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Costello syndrome: clinical diagnosis in the first year of life

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Abstract

We report on three patients with Costello syndrome (CS) diagnosed during the first year of life and try to outline the clinical characteristics facilitating early recognition of this syndrome, which can now be corroborated by testing the HRAS gene. Phenotypical overlap of CS with Noonan (NS) and cardiofaciocutaneous syndrome (CFCS), particularly in neonatal age, is well known. Diagnostic features useful for recognition of CS in the first year of life are the following: (1) fetal and neonatal macrosomia with subsequent slow growth due to severe feeding difficulties, (2) developmental delay, (3) particularly coarse facial dysmorphisms and gingival hyperplasia, (4) skeletal anomalies as osteoporosis and metaphyseal enlargement, (5) hypertrophic cardiomyopathy (HCM) with asymmetric septal thickening and systolic anterior motion of the mitral valve, and (6) specific atrial arrhythmias. Following a clinical suspect of CS based on specific features, molecular screening of HRAS gene mutations should precede analysis of the other genes in the Ras-MAPK pathway implicated in related disorders with overlapping phenotypes.

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Abbreviations

CS:

Costello syndrome

NS:

Noonan syndrome

CFCS:

cardiofaciocutaneous syndrome

MRI:

magnetic resonance imaging

HCM:

hypertrophic cardiomyopathy

References

  1. Allanson JE (1987) Noonan syndrome. J Med Genet 24:9–13

    PubMed  CAS  Google Scholar 

  2. Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato S, Suzuki Y, Kure S, Matsubara Y (2005) Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37:1038–1040

    Article  PubMed  CAS  Google Scholar 

  3. Boente MC, Carrero-Valenzuela RD, Frontini MV, Asial RA (2001) Costello syndrome: report of a new case with choanal atresia and fatal outcome. Eur J Dermatol 11:453–457

    PubMed  CAS  Google Scholar 

  4. Borochowitz Z, Pavone L, Mazor G, Rizzo R, Dar H (1992) New multiple congenital anomalies: Mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement. Am J Med Genet 43:678–685

    Article  PubMed  CAS  Google Scholar 

  5. Burch M, Sharland M, Shinebourne E, Smith G, Patton M, McKenna W (1993) Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment in 118 patients. J Am Coll Cardiol 22:1189–1192

    Article  PubMed  CAS  Google Scholar 

  6. Coppin BD, Temple IK (1997) Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet 34:582–586

    PubMed  CAS  Google Scholar 

  7. Der Kaloustian VM (1993) Not a new MCA/MR syndrome but probably Costello syndrome? Am J Med Genet 47:170–171

    Article  Google Scholar 

  8. Digilio MC, Marino B (2001) Clinical manifestations of Noonan syndrome. Images Paediatr Cardiol 7:19–30

    Google Scholar 

  9. Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B (2002) Grouping of Multiple Lentigines / LEOPARD and Noonan syndrome on the PTPN11 gene. Am J Hum Genet 71:389–394

    Article  PubMed  CAS  Google Scholar 

  10. Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R, Calabrò R, Marino B, Dallapiccola B (2006) LEOPARD syndrome: Clinical diagnosis in the first year of life. Am J Med Genet 140A:740–746

    Article  Google Scholar 

  11. Digilio MC, Sarkozy A, Pacileo G, Limongelli G, Marino B, Dallapiccola B (2006) PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD syndrome phenotype”. Eur J Pediatr 165:803–805

    Article  PubMed  CAS  Google Scholar 

  12. Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA (2006) 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 140A:8–16

    Article  CAS  Google Scholar 

  13. Fukao T, Sakai S, Shimozawa N, Kawahara T, Kano M, Goto E, Nakashima Y, Katagiri-Kawade M, Ichihashi H, Masuno M, Orii T, Kondo N (1996) Life-threatening cardiac involvement throughout life in a case of Costello syndrome. Clin Genet 50:244–247

    Article  PubMed  CAS  Google Scholar 

  14. Gibbs JB, Sigal IS, Poe M, Scolnick EM (1984) Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci USA 81:5704–5708

    Article  PubMed  CAS  Google Scholar 

  15. Gripp KW (2005) Tumor predisposition in Costello syndrome. Am J Med Genet 137C:72–77

    Article  PubMed  Google Scholar 

  16. Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI Jr, Doyle D, Aoki Y, Matsubara Y, Zackai EH, Lapunzina P, Gonzales-Meneses A, Holbrook J, Agresta CA, Gonzales IL, Sol-Church K (2006) HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation. Am J Med Genet 140A:1–7

