Molecular Genetics of LEOPARD Syndrome


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 NSH2 domain occupies the active site of the PTP domain (autoinhibited closed configuration). Image modified from the RCSB PDB ( 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.



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Further Reading

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