Alternative titles; symbols

• LENTIGINOSIS, CARDIOMYOPATHIC
• MULTIPLE LENTIGINES SYNDROME

Gene map locus: 12q24.1

Clinical Synopsis

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A number sign (#) is used with this entry because LEOPARD syndrome can be caused by mutations in the PTPN11 gene (176876) on chromosome 12q24.

The disorder is allelic to Noonan syndrome (163950). Another form of LEOPARD syndrome (611554) is caused by mutation in the RAF1 gene (164760), which also causes a form of Noonan syndrome (NS5; 611553).

DescriptionBack to Top

LEOPARD is an acronym for the manifestations of this syndrome as listed by Gorlin et al. (1969): multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness.

Clinical FeaturesBack to Top

Walther et al. (1966) found asymptomatic cardiac changes associated with generalized lentigo in a mother and her son and daughter. The electrocardiogram in the son suggested myocardial infarction. The mother was shown by cardiac catheterization to have mild pulmonary stenosis. Similar generalized lentigines were described by Moynahan (1962) in 3 unrelated patients (2 females, 1 male). Growth was stunted. In 1 girl, one ovary was absent and the other hypoplastic. The boy had hypospadias and undescended testes. Endocardial and myocardial fibroelastosis may have been present. Intelligence was normal but behavior childish. Matthews (1968) reported mother and 2 half-sib children with generalized lentigines, electrocardiographic changes and murmurs. A history of male-to-male transmission was recorded. Lentigines were also present in the cardiac syndrome reported by Forney et al. (see mitral regurgitation, conductive deafness, etc.; 157800).

Polani and Moynahan (1972) gave a full report of 8 patients and their families. They were impressed with the occurrence of left-sided obstructive cardiomyopathy and none of their patients was deaf. They proposed the designation 'progressive cardiomyopathic lentiginosis' for this disorder. St. John Sutton et al. (1981) reported 11 patients, 10 of them male, with classic hypertrophic obstructive cardiomyopathy and lentiginosis. All were sporadic. Mental retardation, deafness, and gonadal and somatic infantilism were uncommon in this series. The 21-year-old patient of Senn et al. (1984) had severe hypertrophic obstructive cardiomyopathy for which surgery was performed on the left ventricle to relieve severe obstruction. Both parents were unaffected; both were 40 years old at the birth of the patient. Peter and Kemp (1990) described a 19-year-old woman who died as a result of respiratory insufficiency secondary to thoracic deformities which, together with a congenital heart defect, led to pulmonary hypertension. The syndrome of cafe-au-lait spots and pulmonic stenosis, described by Watson (1967), is distinct (193520).

Coppin and Temple (1997) provided a review of the condition and added 5 cases, including relatives of one of the cases described by Polani and Moynahan (1972). Coppin and Temple (1997) pointed out the difficulty of differentiating LEOPARD syndrome from Noonan syndrome (163950) given previous reports of lentiginosis without lentigines.

Shamsadini et al. (1999) described an 18-year-old Iranian girl with LEOPARD syndrome. Clinical manifestations included lentigines, ocular hypertelorism, mental and growth retardation, deaf mutism, and several patches of hair loss on her scalp. There was no family history of lentiginosis or any other inherited condition.

Schrader et al. (2009) reported a patient with LEOPARD syndrome, confirmed by genetic analysis (176876.0006), who developed multiple granular cell tumors of the skin and subcutaneous tissues during adolescence. Studies of tumor tissue did not reveal loss of heterozygosity at the PTPN11 or NF1 (613113) genes. A review of the literature on multiple granular cell tumors associated with other syndromic features indicated that many reported cases also exhibited features of neuro-cardio-facial-cutaneous syndromes, such as lentiginosis, cryptorchidism, pulmonary stenosis, ptosis, and short stature.

Lehmann et al. (2009) reported a 37-year-old woman with genetically confirmed LEOPARD syndrome who had hypertrophic cardiomyopathy, multiple lentigines, deafness, growth retardation, hypertelorism, and strabismus. Extensive cardiac workup showed biventricular apical hypertrophy, right ventricular fibrosis, and coronary artery dilatation. Pulmonary stenosis was not a feature.

DiagnosisBack to Top

Digilio et al. (2006) confirmed the diagnosis of LEOPARD syndrome by molecular analysis in 8 (80%) of 10 infants clinically suspected to have the disorder in the first year of life. One additional patient was subsequently found to have neurofibromatosis type I (NF1; 162200) following evaluation of the mother. Review of the clinical characteristics of the 8 LS patients with PTPN11 mutations demonstrated characteristic facial features in 100%, hypertrophic cardiomyopathy in 87%, and cafe-au-lait spots in 75%. Common facial features included hypertelorism (100%), malformed ears (87%), and low-set ears with overfolded helix (50%). Six (75%) patients had skeletal thorax anomalies.

InheritanceBack to Top

Gorlin et al. (1969) presented evidence for dominant inheritance.

Molecular GeneticsBack to Top

Digilio et al. (2002) screened for mutations in the PTPN11 gene, known to be mutated in Noonan syndrome, in 9 patients with LEOPARD syndrome (including a mother-daughter pair) and 2 children with Noonan syndrome who had multiple cafe-au-lait spots. In 10 of the 11 patients, they found 1 of 2 mutations: tyr279 to cys (Y279C; 176876.0005) or thr468 to met (T468M; 176876.0006).

In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004) identified 1 of 3 heterozygous missense mutations: Y279C, ala461 to thr (A461T; 176876.0020), or gly464 to ala (G464A; 176876.0021).

Kalidas et al. (2005) performed mutation screening and linkage analysis of PTPN11 in 3 families in each of which LEOPARD syndrome occurred in 3 generations. 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.

Tartaglia et al. (2006) showed that the recurrent LEOPARD syndrome-causing Y279C (176876.0005) and T468M (176876.0006) amino acid substitutions engender loss of SHP2 catalytic activity, thus identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.

Kontaridis et al. (2006) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see 176948)-mediated signaling. Molecular modeling and biochemical studies suggested that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. Kontaridis et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation.

Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells (iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous for the T468M mutation in PTPN11 (176876.0006). The iPSCs were extensively characterized and produced multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization, and have preferential localization of NFATC4 (602699) in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. Carvajal-Vergara et al. (2010) also provided molecular insights into signaling pathways that may promote the disease phenotype. Carvajal-Vergara et al. (2010) showed that basic fibroblast growth factor treatment increased the phosphorylation of ERK1/2 levels over time in several cell lines but did not have a similar effect in the LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in the LEOPARD syndrome iPSCs compared with the other cell lines.

Genotype/Phenotype CorrelationsBack to Top

Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene, and 6 in whom no mutation had been found. Patients without PTPN11 mutations showed a significantly higher frequency of family history of sudden death, increased left atrial dimensions, and cardiac arrhythmias, and seemed to be at higher risk for adverse cardiac events. Three patients with mutations in exon 13 of the PTPN11 gene had a severe form of biventricular obstructive LVH with early onset of heart failure symptoms, consistent with previous observations.

HistoryBack to Top

In a family in which the mother and 2 daughters had the multiple lentigines syndrome, Edman Ahlbom et al. (1995) demonstrated that the gene is not linked to the neurofibromatosis type 1 locus (NF1; 613113). Wu et al. (1996) described a de novo missense mutation (M1035R) in exon 18 of the NF1 gene in a 32-year-old woman with a prior mistaken diagnosis of LEOPARD syndrome.

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