Molecular Genetics of Costello Syndrome


The molecular basis of Costello syndrome (CS) is heterozygous germline mutations in HRAS. Over 95% of patients with CS have been found to have mutations in codon 12 or codon 13, with over 80% having the single mutation c.34G>A, p.(Gly12Ser). The mutational spectrum is similar, but not identical, to that observed for somatic HRAS mutations in cancer. These mutations result in constitutive activation of the HRAS protein. The function of HRAS as a molecular switch is therefore perturbed, resulting in increased downstream Ras‐MAPK pathway activity. The severity of clinical features of CS in any given individual may be influenced by which mutation is present, with mutations more commonly observed in cancer, such as p.(Gly12Val), which have more dramatic effects at the cellular level, tending to lead to a more severe presentation. As for other germline disorders, however, much variability is seen, which may be due to further genomic and other modifying factors.

Key Concepts:

  • Germline gain of function mutations in HRAS cause Costello syndrome (CS).

  • Somatic gain‐of‐function HRAS mutations (often with more extreme biochemical effects) are also found in cancer.

  • HRAS p.(Gly12Ser) is the cause of CS in 80% of patients diagnosed with this condition.

  • CS is associated with advanced paternal age.

  • Spermatogonia in the testes of older fathers may be enriched for mutations conferring a proliferative advantage, such as the HRAS mutations that underlie CS.

Keywords: Costello syndrome; HRAS; germline mutation; paternal age effect; selfish spermatogonial selection

Figure 1.

Ras‐MAPK pathway signal transduction. Schematic of the Ras‐MAPK signal transduction pathway. The position of the Ras proteins, at the head of this cascade, is shown, with the stars indicating GTP‐mediated activation.

Figure 2.

HRAS mutations in Costello syndrome and cancer.

Figure 3.

Schematic of the HRAS locus, transcript and HRAS protein. The genomic locus of HRAS is shown, consisting of 7 exons, with the transcript which is translated into the active HRAS protein, p21. (This splice variant does not include exon 5; the transcript which does include this has a shorter open reading frame, denoted p19, due to the presence of a stop codon, asterisk.) The HRAS protein is shown, with the locations of CS‐associated mutations arrowed. Note that codons for which mutations have been described in classical CS are clustered in and around the G‐domains and switch regions, each crucial to the interaction of HRAS with GTP.



Abe Y, Aoki Y, Kuriyama S et al. (2012) Prevalence and clinical features of Costello syndrome and cardio‐facio‐cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. American Journal of Medical Genetics. Part A 158A(5): 1083–1094.

Aoki Y, Niihori T, Kawame H et al. (2005) Germline mutations in HRAS proto‐oncogene cause Costello syndrome. Nature Genetics 37(10): 1038–1040.

Bamford S, Dawson E, Forbes S et al. (2004) The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. British Journal of Cancer 91: 355–358.

Barbacid M (1987) ras genes. Annual Review of Biochemistry 56: 779–827.

Bertola DR, Pereira AC, Brasil AS et al. (2007) Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene. Journal of Human Genetics 52(6): 521–526.

Borrello MG, Pierotti MA, Tamborini E et al. (1992) DNA methylation of coding and non‐coding regions of the human H‐RAS gene in normal and tumor tissues. Oncogene 7(2): 269–275.

van der Burgt I, Kupsky W, Stassou S et al. (2007) Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. Journal of Medical Genetics 44(7): 459–462.

Burkitt‐Wright EM, Bradley L, Shorto J et al. (2012) Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val. American Journal of Medical Genetics. Part A 158A(5): 1102–1110.

Burkitt Wright EM and Kerr B (2010) RAS‐MAPK pathway disorders: important causes of congenital heart disease, feeding difficulties, developmental delay and short stature. Archives of Disease in Childhood 95(9): 724–730.

Carvajal‐Vergara X, Sevilla A, D'Souza SL et al. (2010) Patient‐specific induced pluripotent stem‐cell‐derived models of LEOPARD syndrome. Nature 465(7299): 808–812.

Chen X, Mitsutake N, LaPerle K et al. (2009) Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene. Proceedings of the National Academy of Sciences of the USA 106(19): 7979–7984.

Costello JM (1977) A new syndrome: mental subnormality and nasal papillomata. Australian Paediatric Journal 13(2): 114–118.

Der Kaloustian VM, Moroz B, McIntosh N, Watters AK and Blaichman S (1991) Costello syndrome. American Journal of Medical Genetics 41(1): 69–73.

Giannoulatou E, McVean G, Taylor IB et al. (2013) Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline. Proceedings of the National Academy of Sciences of the USA. doi:10.1073/pnas.1311381110.

Goriely A, Hansen RM, Taylor IB et al. (2009) Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nature Genetics 41(11): 1247–1252.

Goriely A, McVean GA, Rojmyr M, Ingemarsson B and Wilkie AO (2003) Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 301(5633): 643–646.

Goriely A and Wilkie AO (2010) Missing heritability: paternal age effect mutations and selfish spermatogonia. Nature Reviews. Genetics 11(8): 589.

Goriely A and Wilkie AO (2012) Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. American Journal of Human Genetics 90(2): 175–200.

Gremer L, De Luca A, Merbitz‐Zahradnik T et al. (2010) Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor‐dependent MAPK and AKT activation. Human Molecular Genetics 19(5): 790–802.

