LEOPARD Syndrome 

  • Author: Sergiusz Jozwiak, MD, PhD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 24, 2012
 

Background

LEOPARD syndrome is a complex dysmorphogenetic disorder of variable penetrance and expressivity. Gorlin et al introduced the acronym LEOPARD as the name of the syndrome in 1969 to recall the main features of the disorder.

  • Lentigines (multiple) as shown belowMultiple lentigines on the face of a child with LEMultiple lentigines on the face of a child with LEOPARD syndrome.
  • Electrocardiographic conduction abnormalities
  • Ocular hypertelorism
  • Pulmonary stenosis
  • Abnormalities of genitalia
  • Retardation of growth
  • Deafness

Not all of the findings are present in any given patient. Zeisler and Becker first described the syndrome in 1936 in a 24-year-old woman with progressive generalized lentigines, hypertelorism, pectus carinatum, and prognathism. The first familial cases were reported in twins by Rosen and subsequently in 8 persons from a large 3-generation pedigree reported by Pipkin. Subsequent communications added new findings in isolated patients or families. Moynahan first documented the association of the syndrome with cardiac abnormalities and short stature in 1962.

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Pathophysiology

Molecular studies have proven that LEOPARD syndrome and Noonan syndrome are allelic disorders caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at band 12q24.1.[1]

In 2005, Ogata and Yoshida documented that PTPN11 mutations can be identified in approximately 40% of Noonan syndrome patients and in greater than 80% of LEOPARD syndrome patients.[2] Because the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities.

In 2006, Hanna et al found that Noonan syndrome mutations enhance SHP-2 catalytic activity, whereas the activity of representative LS mutants is undetectable when assayed using a standard PTP substrate.[3] The results are also supported by studies by Kontaridis et al.[4] They revealed that whereas Noonan syndrome is caused by gain-of-function PTPN11 mutations, LEOPARD syndrome mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinase–mediated signaling.

In 2006, Tartaglia et al reported that germline mutations in the PTPN11 gene cause LEOPARD and Noonan syndromes, whereas somatic mutations in the same gene contribute to leukemogenesis.[5] To date, 2 patients with LEOPARD syndrome and myelomonocytic or acute lymphoblastic leukemias have been reported.[6, 7]

Importantly, however, not all patients with LEOPARD syndrome demonstrate linkage to 12q24.1.

Reported in 2005, Kalidas et al performed mutation screening and linkage analysis of PTPN11 in 3 families, each of which had a history of LEOPARD syndrome for 3 generations.[8] One family was found to carry a novel mutation (Q510P; 176876.0022). No variations in sequence were observed in the other 2 families, and negative lod scores excluded linkage to the PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.

Writzl et al reported a family with molecularly proven (p.Thr468Met in PTPN11) LEOPARD syndrome in a father and his adult son.[9] The father had multiple lentigines equally dispersed over his body as depicted below, whereas his son was devoid of lentigines on the left part of the thorax, back, and left arm. In addition, the son was found to have a mosaic karyotype in lymphocytes (47, XXY/46XY). On skin biopsy, mainly 47,XXY karyotype was present in the pigmented skin and 46,XY karyotype in the unpigmented areas. The authors considered various pathogenetic mechanisms: revertant mosaicism, silencing of a second PTPN11 mutation, genes located on a sex chromosome influencing the phenotype, and epigenetic influences.

Multiple, small lentigines evenly distributed overMultiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome.
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Epidemiology

Frequency

International

No epidemiologic data are available. The syndrome seems to be rare both in the United States and internationally.

Mortality/Morbidity

Most patients with LEOPARD syndrome lead a normal life. Cardiac pathologic findings (eg, obstructive cardiomyopathy, cardiac dysrhythmias) may be a cause of death in selected patients. A 19-year-old woman who died as a result of respiratory insufficiency secondary to thoracic deformities and a congenital heart defect has been reported.

Race

LEOPARD syndrome has no clear racial predilection.

Sex

In a large collected series of 77 patients, a slight preponderance of men has been documented (47 men, 30 women).

Age

Lentigines may be present at birth or develop during childhood. They become more numerous and darker with age. Other skin lesions, such as nevocellular nevi and malignant melanomas, reported sporadically in the LEOPARD syndrome, may undergo depigmentation.

