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�/R"�?�/�/�12�������um�����***	2=5�@0�@2ET.rE2E�2$R"R"�/R"R"R"R"R"@@�/R"R"R"�@R"R"R"R"��������������������������������������������������������������������ER"R"R"R"R"R"R"R"R"<,h:	LEOPARD syndrome
Changsheng Zhua,b, �, Jizheng Wang c, �, Shuiyun Wanga,b,*

a Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
b State Key Laboratory of Cardiovascular Disease, Beijing, China
c Sino-German Laboratory for Molecular Medicine, Beijing, China
� These authors contributed equally to this work
* Corresponding author. No. 167, Beilishi Road, Xicheng District, Beijing 100037, China. Tel: +86-10-88396636; fax: +86-10-68330739; e-mail: HYPERLINK "mailto:wsymd@hotmail.com"wsymd@hotmail.com (S. Wang).

Abstract
  LEOPARD syndrome is traditionally thought as an autosomal dominant disease. It was firstly reported by Gorlin RJ et al as a distinct disorder in 1969. LEOPARD is a mnemonic acronym of clinical features including multiple Lentigines, Electrocardiographic-conductional abnormality, Ocular hypertelorism, Pulmonary valve stenosis, Anomaly of genitalia , Retardation of statue, and sensorineural Deafness. Since its clinical presentation overlaps with Noonan syndrome, LEOPARD syndrome has been identified as a subtype of the latter. Thus, reviews specifically giving insight to it are rare, and for most of time LEOPARD syndrome is additionally discussed following Noonan syndrome. However, LEOPARD syndrome has its own properties especially in patients exhibiting hypertrophic cardiomyopathy, which need our attention. Here, we review this disease thoroughly, so that we can understand it to more extent.
Keywords
  LEOPARD syndrome, lentigines, hypertrophic cardiomyopathy
Introduction
  LEOPARD syndrome[1] is commonly regarded as an autosomal dominant disorder, which was firstly reported by Gorlin RJ et al as a distinct disorder in 1969. LEOPARD is the acronym of multiple Lentigines, Electrocardiographic-conductional abnormality, Ocular hypertelorism, Pulmonary valve stenosis, Anomaly of genitalia, Retardation of growth, and sensorineural Deafness. Voron DA et al established LEOPARD syndrome�s diagnostic criteria in 1976 based on clinical features, which is still adopted by clinicians today[2]. Unfortunately, the mechanism underlying it was unclear at that time. It was in 2002 that Maria CD et al firstly located mutation causing LEOPARD syndrome in PTPN11 gene[3]. Afterwards several other genes corresponding to LEOPARD syndrome also were identified[4,5].  Moreover, Ras-MAPK pathway responsible for LEOPARD syndrome, has been elucidated. Thus, LEOPARD syndrome is viewed as a rare disorder that belongs to the Rasopathies[6]. A most cited estimated incidence of Noonan syndrome is 1 in 1,000-2,500 live births firstly reported by Nora et al in 1974. LEOPARD syndrome is probably the second most common disorder after Noonan syndrome within the Rasopathies, though its accurate prevalence remain unknown[7]. To be brief, we indeed have made some progress in approaching to revealing the truth of LS. 
Clinical presentation    
Multiple lentigines
Nearly all patients are free from lentigines, when born. Instead, cafe�-au-lait spots appear preceding lentigines. Caf�-au-lait spots are found in 75% of the patients in the first month of life and are present very soon after their birth in most of them[8]. Generally lentigines develop in childhood and increase in puberty, darkening with age[9,10]. Lentigines that are flat, black and brown independently from sun exposure usually distribute on the face, trunk, neck, and axilla. Moreover, nearly 100% of the patients present lentigines at 4�5 years old[9,11].
The character of lentigines present in LS is a distinct symptom from NS and other related disorders[10].
Facial anomalies
Dysmorphic features of face appear in nearly 100 percent of patient which including hypertelorism, low-slanting ears, ptosis and flat nasal bridge et al. In one word, facial abnormalities manifest in kinds of shapes.  
Congenital heart defects
Congenital heart defects are another important character that are contained by LEOPARD syndrome and often are the primary reason for hospitalization particularly in patients with hypertrophic cardiomyopathy [9]. The common congenital heart diseases include hypertrophic cardiomyopathy, pulmonary valve stenosis, atrial septal defect, atrioventricular canal, and coronary anomalies [8,10,12]. 
