Molecular Genetics of LEOPARD Syndrome

Abstract

LEOPARD syndrome (LS) is an acronym for the cardinal features lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensorineural deafness. However, other disorders, such as hypertrophic cardiomyopathy, occur frequently and represent a potentially life‐threatening problem. PTPN11 mutations, located on chromosome 12q24, are observed in up to 90% of patients with LS. Meanwhile, mutations in the RAF1 gene on chromosome 3p25.2 and mutations in the BRAF gene on chromosome 7q34 occur in 5% of the cases. Eleven different missense PTPN11 mutations, characterised by a decrease in physiological activity of the mutated protein (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro and Gln510Glu/Pro) have been reported, two of which (Tyr279Cys and Thr468Met) occur in approximately 65% of the cases.

Key Concepts:

  • LEOPARD syndrome (LS) (OMIM #151100) and Noonan syndrome (NS) (OMIM #163950) are two disorders that are part of a newly classified family of autosomal dominant syndromes termed ‘RASopathies’, which are caused by germline mutations in components of the RAS‐MAPK (mitogen‐activated protein kinases) signal transduction pathway that is involved in the regulation of normal cell proliferation, survival and differentiation.

  • LS is an acronym for the cardinal features lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensorineural deafness.

  • The diagnosis of LS is made on clinical grounds by observation of key features.

  • PTPN11, RAF1 and BRAF are the genes known to be associated with LS. Molecular genetic testing of the three genes identifies mutations in approximately 95% of affected individuals.

  • LS may be sporadic (de‐novo mutation) or inherited as an autosomal dominant trait.

  • Lentigines are the most prominent manifestation of LS and are found in more than 90% of the patients.

  • On the whole, 85% of patients with LS have heart defects. Hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life‐threatening problem in these patients.

  • To date, it is unclear whether the genotype may influence the clinical course in LS patients with hypertrophic cardiomyopathy.

  • Although some haematologic tumours have been reported in patients with LS the association is inconclusive.

  • Genetic counselling helps families and patients to understand and cope with the diagnosis of their genetic condition and its implications.

Keywords: LEOPARD syndrome; Noonan syndrome; hypertrophic cardiomyopathy; PTPN11; RAF1; BRAF ; mutations; RASopathies; RAS/MAPK pathway

Figure 1.

Schematic diagram showing the RAS‐MAPK signal transduction pathway and proteins that are affected in both syndromes (LS, Leopard syndrome and NS, Noonan syndrome).

Figure 2.

The wild‐type tyrosine–protein phosphatase nonreceptor type 11 (SHP2) protein. Diagram showing secondary structure and organisation of the domains (a) and 3D image (b) of SHP2 (structures in (a) and (b) are in similar orientations). In the protein tyrosine phosphatases (PTP) family, a subgroup of cytoplasmic PTPs characterised by containing two Src homology 2 (SH2), NH2‐terminal domains and a C‐terminal protein‐tyrosine phosphatase domain, are referred to as SHP. Note that the peptide‐binding sites of both SH2 domains are exposed on the molecular surface. A distinct surface of the N‐SH2 domain occupies the active site of the PTP domain (autoinhibited closed configuration). Image modified from the RCSB PDB (www.pdb.org) of PDB ID 10.2210 (Yu et al., ).

Figure 3.

A LEOPARD syndrome patient with hearing aids due to sensorineural deafness (a); numerous lentigines on the skin of the face (b), chest (c) and legs (d).

Figure 4.

(a) Posteroanterior chest X‐ray showing mild vertical displacement of the left ventricular apex in the context of left ventricular hypertrophy in a patient with LEOPARD syndrome. (b) Twelve‐lead ECG showing high R waves in the right precordial leads with ST depression in the context of LVH and systolic ventricular overload.

Figure 5.

Two‐dimensional echocardiogram performed in the parasternal short‐axis view (a) and coronal view of magnetic resonance angiography (b) showing left ventricular hypertrophy involving the intraventricular septum (asterisk). RV: right ventricle, LV: left ventricle.

close

References

Aoki Y , Niihori T , Narumi Y et al. (2008) The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Human Mutation 29(8): 992–1006.

Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Research 49: 4682–4689.

van der Burgt I (2007) Noonan syndrome. Orphanet Journal of Rare Diseases 2: 4.

Digilio MC , Lepri F , Baban A et al. (2011) RASopathies: clinical diagnosis in the first year of life. Molecular Syndromology 1(6): 282–289.

Digilio MC , Sarkozy A , de Zorzi A et al. (2006) LEOPARD syndrome: clinical diagnosis in the first year of life. American Journal of Medical Genetics Part A 140: 740–746.

Gelb BD and Tartaglia M (1993–2013) LEOPARD Syndrome. GeneReviews™ [Internet]. Seattle, WA: University of Washington.