Gripp KW, Bifeld E, Stabley DL et al. (2012) A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development. American Journal of Medical Genetics. Part A 158A(9): 2106–2118.

Gripp KW, Hopkins E, Sol‐Church K et al. (2011a) Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C. American Journal of Medical Genetics. Part A 155A(4): 706–716.

Gripp KW, Innes AM, Axelrad ME et al. (2008) Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? American Journal of Medical Genetics. Part A 146A(6): 683–690.

Gripp KW and Lin AE (2012) Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations. Genetics in Medicine: Official Journal of the American College of Medical Genetics 14(3): 285–292.

Gripp KW, Lin AE, Nicholson L et al. (2007) Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio‐facio‐cutaneous syndrome from Costello syndrome. American Journal of Medical Genetics Part A 143A(13): 1472–1480.

Gripp KW, Lin AE, Stabley DL et al. (2006a) HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. American Journal of Medical Genetics. Part A 140(1): 1–7.

Gripp KW, Stabley DL, Geller PL et al. (2011b) Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome. American Journal of Medical Genetics. Part A 155A(9): 2263–2268.

Gripp KW, Stabley DL, Nicholson L, Hoffman JD and Sol‐Church K (2006b) Somatic mosaicism for an HRAS mutation causes Costello syndrome. American Journal of Medical Genetics. Part A 140(20): 2163–2169.

Groesser L, Herschberger E, Ruetten A et al. (2012) Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nature Genetics 44(7): 783–787.

Hafner C, Toll A and Real FX (2011) HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. New England Journal of Medicine 365(20): 1940–1942.

Happle R (1987) Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. Journal of the American Academy of Dermatology 16(4): 899–906.

Ishida H, Kogaki S, Narita J et al. (2011) LEOPARD‐type SHP2 mutant Gln510Glu attenuates cardiomyocyte differentiation and promotes cardiac hypertrophy via dysregulation of Akt/GSK‐3beta/beta‐catenin signaling. American Journal of Physiology. Heart and Circulatory Physiology 301(4): H1531–H1539.

Kerr B (2009) The clinical phenotype of Costello syndrome. In: M Zenker (ed.) Noonan Syndrome and Related Disorders, vol. 1, pp. 83–93. Basel: Karger.

Kerr B, Allanson J, Delrue MA et al. (2008) The diagnosis of Costello syndrome: nomenclature in Ras/MAPK pathway disorders. American Journal of Medical Genetics. Part A 146A(9): 1218–1220.

Kerr B, Delrue MA, Sigaudy S et al. (2006) Genotype‐phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. Journal of Medical Genetics 43(5): 401–405.

Kerr B, Eden OB, Dandamudi R et al. (1998) Costello syndrome: two cases with embryonal rhabdomyosarcoma. Journal of Medical Genetics 35(12): 1036–1039.

Kinsler V (2012) Multiple Congenital Melanocytic Naevi and Neurocutaneous Melanosis are Caused by Mosaicism for NRAS Codon 61 Mutations, Leading to an Increased Risk of Melanoma in Affected Tissues 23rd Mammalian Genetics and Development Workshop. London: UCL Institute of Child Health.

Lindhurst MJ, Parker VE, Payne F et al. (2012) Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nature Genetics 44(8): 928–933.

Lo IF, Brewer C, Shannon N et al. (2008) Severe neonatal manifestations of Costello syndrome. Journal of Medical Genetics 45(3): 167–171.

Lorenz S, Lissewski C, Simsek‐Kiper PO et al. (2013) Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome. Human Molecular Genetics 22(8): 1643–1653.

Malumbres M and Barbacid M (2003) RAS oncogenes: the first 30 years. Nature Reviews. Cancer 3(6): 459–465.

Marin TM, Keith K, Davies B et al. (2011) Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome‐associated PTPN11 mutation. Journal of Clinical Investigation 121(3): 1026–1043.

NSEuronet database. European Network on Noonan syndrome and related disorders.

Pai EF, Kabsch W, Krengel U et al. (1989) Structure of the guanine‐nucleotide‐binding domain of the Ha‐ras oncogene product p21 in the triphosphate conformation. Nature 341(6239): 209–214.

Parada LF, Tabin CJ, Shih C and Weinberg RA (1982) Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297(5866): 474–478.

Pfeifer GP (2000) p53 mutational spectra and the role of methylated CpG sequences. Mutation Research 450(1–2): 155–166.

Rauen KA (2006) Distinguishing Costello versus cardio‐facio‐cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. American Journal of Medical Genetics. Part A 140(15): 1681–1683.

Santoriello C, Deflorian G, Pezzimenti F et al. (2009) Expression of H‐RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells. Disease Models & Mechanisms 2(1–2): 56–67.

Schuhmacher AJ, Guerra C, Sauzeau V et al. (2008) A mouse model for Costello syndrome reveals an Ang II‐mediated hypertensive condition. Journal of Clinical Investigation 118(6): 2169–2179.

Zampino G, Pantaleoni F, Carta C et al. (2007) Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Human Mutation 28(3): 265–272.

Further Reading

Zenker M (ed.) (2009) Noonan Syndrome and Related Disorders. Monographs in Human Genetics, vol. 17, pp. 1–164. Basel: Karger.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Burkitt Wright, Emma MM, and Kerr, Bronwyn(Sep 2014) Molecular Genetics of Costello Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021471]