and division pathway. These interactions help explain why mutations in different genes can cause conditions with overlapping signs and symptoms.

Related Gene(s)

Changes in this gene are associated with Costello syndrome.

  • HRAS

How do people inherit Costello syndrome?

Costello syndrome is considered to be an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Almost all reported cases have resulted from new gene mutations and have occurred in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of Costello syndrome?

These resources address the diagnosis or management of Costello syndrome and may include treatment providers.

  • Gene Review: Costello Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1507)
  • Genetic Testing Registry: Costello syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0587248)

You might also find information on the diagnosis or management of Costello syndrome in Educational resources (http://ghr.nlm.nih.gov/condition/costello-syndrome/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/costello-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Costello syndrome?

You may find the following resources about Costello syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Costello syndrome?

  • faciocutaneoskeletal syndrome
  • FCS syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Costello syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/gard).

What glossary definitions help with understanding Costello syndrome?

anus ; arrhythmia ; autosomal ; autosomal dominant ; cancer ; carcinoma ; cardiomyopathy ; cell ; cell division ; disability ; gene ; growth hormone ; hormone ; hypertrophic ; hypotonia ; malformation ; muscle tone ; mutation ; prevalence ; protein ; rhabdomyosarcoma ; short stature ; stature ; syndrome ; tissue ; transitional cell carcinoma ; tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, Ohashi H, Mizuno S, Ogata T, Kure S, Niihori T, Matsubara Y; Costello and CFC syndrome study group in Japan. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. Am J Med Genet A. 2012 May;158A(5):1083-94. doi: 10.1002/ajmg.a.35292. Epub 2012 Apr 11. (http://www.ncbi.nlm.nih.gov/pubmed/22495831?dopt=Abstract)
  • Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005 Oct;37(10):1038-40. Epub 2005 Sep 18. (http://www.ncbi.nlm.nih.gov/pubmed/16170316?dopt=Abstract)
  • Axelrad ME, Schwartz DD, Fehlis JE, Hopkins E, Stabley DL, Sol-Church K, Gripp KW. Longitudinal course of cognitive, adaptive, and behavioral characteristics in Costello syndrome. Am J Med Genet A. 2009 Dec;149A(12):2666-72. doi: 10.1002/ajmg.a.33126. (http://www.ncbi.nlm.nih.gov/pubmed/19919001?dopt=Abstract)
  • Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006 Jan 1;140(1):8-16. (http://www.ncbi.nlm.nih.gov/pubmed/16372351?dopt=Abstract)
  • Gene Review: Costello Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1507)
  • 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. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006 Jan 1;140(1):1-7. (http://www.ncbi.nlm.nih.gov/pubmed/16329078?dopt=Abstract)
  • Gripp KW, Stabley DL, Nicholson L, Hoffman JD, Sol-Church K. Somatic mosaicism for an HRAS mutation causes Costello syndrome. Am J Med Genet A. 2006 Oct 15;140(20):2163-9. (http://www.ncbi.nlm.nih.gov/pubmed/16969868?dopt=Abstract)
  • Kerr B, Delrue MA, Sigaudy S, Perveen R, Marche M, Burgelin I, Stef M, Tang B, Eden OB, O'Sullivan J, De Sandre-Giovannoli A, Reardon W, Brewer C, Bennett C, Quarell O, M'Cann E, Donnai D, Stewart F, Hennekam R, Cavé H, Verloes A, Philip N, Lacombe D, Levy N, Arveiler B, Black G. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. Epub 2006 Jan 27. (http://www.ncbi.nlm.nih.gov/pubmed/16443854?dopt=Abstract)
  • Quezada E, Gripp KW. Costello syndrome and related disorders. Curr Opin Pediatr. 2007 Dec;19(6):636-44. (http://www.ncbi.nlm.nih.gov/pubmed/18025929?dopt=Abstract)
  • Rauen KA. Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. Am J Med Genet A. 2006 Aug 1;140(15):1681-3. (http://www.ncbi.nlm.nih.gov/pubmed/16804887?dopt=Abstract)
  • Rauen KA. HRAS and the Costello syndrome. Clin Genet. 2007 Feb;71(2):101-8. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17250658?dopt=Abstract)
  • Stevenson DA, Yang FC. The musculoskeletal phenotype of the RASopathies. Am J Med Genet C Semin Med Genet. 2011 May 15;157C(2):90-103. doi: 10.1002/ajmg.c.30296. Epub 2011 Apr 14. Review. (http://www.ncbi.nlm.nih.gov/pubmed/21495174?dopt=Abstract)
  • White SM, Graham JM Jr, Kerr B, Gripp K, Weksberg R, Cytrynbaum C, Reeder JL, Stewart FJ, Edwards M, Wilson M, Bankier A. The adult phenotype in Costello syndrome. Am J Med Genet A. 2005 Jul 15;136(2):128-35. Erratum in: Am J Med Genet A. 2005 Nov 15;139(1):55. (http://www.ncbi.nlm.nih.gov/pubmed/15940703?dopt=Abstract)
  • Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G, Tartaglia M. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007 Mar;28(3):265-72. (http://www.ncbi.nlm.nih.gov/pubmed/17054105?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: July 2012
Published: February 23, 2015