    Article  CAS  Google Scholar 

  17. Gripp KW, Lin AE (2006) Costello syndrome. http://www.genetests.org

  18. Hennekam RCM (2003) Costello syndrome: an overview. Am J Med Genet 117C:42–48

    Article  PubMed  Google Scholar 

  19. Hirsch HD, Gelband H, Garcia O, Gottlieb S, Tamer DM (1975) Rapidly progressive obstructive cardiomyopathy in infants with Noonan’s syndrome. Reports of two cases. Circulation 52:1161–1165

    PubMed  CAS  Google Scholar 

  20. Johnson JP, Golabi M, Norton ME, Rosenblatt RM, Feldman GM, Yang SP, Hall BD, Fries MH, Carey JC (1998) Costello syndrome. Phenotype, natural history, differential diagnosis and possible cause. J Pediatr 133:441–448

    Article  PubMed  CAS  Google Scholar 

  21. Kerr B, Delrue M-A, Sigaudy S, Pervee 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 (2006) Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet 43:401–405

    Article  PubMed  CAS  Google Scholar 

  22. Levaillant J-M, Gérard-Blanluet M, Holder-Espinasse M, Valat-Rigot A-S, Devisme L, Cavé H, Manouvrier-Hanu S (2006) Prenatal phenotypic overlap of Costello syndrome and severe Noonan syndrome by tri-dimensional ultrasonography. Prenat Diagn 26:340–344

    Article  PubMed  Google Scholar 

  23. Lin AE, Grossfeld PD, Hamilton RM, Smoot L, Gripp KW, Proud V, Weksberg R, Wheeler P, Picker J, Irons M, Zackai E, Marino B, Scott CI Jr, Nicholson L (2002) Further delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet 111:115–129

    Article  PubMed  Google Scholar 

  24. Lin AE, Gripp KG, Kerr BK (2005) Costello syndrome. In: Cassidy SB, Allanson JE (eds). Management of genetic syndromes, 2nd edn. Wiley Liss, Hoboken, pp 151–162

    Google Scholar 

  25. Marino B, Gagliardi MG, Digilio MC, Polletta B, Grazioli S, Agostino D, Giannotti A, Dallapiccola B (1995) Noonan syndrome: structural abnormalities of the mitral valve causing subaortic obstruction. Eur J Pediatr 154:949–952

    Article  PubMed  CAS  Google Scholar 

  26. Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B (1999) Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr 135:703–706

    Article  PubMed  CAS  Google Scholar 

  27. Martin RA, Lyons Jones K (1993) Facio-cutaneous-skeletal syndrome is the Costello syndrome. Am J Med Genet 47:169

    Article  PubMed  CAS  Google Scholar 

  28. McGrath JP, Capon DJ, Goeddel DV, Levinson AD (1984) Comparative biochemical properties of normal and activated human ras p21 protein. Nature 310:644–649

    Article  PubMed  CAS  Google Scholar 

  29. Mendez HMM, Opitz JM (1985) Noonan syndrome: a review. Am J Med Genet 21:493–506

    Article  PubMed  CAS  Google Scholar 

  30. Nisbet DL, Griffin DR, Chitty LS (1999) Prenatal features of Noonan syndrome. Prenat Diagn 19:642–647

    Article  PubMed  CAS  Google Scholar 

  31. Philip N, Mancini J (1993) Costello syndrome and facio-cutaneous-skeletal syndrome. Am J Med Genet 47:174–175

    Article  PubMed  CAS  Google Scholar 

  32. Philip N, Sigaudy S (1998) Costello syndrome. J Med Genet 35:238–240

    PubMed  CAS  Google Scholar 

  33. Popa M, Ioan DM, Fryns JP (1996) Costello syndrome: report of an 8-month-old marasmic boy. Genet Couns 7:27–30

    PubMed  CAS  Google Scholar 

  34. Proud VK, Davis B, Rutledge SL, Gupyta B, Bence L, Schoyer L (2001) Clinical phenotype and natural history of connective tissue problems in 16 individuals with Costello syndrome evaluated at the 1st International Costello Syndrome Conference, April 1999. Proc Greenwood Genet Ctr 20:115A

    Google Scholar 

  35. Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, Young T, Neri G (2006) The cardio-facio-cutaneous (CFC) syndrome: a review. J Med Genet 43:833–842

    Article  PubMed  CAS  Google Scholar 

  36. Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio VM, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B (2003) Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 40:704–708