A cardiac abnormality is present in 71-99% of the patients with LEOPARD syndrome, with 80-87% of those showing hypertrophic cardiomyopathy [8,10,12]. In patients with hypertrophic cardiomyopathy, 73% have left ventricular hypertrophy, of which left ventricular outflow tract obstruction is 37-87%[8,13]. Right ventricular hypertrophy is present in about 30% of patients with LEOPARD syndrome, associated with left ventricular hypertrophy and pulmonary stenosis [13]. Pulmonary valve stenosis, on the contrary, is less seen than that in Noonan syndrome, and ranks only second to hypertrophic cardiomyopathy [14]. Its frequency is about 12-23% [12,13].Mitral valve anomalies and aortic valve anomalies are manifested in 56% and 12% of patients, respectively[12].
Coronary abnormalities are present in 15-19% of LEOPARD syndrome[12,13]. They mainly influence the main left coronary artery, the left anterior descending artery, and the right coronary artery[13]. Myocardial bridge appears in this kind of patients, too. In a case report, a cardiac catheterisation showed diffuse aneurysms of the right and anterior descending coronary arteries. To our best knowledge, aneurysms of coronary are rarely seen in LEOPARD syndrome among the rough 100 cases which have been described in the literature hitherto[15]. 
Other less common congenital heart diseases are atrioventricular canal defect and atrial septal defect[14]. 
The heterogeneity of congenital heart diseases is complex in LEOPARD syndrome. Above all, hypertrophic cardiomyopathy is the primary cause for adverse events, such as sudden death, especially in patients with sever hypertrophic cardiomyopathy[12].
Short stature          
Retardation of growth is usually seen in 50% of patients after birth whose body length is normal in newborns, and the percentage of finally short statue is 65%[7,13]. Height below the 3rd centile is observed in 25% of affected individuals[7]. LEOPARD syndrome has a lower incidence of short stature comparing with Noonan syndrome[10].    
Other features
Except the four cardinal features above, patients with LEOPARD syndrome also present other anomalies resulting from its underlying heterogeneity of pathogenesis including skeletal anomalies, genital and urinary tract anomalies, hearing loss, neurological abnormalities and tumours.    
Diagnosis 
Clinical diagnosis
Leopard syndrome  was first classified by Gorlin RJ et al in 1969[1] and its clinical diagnostic criteria was established in 1976 by Voron DA et al which include multiple lentigines plus two other recognized features or a first-degree relative with multiple lentigines plus three other recognized features[2].
  But the criteria are just reliable in patients with lentigines or familiar cases, because lentigines are not present immediately after birth and some are sporadic without family history. As a result, correct diagnosis may be missed in neonatal and adolescent patients. In case of this occasion, another set of diagnostic criteria[8] can be applied additionally. The diagnosis of LEOPARD syndrome in early life can be clinically suspected in patients presenting with three main features including characteristic facial features (100%), hypertrophic cardiomyopathy(87%), and cafe-au-lait spots (75%). Classically facial features can be mild or severe, and consist of hypertelorism, down-slanting palpebral fissures, ptosis, and dysmorphic ears.
Genetic conforming 
To date, mutations associated with LEOPARD syndrome have been identified in exons 7, 12 and 13 of the PTPN11 gene, exon 7, 14 and 17 of the RAF1 gene, and exon 6 of the BRAF gene[4,8]. Almost 90% of patients with LEOPARD syndrome are identified mutations in gene PTPN11 on chromosome 12q24, which encoding the components of Ras/mitogen activated protein kinases signaling pathway [4]. The other can be caused by mutations in the RAF1 (v-Raf-1 murine leukemia viral oncogene homolog 1) gene on chromosome 3p25.2 and the BRAF (v-Raf murine sarcoma viral oncogene homolog B1) gene on chromosome 7q34. Totally molecular genetic testing of these 3 loci identifies mutations in about 95% of affected individuals[16]. 
  Thus, the clinical suspicion of LEOPARD syndrome should be confirmed by molecular screening[8,13]. Combining clinical diagnosis with genetic screening is useful for diagnosis in patients without classic symptoms.
Molecule mechanism  
PTPN11
PTPN11 refers to protein-tyrosine phosphotase (PTP), none receptor 11, which is encoded by gene PTPN11. As previous reported, mutations of PTPN11 contribute to 90% or even as high as 95% of patients suffering LEOPARD syndrome [4,13]. PTPN11 contains two N-terminal SH2 domains, one C-terminal SH2 domain that are of great importance for PTPN11 to binding to some growth factor receptors and a catalytic(PTP) domain[16]. Full and sustained function of PTPN11 catalytic domain is necessary for normal development. 
