Abstract
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.
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Abbreviations
- SHP-2:
-
src homology-2 (SH2)-containing protein tyrosine phosphatase (PTP)
- PTPN11:
-
Protein-tyrosine phosphatase, non-receptor type 11
References
Adriaenssens T, Ibrahim T, Seyfarth M (2007) The LEOPARD syndrome: a rare condition associated with hypertrophic cardiomyopathy. Eur Heart J 28(24):3066
Conti E, Dottorini T, Sarkozy A, Tiller GE, Esposito G, Pizzuti A, Dallapiccola B (2003) A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat 21:654
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 71:389–394
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
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
Gorlin RJ, Anderson RC, Blaw M (1969) Multiple lentigines syndrome. Am J Dis Child 17:652–662
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
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
Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns J-P (2002) PTPN11 mutations in LEOPARD syndrome. J Med Genet 39:571–574
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 100:736–741
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:620–628
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):1007–1012
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
Sarkozy A, Digilio MC, Dallapiccola B (2008) Leopard syndrome. Orphanet J Rare Dis 3:13
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 30:695–702
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 29:465–468
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:432–434
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 8:51–56
Acknowledgements
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.
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Kalev, I., Muru, K., Teek, R. et al. LEOPARD syndrome with recurrent PTPN11 mutation Y279C and different cutaneous manifestations: two case reports and a review of the literature. Eur J Pediatr 169, 469–473 (2010). https://doi.org/10.1007/s00431-009-1058-1
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DOI: https://doi.org/10.1007/s00431-009-1058-1