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Contributor Information and Disclosures
Author

Sergiusz Jozwiak, MD, PhD  Head, Professor, Department of Child Neurology, The Children's Memorial Health Institute of Warsaw, Poland

Sergiusz Jozwiak, MD, PhD is a member of the following medical societies: Sigma Xi

Disclosure: Novartis Honoraria Speaking and teaching

Coauthor(s)

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

James J Nordlund, MD  Professor Emeritus, Department of Dermatology, University of Cincinnati College of Medicine

James J Nordlund, MD is a member of the following medical societies: American Academy of Dermatology, Sigma Xi, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD  Assistant Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

References

  1. Kim J, Kim MR, Kim HJ, Lee KA, Lee MG. LEOPARD Syndrome with PTPN11 Gene Mutation Showing Six Cardinal Symptoms of LEOPARD. Ann Dermatol. May 2011;23(2):232-5. [Medline]. [Full Text].

  2. Ogata T, Yoshida R. PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev. Jun 2005;2(4):669-74. [Medline].

  3. Hanna N, Montagner A, Lee WH, Miteva M, Vidal M, Vidaud M, et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. May 1 2006;580(10):2477-82. [Medline].

  4. Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. Mar 10 2006;281(10):6785-92. [Medline].

  5. Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. Feb 2006;78(2):279-90. [Medline].

  6. Ucar C, Calyskan U, Martini S, Heinritz W. Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive). J Pediatr Hematol Oncol. Mar 2006;28(3):123-5. [Medline].

  7. Laux D, Kratz C, Sauerbrey A. Common acute lymphoblastic leukemia in a girl with genetically confirmed LEOPARD syndrome. J Pediatr Hematol Oncol. Aug 2008;30(8):602-4. [Medline].

  8. Kalidas K, Shaw AC, Crosby AH, Newbury-Ecob R, Greenhalgh L, Temple IK, et al. Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11. J Hum Genet. 2005;50(1):21-5. [Medline].

  9. Writzl K, Hoovers J, Sistermans EA, Hennekam RC. LEOPARD syndrome with partly normal skin and sex chromosome mosaicism. Am J Med Genet A. Nov 1 2007;143A(21):2612-5. [Medline].

  10. Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines syndrome. Case report and review of the literature. Am J Med. Mar 1976;60(3):447-56. [Medline].

  11. Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R, et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am J Med Genet A. Apr 1 2006;140(7):740-6. [Medline].

  12. Bujaldon AR. LEOPARD syndrome: what are café noir spots?. Pediatr Dermatol. Jul-Aug 2008;25(4):444-8. [Medline].

  13. Xing Q, Chen X, Wang M, Bai W, Peng X, Gao R, et al. A locus for familial generalized lentiginosis without systemic involvement maps to chromosome 4q21.1-q22.3. Hum Genet. Jul 2005;117(2-3):154-9. [Medline].

  14. Limongelli G, Sarkozy A, Pacileo G, Calabro P, Digilio MC, Maddaloni V, et al. Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am J Med Genet A. Mar 1 2008;146A(5):620-8. [Medline].

  15. Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P, et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol. Aug 15 2007;100(4):736-41. [Medline].

  16. Yagubyan M, Panneton JM, Lindor NM, Conti E, Sarkozy A, Pizzuti A. LEOPARD syndrome: a new polyaneurysm association and an update on the molecular genetics of the disease. J Vasc Surg. Apr 2004;39(4):897-900. [Medline].

  17. Porciello R, Divona L, Strano S, Carbone A, Calvieri C, Giustini S. Leopard syndrome. Dermatol Online J. Mar 15 2008;14(3):7. [Medline].

  18. Rudolph G, Haritoglou C, Kalpadakis P, Boergen KP, Meitinger T. [LEOPARD syndrome with iris-retina-choroid coloboma. Discordant findings in monozygotic twins (MIM # 151 100)]. Ophthalmologe. Nov 2001;98(11):1101-3. [Medline].

  19. Lodish MB, Stratakis CA. The differential diagnosis of familial lentiginosis syndromes. Fam Cancer. Sep 2011;10(3):481-90. [Medline].

  20. Ahlbom BE, Dahl N, Zetterqvist P, Anneren G. Noonan syndrome with cafe-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus. Clin Genet. Aug 1995;48(2):85-9. [Medline].

