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Vol. 66. Issue 9.
Pages 756-757 (September 2013)
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Vol. 66. Issue 9.
Pages 756-757 (September 2013)
Letter to the Editor
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RASopathies: From Noonan to LEOPARD Syndrome
RASopatías: del síndrome de Noonan al síndrome LEOPARD
Efrén Martínez-Quintanaa,
Corresponding author

Corresponding author:
, Fayna Rodríguez-Gonzálezb
a Servicio de Cardiología, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain
b Servicio de Oftalmología, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain
Related content
Rev Esp Cardiol. 2013;66:350-610.1016/j.rec.2012.09.015
Atilano Carcavilla, José L. Santomé, Isabel Pinto, Jaime Sánchez-Pozo, Encarna Guillén-Navarro, María Martín-Frías, Pablo Lapunzina, Begoña Ezquieta
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To the Editor,

We have read with interest the article recently published by Carcavilla et al.1 titled “LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy.” However, we would like to add some comments that we find interesting.

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 pathway2 that is involved in the regulation of normal cell proliferation, survival, and differentiation.

Although the diagnosis of LS is made on clinical grounds by observation of key features, none of which is pathognomonic, to provide a valid overview on symptoms and features of LS we should not overestimate the reports published in the premolecular era, because these cohorts may consist of heterogeneous diseases. In fact, in early childhood the phenotype of LS can be typical of NS; however, with age other characteristic features of LS, including lentigines, hypertrophic cardiomyopathy (HCM), and hearing loss, may appear. For this reason, anomalies observed in molecularly confirmed cases should be regarded as more reliable.

Genetically, both syndromes share mutations in the PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) gene on chromosome 12q24, as they are heterozygous missense mutations in PTPN11 observed in up to 90% and 50% of LS and NS cases, respectively. Similarly, mutations in the RAF1 (v-Raf-1 murine leukemia viral oncogene homolog 1) gene on chromosome 3p25.2 and mutation in the BRAF (v-Raf murine sarcoma viral oncogene homolog B1) gene on chromosome 7q34 are also seen. However, the point mutations identified in PTPN11 that are associated with NS are distinct from those associated with LS and therefore with different biochemical properties: gain-of-function mutations in PTPN11 are more frequent in NS patients3,4 while a loss-of-function or dominant-negative mutations in PTPN11 are more prevalent in patients with LS.5,6 These gain-of-function and loss-of-function mutations may explain the differences in phenotypes between these two syndromes.

Although it is not included in the LEOPARD acronym, HCM is the most frequent anomaly observed, representing a potentially life-threatening problem in these patients. HCM, which is generally asymmetric and progressive and commonly involves the intraventricular septum, is detected in up to 80% of patients with a cardiac defect and may associate with significant left ventricular outflow tract obstruction in up to 40% of cases7,8. Although treatment algorithms are similar between LS patients with ventricular hypertrophy and patients with familial HCM, without an evidence-based diagnosis, despite their analogous character it is clear that the pathophysiology and dynamics of HCM in LS differ from ventricular hypertrophy of other causes. On the contrary, the most common cardiac manifestation in NS is pulmonic stenosis resulting from dysplastic valve leaflets, followed (less frequently) by HCM, mitral stenosis, and atrial, ventricular and atrioventricular septal defects, or (rarely) by double outlet right ventricle.

To date, it is unclear whether the genotype may influence the clinical course in LS patients with HCM, especially because many of the affected individuals described in the literature are children and no clear risk figures based on a follow-up patient cohort study of a sufficient size is available. However, anecdotal reports provide enough evidence to state that long-term prognosis seems benign in LS patients with only mild cardiac abnormalities, whereas HCM in LS is indeed associated with a risk of fatal cardiac events as seen in primary HCM9.


A. Carcavilla, J.L. Santomé, I. Pinto, J. Sánchez-Pozo, E. Guillén-Navarro, M. Martín-Frías, et al.
Síndrome LEOPARD: una variante del síndrome de Noonan con fuerte asociación a miocardiopatía hipertrófica.
Rev Esp Cardiol, 66 (2013), pp. 350-356
J. Lauriol, M.I. Kontaridis.
PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots?.
Trends Cardiovasc Med, 21 (2011), pp. 97-104
L. Musante, H.G. Kehl, F. Majewski, P. Meinecke, S. Schweiger, G. Gillessen-Kaesbach, et al.
Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.
Eur J Hum Genet, 11 (2003), pp. 201-206
T. Niihori, Y. Aoki, Y. Narumi, G. Neri, H. Cavé, A. Verloes, et al.
Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.
Nat Genet, 38 (2006), pp. 294-296
M.I. Kontaridis, K.D. Swanson, F.S. David, D. Barford, B.G. Neel.
PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.
J Biol Chem, 281 (2006), pp. 6785-6792
M. Tartaglia, S. Martinelli, L. Stella, G. Bocchinfuso, E. Flex, V. Cordeddu, et al.
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.
Am J Hum Genet, 78 (2006), pp. 279-290
A. Sarkozy, M.C. Digilio, B. Dallapiccola.
LEOPARD syndrome.
Orphanet J Rare Dis, 3 (2008), pp. 13
E. Martínez-Quintana, F. Rodríguez-González.
LEOPARD syndrome: clinical features and gene mutations.
Mol Syndromol, 3 (2012), pp. 145-157
G. Limongelli, A. Sarkozy, G. Pacileo, P. Calabrò, M.C. Digilio, V. Maddaloni, et al.
Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome.
Am J Med Genet A, 146A (2008), pp. 620-628
Copyright © 2013. Sociedad Española de Cardiología
Revista Española de Cardiología (English Edition)

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