Hafner C and Groesser L (2013) Mosaic RASopathies. Cell Cycle 12(1): 43–50.

Kontaridis MI , Swanson KD , David FS , Barford D and Neel BG (2006) PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. Journal of Biological Chemistry 281(10): 6785–6792.

Kratz CP , Rapisuwon S , Reed H , Hasle H and Rosenberg PS (2011) Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. American Journal of Medical Genetics Part C Seminars in Medical Genetics 157C(2): 83–89.

Lauriol J and Kontaridis MI (2011) PTPN11‐associated mutations in the heart: has LEOPARD changed its RASpots? Trends in Cardiovascular Medicine 21(4): 97–104.

Laux D , Kratz C and Sauerbrey A (2008) Common acute lymphoblastic leukemia in a girl with genetically confirmed LEOPARD syndrome. Journal of Pediatric Hematology/Oncology 30: 602–604.

Limongelli G , Pacileo G , Marino B et al. (2007) Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. American Journal of Cardiology 100: 736–741.

Limongelli G , Sarkozy A , Pacileo G et al. (2008) Genotype‐phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. American Journal of Medical Genetics Part A 146A: 620–628.

Martínez‐Quintana E and Rodríguez‐González F (2011) Leopard syndrome and hypertrophic cardiomyopathy. Radiologia 53(3): 284–286.

Martínez‐Quintana E and Rodríguez‐González F (2012a) LEOPARD syndrome caused by Tyr279Cys mutation in the PTPN11 gene. Molecular Syndromology 2(6): 251–253.

Martínez‐Quintana E and Rodríguez‐González F (2012b) LEOPARD syndrome: clinical features and gene mutations. Molecular Syndromology 3(4): 145–157.

Martínez‐Quintana E and Rodríguez‐González F (2013) RASopathies: from Noonan to LEOPARD syndrome. Revista Española de Cardiología 66(9): 756–757.

Musante L , Kehl HG , Majewski F et al. (2003) Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio‐facio‐cutaneous syndrome. European Journal of Human Genetics 11: 201–206.

Niihori T , Aoki Y , Narumi Y et al. (2006) Germline KRAS and BRAF mutations in cardio‐facio‐cutaneous syndrome. Nature Genetics 38: 294–296.

Pandit B , Sarkozy A , Pennacchio LA et al. (2007). Gain‐of‐function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics 39: 1007–1012.

Parikh C , Subrahmanyam R and Ren R (2007) Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Cancer Research 67(15): 7139–7146.

Pearson G , Robinson F , Beers Gibson T et al. (2001) Mitogen‐activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrine Reviews 22(2): 153–183.

Sarkozy A , Carta C , Moretti S et al. (2009) Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Human Mutation 30: 695–702.

Sarkozy A , Conti E , Digilio MC et al. (2004) Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. Journal of Medical Genetics 41: e68.

Sarkozy A , Digilio MC and Dallapiccola B (2008) Leopard syndrome. Orphanet Journal of Rare Diseases 3: 13.

Schrader KA , Nelson TN , De Luca A , Huntsman DG and McGillivray BC (2009) Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11. Clinical Genetics 75(2): 185–189.

Tartaglia M , Martinelli S , Stella L et al. (2006) Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. American Journal of Human Genetics 78: 279–290.

Tartaglia M , Zampino G and Gelb BD (2010) Noonan syndrome: clinical aspects and molecular pathogenesis. Molecular Syndromology 1(1): 2–26.

Tidyman WE and Rauen KA (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Current Opinion in Genetics & Development 19(3): 230–236.

Uçar C , Calýskan U , Martini S and Heinritz W (2006) Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive). Journal of Pediatric Hematology/Oncology 28(3): 123–125.

Yoon S and Seger R (2006) The extracellular signal‐regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24: 21–44.

Yu DH , Qu CK , Henegariu O , Lu X and Feng GS (1998). Protein–tyrosine phosphatase Shp‐2 regulates cell spreading, migration, and focal adhesion. Journal of Biological Chemistry 273(33): 21125–21131.

Yu ZH , Xu J , Walls CD et al. (2013) Structural and mechanistic insights into LEOPARD syndrome‐associated SHP2 mutations. Journal of Biological Chemistry 288(15): 10472–10482.

Further Reading

Katherine AR (1993–2013) Cardiofaciocutaneous syndrome. In: Pagon RA , Adam MP , Bird TD et al. (eds) GeneReviews™ [Internet]. Seattle, WA: University of Washington.

Martin Z (2009) Noonan Syndrome and Related Disorders. A Matter of Deregulated Ras Signaling. Unionville, CT: S Karger Publishers Inc.

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

* Required Field

How to Cite close
Martínez‐Quintana, Efrén, and Rodríguez‐González, Fayna(Nov 2013) Molecular Genetics of LEOPARD Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025243]