While previous studies have shown that LEOPARD syndrome shares quite a few clinical features with Noonan syndrome[16,17,18], unlike Noonan syndrome whose mutations are spread around in PTPN11, all LEOPARD syndrome variations are clustered in the catalytic domain[16,19]. Moreover, to our best knowledge, all known amino substitutions involved in LEOPARD syndrome are Tyr279Cys(exon7), Tyr279Ser,Ala461Thr,Gly464Ala,Thr468Met(exon12),Thr468Pro,Arg498Leu,Arg498Trp,Gln506Pro,Gln510Pro,Gln510Glu(exon13)[8,13,16,20], in which Tyr279Cys and Thr468Met cause 65% of LEOPARD syndrome patients[11]. These suggest that LEOPARD syndrome may have its own characteristics. The fact is indeed so. LEOPARD syndrome shows a loss of function rather than a gain of function as has been found in the typical Noonan syndrome patients[10]. 
Loss-of-function PTPN11 mutations[16]: a panel of LEOPARD syndrome mutants� examination, including the two most common alleles Tyr279Cys and Thr468Met, reveals the fact that LEOPARD syndrome mutants are catalytically defective and act dominantly negative in contact with growth-factor/ Erk-mitogen-activated protein kinase mediated signaling as the consequence of LEOPARD syndrome mutations contorting the PTPN11 catalytic domain and engendering open, inactive forms of PTPN11. 
RAF1
RAF1 gene[4] encodes a serine-threonine kinase that activates MEK1 and MEK2. In its inactive form, the N-terminal of RAF1 is to interact with and inhibit the kinase domain of RAF1�s C-terminal. The stability of this condition is sustained by the 14-3-3 protein dimmers, which bind to ser259 and ser621 of RAF1. Most mutations engendering LEOPARD syndrome are at Arg256, Ser257, Ser259, Pro261 in the conserved region. Amino acid changes in the conserved region induce increased ERK activity. Whereas amino acid mutants in activation segment either substantially enhance ERK activation such as Thr491 or impair ERK activity such as Asp486. Though RAF1 mutants have bi-directional effect on LEOPARD syndrome, the gain of function is predominant.      
BRAF
Mammalian genomes have three RAF genes whose encoding products are ARAF, RAF1 and BRAF. Among them, BRAF has the strongest MEK activation, but its regulation is relatively simple[4]. Resembling the RAF1, BRAF[5] comprising three highly conserved regions. Mutations were detected in exon6, 13, and 15, and were predicted to affect residues located in the cysteine-rich domain within the conserved region 1, and the kinase domain. The Thr241Pro amino acid substitution identified in the subjects with LEOPARD syndrome had previously been reported in three children with a phenotype apparently fitting Cardiofaciocutaneous syndrome. Comparing with the widespread expression of the Val600Glu BRAF change which accounts for the large majority (49%) of total BRAF amino acid substitutions in human cancers, the Thr241Pro amino acid substitution has reduced transforming competence, indicating that the LEOPARD syndrome-causing BRAF mutant is less capable of deregulating the BRAF-mediated signal flow, resulting in relatively enhanced MEK/ERK activity.
Hypertrophic cardiomyopathy and underlying mechanism 
Congenital heart diseases, particularly hypertrophic cardiomyopathy and pulmonary stenosis are prominent features in Rasopathies[20], while cardiomyopathy is more common in LEOPARD syndrome especially in association with mutations in exon7 and 12 of PTPN11[20]. The facts above are in accordance with the most common mutations Tyr279Cys(exon7) and Thr468Met(exon12)[16]. 
  Revising the literature suggests that specific mutations at codon510 in PTPN11 (Gln510Glu, Gln510His, but not Gln510Pro) might be a predictor of fatal cardiac events in LEOPARD syndrome[21,22].However, a rapidly progressive form of hypertrophic cardiomyopathy is described in patients with LEOPARD syndrome /Noonan syndrome phenotypes in association with the Gln510Glu mutation in exon13 of PTPN11[20]. Moreover, the Gln510Glu mutation in exon13 of the PTPN11gene was thought to have a high specificity for the severe form of hypertrophic cardiomyopathy, in character with early onset of heart failure symptoms and possibly sudden death in an early year of life. Infant hypertrophic cardiomyopathy is a very severe disease with nonspecific symptoms and a high mortality rate, especially when it presents in the first month of life[21].