  21. Arnsmeier SL, Paller AS. Pigmentary anomalies in the multiple lentigines syndrome: Is it distinct from LEOPARD syndrome?. Pediatr Dermatol. Mar-Apr 1996;13(2):100-4. [Medline].

  22. Bonioli E, Di Stefano A, Costabel S, Bellini C. Partial agenesis of corpus callosum in LEOPARD syndrome. Int J Dermatol. Nov 1999;38(11):855-62. [Medline].

  23. Cetinkaya E, Gunal N, Sonmez N, Aycan Z, Vidinlisan S, Kahramanyol O, et al. LEOPARD syndrome and hypertrophic obstructive cardiomyopathy: a case report. Turk J Pediatr. Oct-Dec 2004;46(4):373-6. [Medline].

  24. Chan HH, Fung WK, Ying SY, Kono T. An in vivo trial comparing the use of different types of 532 nm Nd:YAG lasers in the treatment of facial lentigines in Oriental patients. Dermatol Surg. Aug 2000;26(8):743-9. [Medline].

  25. Choi WW, Yoo JY, Park KC, Kim KH. LEOPARD syndrome with a new association of congenital corneal tumor, choristoma. Pediatr Dermatol. Mar-Apr 2003;20(2):158-60. [Medline].

  26. Chong WS, Klanwarin W, Giam YC. Generalized lentiginosis in two children lacking systemic associations: case report and review of the literature. Pediatr Dermatol. Mar-Apr 2004;21(2):139-45. [Medline].

  27. Conti E, Dottorini T, Sarkozy A, Tiller GE, Esposito G, Pizzuti A, et al. A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat. Jun 2003;21(6):654. [Medline].

  28. Coppin BD, Temple IK. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet. Jul 1997;34(7):582-6. [Medline].

  29. Dacey MJ, Kulp-Shorten CL, Callen JP. LEOPARD syndrome in a patient with morphea and acro-osteolysis. J Cutan Med Surg. Jul 1998;3(1):25-8. [Medline].

  30. Digilio MC, Capolino R, Marino B, Sarkozy A, Dallapiccola B. Congenital intrahepatic portosystemic venous shunt: an unusual feature in LEOPARD syndrome and in neurofibromatosis type 1. Am J Med Genet A. May 1 2005;134(4):457-8. [Medline].

  31. Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. Aug 2002;71(2):389-94. [Medline].

  32. Digilio MC, Pacileo G, Sarkozy A, Limongelli G, Conti E, Cerrato F, et al. Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations. Birth Defects Res A Clin Mol Teratol. Feb 2004;70(2):95-8. [Medline].

  33. Froster UG, Glander HJ, Heinritz W. [Molecular genetic mutation analysis of the PTPN11 gene in the multiple lentigines (LEOPARD) syndrome]. Hautarzt. Dec 2003;54(12):1190-2. [Medline].

  34. Goyal SB, Aragam JR. Aortic root dilatation with redundancy of mitral and aortic leaflets associated with the LEOPARD syndrome. Int J Cardiol. Jun 7 2006;110(1):110-1. [Medline].

  35. Gupta P, Loiwal V, Rai R, Baruah MC, Mishra K, Krishna A. Leopard syndrome: a tropical rarity. J Dermatol. May 1998;25(5):341-3. [Medline].

  36. Hagspiel KD, Candinas RC, Hagspiel HJ, Amann FW. LEOPARD syndrome: cardiac imaging findings. AJR Am J Roentgenol. Mar 2005;184(3 Suppl):S21-4. [Medline].

  37. Ishigami T, Wakamatsu A, Kishida T, Yokoyama K, Sugiyama K. [ECG changes during emergence from anesthesia in a patient with LEOPARD syndrome]. Masui. Oct 2003;52(10):1115-7. [Medline].

  38. Jozwiak S, Schwartz RA, Janniger CK. LEOPARD syndrome (cardiocutaneous lentiginosis syndrome). Cutis. Apr 1996;57(4):208-14. [Medline].

  39. Jozwiak S, Schwartz RA, Janniger CK, Zaremba J. Familial occurrence of the LEOPARD syndrome. Int J Dermatol. Jan 1998;37(1):48-51. [Medline].

  40. Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. Nov 2004;41(11):e117. [Medline].