    Article  PubMed  CAS  Google Scholar 

  37. Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Wilson M, Calabrò R, Pizzuti A, Dallapiccola B (2004) Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet 41:e68

    Article  PubMed  CAS  Google Scholar 

  38. Shah N, Rodriguez M, St Louis D, Lindley K, Milla PJ (1999) Feeding difficulties and foregut dysmotility in Noonan’s syndrome. Arch Dis Child 81:28–31

    Article  PubMed  CAS  Google Scholar 

  39. Sharland M, Burch M, McKenna WM, Patton MA (1992) A clinical study of Noonan syndrome. Arch Dis Child 67:178–183

    PubMed  CAS  Google Scholar 

  40. Siwik ES, Zahka KG, Wiesner GL, Limwongse C (1998) Cardiac disease in Costello syndrome. Pediatrics 101:706–709

    Article  PubMed  CAS  Google Scholar 

  41. Sol-Church K, Stabley DL, Nicholson L, Gonzales IL, Gripp KW (2006) Paternal bias in parental origin of HRAS mutations in Costello syndrome. Hum Mut 27:736–741

    Article  PubMed  CAS  Google Scholar 

  42. Somerville J, Bonham-Carter RE (1972) The heart in lentiginosis. Br Heart J 34:58–66

    Article  PubMed  CAS  Google Scholar 

  43. Sweet RW, Yokoyama S, Kamata T, Feramisco JR, Rosenberg M, Gross M (1984) The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature 311:273–275

    Article  PubMed  CAS  Google Scholar 

  44. Tomita H, Fuse S, Ikeda K, Matsuda K, Chiba S (1998) An infant with Costello syndrome complicated by fatal hypertrophic obstructive cardiomyopathy. Acta Paediatr Jap 40:608–611

    CAS  Google Scholar 

  45. Umans S, Decock P, Fryns JP (1995) Costello syndrome: the natural history of a true postnatal growth retardation syndrome. Genet Couns 6:121–125

    PubMed  CAS  Google Scholar 

  46. Van den Bosch T, Van Schoubroeck D, Fryns J-P, Naulaers G, Inion AM, Devriendt K (2002) Prenatal findings in a monozygotic twin pregnancy with Costello syndrome. Prenat Diagn 22:415–417

    Article  PubMed  Google Scholar 

  47. van Eeghen AM, van Gelderen I, Hennekam RCM (1999) Costello syndrome: Report and review. Am J Med Genet 82:187–193

    Article  PubMed  Google Scholar 

  48. Verloes A, Le Merrer M, Soyeur D, Kaplan J, Pangalos C, Rigo J, Briard M-L (1988) CFC syndrome: a syndrome distinct from Noonan syndrome. Ann Génét 31:230–234

    PubMed  CAS  Google Scholar 

  49. Wieczorek D, Majewski F, Gillessen-Kaesbach G (1997) Cardio-facio-cutaneous (CFC) syndrome - distinct entity? Report of three patients demonstrating diagnostic difficulties in delineation of CFC syndrome. Clin Genet 52:37–46

    Article  PubMed  CAS  Google Scholar 

  50. Zampino G, Mastroiacovo P, Ricci R, Zollino M, Segni G, Martini-Neri ME, Neri G (1993) Costello syndrome: Further clinical delineation, natural history, genetic definition, and nosology. Am J Med Genet 47:176–183

    Article  PubMed  CAS  Google Scholar 

  51. 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 (2006) Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat 28:265–272

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Medical Genetics, Pediatric Cardiology, Bronchopneumology, Bambino Gesù Hospital, Rome, Italy

    M. Cristina Digilio, Rossella Capolino, M. Beatrice Chiarini Testa, Andrea de Zorzi & Renato Cutrera

  2. IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome and Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy

    Anna Sarkozy, Giorgia Esposito & Bruno Dallapiccola

  3. Pediatric Cardiology, Department of Pediatrics, University La Sapienza, Rome, Italy

    Bruno Marino

Authors
  1. M. Cristina Digilio
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  2. Anna Sarkozy
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  3. Rossella Capolino
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  4. M. Beatrice Chiarini Testa
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  8. Bruno Marino
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  9. Bruno Dallapiccola
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Correspondence to M. Cristina Digilio.

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Digilio, M.C., Sarkozy, A., Capolino, R. et al. Costello syndrome: clinical diagnosis in the first year of life. Eur J Pediatr 167, 621–628 (2008). https://doi.org/10.1007/s00431-007-0558-0

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  • DOI: https://doi.org/10.1007/s00431-007-0558-0

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