PTPN11 mutations causing LEOPARD syndrome facilitate EGF-induced PI3K/AKT/GSK-3 stimulation through impaired GAB1 dephosphorylation that could be involved in LEOPARD syndrome pathology, particularly in the phenotypic development of hypertrophic cardiomyopathy in patients with LEOPARD syndrome[19].
  Besides, two of the three Noonan/LEOPARD syndrome-associated RAF1 mutants (Ser257Leu, Asp486Asn and Leu613Val, except Asp486Asn), also were reported to engender cardiomyocyte hypertrophy[23].
Though researchers have been trying to link LEOPARD syndrome and related disorders with specific mutations, on the contrary, we have discovered more heterogeneity. Then researchers attempted to reveal the genotype-cardiac defects correlation among these disorders, unfortunately they did not achieve some substantial progress, either. What�s more, a combination of two pathologic heterozygous mutations in exon12 of PTPN11 (Thr468Met) and a novel missense variant in SOS1 Pro340Ser was reported[20]. This makes links between hypertrophic cardiomyopathy and specific mutations controversial once more. Since hypertrophic cardiomyopathy occurs in only about 10% of individuals with SOS1-associated Noonan syndrome, then researchers speculate the PTPN11mutations might be the major contributor to the patients� hypertrophic cardiomyopathy, and the SOS1 variant might be a modifier increasing the severity[20].
According to the available data, the appearance of lentigines has been suggested frequently concomitant with the onset or worsening of hypertrophic cardiomyopathy[21]. However, Limongelli G et al. emphasized the contrary[12]. So it is controversial. Though the fact above remains to be confirmed, it has become a consensus that the closely combinative presentation of lentigines and hypertrophic cardiomyopathy in patients is helpful to differential diagnosis. 
Prognostication, prophylaxis and treatment 
Prognosis of patients with LEOPARD syndrome seems to be related to the type of structural, myocardial, and arrhythmogenic cardiac diseases, especially hypertrophic cardiomyopathy[22]. So, here we focus on hypertrophic cardiomyopathy which is the key limits of patients� life span. Giuseppe Limongelli et al. regard these clinical features as predictors of adverse cardiac events during follow-up, including family history of sudden death, syncope, dyspnea, NYHA class, severe left ventricular hypertrophy, significant left ventricular outflow tract obstruction, abnormal blood pressure response during stress test, ventricular arrhythmias during ECG-Holter and molecular analysis such as presence of PTPN11mutations, specific mutations in codon279, 464,468, 498, 510 which locate in different SHP2 domains [12]. Besides, considering that LEOPARD syndrome-associated RAF1 mutants are prominently associated with severe hyertrophic cardiomyopathy, screening of RAF1gene mutations should be taken into consideration, despite of the low number of RAF1-positive patients[23]. Given the high negative predictive accuracy of adverse cardiac events, Giuseppe Limongelli et al. also propose the favorable outcome predictor:the absence of significant left ventricular hypertrophy signs at ECG and echocardiography. 
Subsequently, prophylactic measures aiming at predictors of adverse events can be taken to save patients� lives.
 In terms of treatment, LEOPARD syndrome is a very rare disease whose number of cases is no more than 200[9]. As a result, the management of LEOPARD syndrome with hyertrophic cardiomyopathy is empirical, but it doesn�t matter that the clinicians can still learn something from successful cases. Pharmacotherapy including diuretics and beta-blockers was effective in two patients with progressive hyertrophic cardiomyopathy with left ventricular outflow tract obstruction and congestive heart failure[8,12]. Septal myectomy was required in one and sudden death occurred in one[8,12,21].
LEOPARD syndrome mutations located in PTPN11 catalytic domain have dominant negative-effects in vivo, engendering enhanced mTOR activity that has been thought to play a crucial role in causing LEOPARD syndrome-associated hyertrophic cardiomyopathy. The cardiac defects in mice with LEOPARD syndrome phenotypes and hyertrophic cardiomyopathy was completely reversed by treatment with rapamycin, which is an inhibitor of mTOR[24]. These two findings suggest that mTOR inhibitors be considered as the etiological treatment of hyertrophic cardiomyopathy in LEOPARD syndrome patients.

Acknowledgements
None.

Funding
This work was supported by Beijing Science and Technology Program (China): NO. Z121107001012017.

Conflict of interest: None declared.
  
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