  41. Kontoes PP, Vlachos SP, Marayiannis KV. Intense pulsed light for the treatment of lentigines in LEOPARD syndrome. Br J Plast Surg. Sep 2003;56(6):607-10. [Medline].

  42. Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. Aug 2002;39(8):571-4. [Medline].

  43. Merks JH, Caron HN, Hennekam RC. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet A. Apr 15 2005;134A(2):132-43. [Medline].

  44. Munshi A, Munshi AK. Leopard syndrome--report of a variant case. J Indian Soc Pedod Prev Dent. Mar 1999;17(1):5-8. [Medline].

  45. National Center for Biotechnology Information. Online Mendelian Inheritance in Man. Available at http://www.ncbi.nlm.nih.gov/omim/.

  46. Ohkura T, Ohnishi Y, Kawada A, Tajima S, Ishibashi A, Ono K. Leopard syndrome associated with hyperelastic skin: analysis of collagen metabolism in cultured skin fibroblasts. Dermatology. 1999;198(4):385-7. [Medline].

  47. Pacheco TR, Oreskovich N, Fain P. Genetic heterogeneity in the multiple lentigines/LEOPARD/Noonan syndromes. Am J Med Genet A. Jun 15 2004;127A(3):324-6. [Medline].

  48. Peter JR, Kemp JS. LEOPARD syndrome: death because of chronic respiratory insufficiency. Am J Med Genet. Nov 1990;37(3):340-1. [Medline].

  49. Petter G, Rytter M, Haustein UF. [Multiple lentigines (LEOPARD) syndrome. Case reports and review of the literature]. Hautarzt. Jun 2002;53(6):403-8. [Medline].

  50. Robain A, Perchet H, Fuhrman C. Flecainide-associated pneumonitis with acute respiratory failure in a patient with the LEOPARD syndrome. Acta Cardiol. Feb 2000;55(1):45-7. [Medline].

  51. Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. May 2004;41(5):e68. [Medline].

  52. Sarkozy A, Obregon MG, Conti E, Esposito G, Mingarelli R, Pizzuti A, et al. A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet. Dec 2004;12(12):1069-72. [Medline].

  53. Schepis C, Greco D, Siragusa M, Batolo D, Romano C. An intriguing case of LEOPARD syndrome. Pediatr Dermatol. Mar-Apr 1998;15(2):125-8. [Medline].

  54. Shamsadini S, Abazardi H, Shamsadini F. Leopard syndrome. Lancet. Oct 30 1999;354(9189):1530. [Medline].

  55. Shibusawa Y, Tamura A, Mochiki E, Kamisaka K, Kimura H, Ishikawa O. c-kit Mutation in generalized lentigines associated with gastrointestinal stromal tumor. Dermatology. 2004;208(3):217-20. [Medline].

  56. Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005;6:45-68. [Medline].

  57. Ton'sheva LN, Sidorova LD. [The Leopard syndrome in a patient with sebocystomatosis]. Klin Med (Mosk). 2001;79(6):65-7. [Medline].

  58. Tong KL, Ding ZP, Chua T. Leopard syndrome. Singapore Med J. Jul 2001;42(7):328-31. [Medline].

  59. Torres J, Russo P, Tobias JD. Anaesthetic implications of LEOPARD syndrome. Paediatr Anaesth. Apr 2004;14(4):352-6. [Medline].

  60. Tullu MS, Muranjan MN, Kantharia VC, Parmar RC, Sahu DR, Bavdekar SB, et al. Neurofibromatosis-Noonan syndrome or LEOPARD Syndrome? A clinical dilemma. J Postgrad Med. Apr-Jun 2000;46(2):98-100. [Medline].

  61. Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman JJ, Fryns JP. Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat. 1996;8(1):51-6. [Medline].

  62. Yam AA, Faye M, Kane A, Diop F, Coulybaly-Ba D, Tamba-Ba A, et al. Oro-dental and craniofacial anomalies in LEOPARD syndrome. Oral Dis. May 2001;7(3):200-2. [Medline].

  63. Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet A. Nov 1 2004;130A(4):432-4. [Medline].

 
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Multiple lentigines on the face of a child with LEOPARD syndrome.
Lentigines on the sclerae in a child with LEOPARD syndrome.
Area of disordered pigmentation on the trunk of a patient with LEOPARD syndrome.
Onychodystrophy in a child with LEOPARD syndrome.
Multiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome.
 
 
 
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