European Journal of Pediatrics

, Volume 169, Issue 4, pp 469–473 | Cite as

LEOPARD syndrome with recurrent PTPN11 mutation Y279C and different cutaneous manifestations: two case reports and a review of the literature

  • Ingrid KalevEmail author
  • Kai Muru
  • Rita Teek
  • Riina Zordania
  • Tiia Reimand
  • Kristel Köbas
  • Katrin Õunap
Original Paper


LEOPARD syndrome (LS) is a heterogeneous disease characterised mainly by cutaneous manifestations. LEOPARD is the acronym for its major features—multiple lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of (male) genitalia, retardation of growth and sensorineural deafness. As clinical manifestations are variable, molecular testing is supportive in the diagnosis of LS. We describe two unrelated LS cases with a common PTPN11 mutation Y279C and with completely different clinical features including distinct changes in skin pigmentation. In patient 1, the first complaint was hyperactive behaviour. First lentigines were presented at birth, but intensive growth began at the age of 2–4 years. Multiple dark lentigines were located mainly on the face and the upper part of the trunk, but the oral mucosa was spared. Patient 2 was born from induced labour due to polyhydramnion, and in the second week of life, mitral valve insufficiency and hypertrophic cardiomyopathy were diagnosed. Rapid growth of lentigines began at the age of 3 years. These are mostly located in the joint areas in the lower extremities; the face and upper trunk are spared from lentigines. In both cases, the rapid growth of lentigines made it possible to shift the diagnosis towards LS. Clinicians should give more consideration to rare genetic syndromes, especially in the case of symptoms from different clinical areas.


LEOPARD syndrome PTPN11 gene Y279C SHP-2 Multiple lentigines 



src homology-2 (SH2)-containing protein tyrosine phosphatase (PTP)


Protein-tyrosine phosphatase, non-receptor type 11



The authors are grateful to the patients and their families for their participation. This study was supported by grants from the Estonian Science Foundation GARMP 6573, GARLA 6808 and by target financing grant SF 0180096s08.

Conflict of interest statement

The authors declare no competing financial interests.


  1. 1.
    Adriaenssens T, Ibrahim T, Seyfarth M (2007) The LEOPARD syndrome: a rare condition associated with hypertrophic cardiomyopathy. Eur Heart J 28(24):3066CrossRefPubMedGoogle Scholar
  2. 2.
    Conti E, Dottorini T, Sarkozy A, Tiller GE, Esposito G, Pizzuti A, Dallapiccola B (2003) A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat 21:654CrossRefPubMedGoogle Scholar
  3. 3.
    Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B (2002) Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389–394CrossRefPubMedGoogle Scholar
  4. 4.
    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 165:803–805CrossRefPubMedGoogle Scholar
  5. 5.
    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:740–746CrossRefGoogle Scholar
  6. 6.
    Gorlin RJ, Anderson RC, Blaw M (1969) Multiple lentigines syndrome. Am J Dis Child 17:652–662Google Scholar
  7. 7.
    Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cavé H (2004) PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet 41:e117. doi: 10.1136/jmg.2004.021451 CrossRefPubMedGoogle Scholar
  8. 8.
    Koudova M, Seemanova E, Zenker M (2009) Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. Eur J Med Genet 52:337–340. doi: 10.1016/j.ejmg.2009.04.006 CrossRefPubMedGoogle Scholar
  9. 9.
    Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns J-P (2002) PTPN11 mutations in LEOPARD syndrome. J Med Genet 39:571–574CrossRefPubMedGoogle Scholar
  10. 10.
    Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P, Versacci P, Calabro P, De Zorzi A, Di Salvo G, Syrris P, Patton M, McKenna WJ, Dallapiccola B, Calabro R (2007) Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol 100:736–741CrossRefPubMedGoogle Scholar
  11. 11.
    Limongelli G, Sarkozy A, Pacileo G, Calabrò P, Digilio MC, Maddaloni V, Gagliardi G, Di Salvo G, Iacomino M, Marino B, Dallapiccola B, Calabrò R (2008) Genotype–phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am J Med Genet Part A 146A:620–628CrossRefPubMedGoogle Scholar
  12. 12.
    Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Siguero JPL, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 39(8):1007–1012CrossRefPubMedGoogle Scholar
  13. 13.
    Sarkozy A, Conti E, Digilio CM, 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. doi: 10.1136/jmg.2003.013466 CrossRefPubMedGoogle Scholar
  14. 14.
    Sarkozy A, Digilio MC, Dallapiccola B (2008) Leopard syndrome. Orphanet J Rare Dis 3:13CrossRefPubMedGoogle Scholar
  15. 15.
    Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GMS, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M (2009) Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat 30:695–702CrossRefPubMedGoogle Scholar
  16. 16.
    Tartaglia M, Mehler E, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468CrossRefPubMedGoogle Scholar
  17. 17.
    Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T (2004) Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet 130A:432–434CrossRefPubMedGoogle Scholar
  18. 18.
    Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman JJ, Fryns JP (1996) Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat 8:51–56CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ingrid Kalev
    • 1
    Email author
  • Kai Muru
    • 2
    • 3
  • Rita Teek
    • 2
    • 4
  • Riina Zordania
    • 5
  • Tiia Reimand
    • 2
    • 3
  • Kristel Köbas
    • 6
  • Katrin Õunap
    • 2
    • 3
  1. 1.Department of Human Biology and Genetics, Institute of General and Molecular PathologyUniversity of TartuTartuEstonia
  2. 2.Department of Genetics, United LaboratoriesTartu University HospitalTartuEstonia
  3. 3.Department of PediatricsUniversity of TartuTartuEstonia
  4. 4.Department of Oto-Rhino-LaryngologyUniversity of TartuTartuEstonia
  5. 5.Children’s HospitalTallinnEstonia
  6. 6.Children’s ClinicTartu University HospitalTartuEstonia

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