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RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible., (© 2019 Wiley Periodicals, Inc.)

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT., (© 2018 Wiley Periodicals, Inc.)

Noonan Syndrome with Multiple Lentigines (NSML) is associated with congenital heart disease in form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Genetically, NSML is primarily caused by mutations in the non-receptor protein tyrosine phosphatase SHP2. Importantly, certain SHP2 mutations such as Q510E can cause a particularly severe form of HCM with heart failure in infancy. Due to lack of insight into the underlying pathomechanisms, an effective custom-tailored therapy to prevent heart failure in these patients has not yet been found. SHP2 regulates numerous signaling cascades governing cell growth, differentiation, and survival. Experimental models have shown that NSML mutations in SHP2 cause dysregulation of downstream signaling, in particular involving the protein kinase AKT. AKT, and especially the isoform AKT1, has been shown to be a major regulator of cardiac hypertrophy. We therefore hypothesized that hyperactivation of AKT1 is required for the development of Q510E-SHP2-induced HCM. We previously generated a transgenic mouse model of NSML-associated HCM induced by Q510E-SHP2 expression in cardiomyocytes starting before birth. Mice display neonatal-onset HCM with initially preserved contractile function followed by functional decline around 2months of age. As a proof-of-principle study, our current goal was to establish to which extent a genetic reduction in AKT1 rescues the Q510E-SHP2-induced cardiac phenotype in vivo. AKT1 deletion mice were crossed with Q510E-SHP2 transgenic mice and the resulting compound mutant offspring analyzed. Homozygous deletion of AKT1 greatly reduced viability in our NSML mouse model, whereas heterozygous deletion of AKT1 in combination with Q510E-SHP2 expression was well tolerated. Despite normalization of pro-hypertrophic signaling downstream of AKT, heterozygous deletion of AKT1 did not ameliorate cardiac hypertrophy induced by Q510E-SHP2. However, the functional decline caused by Q510E-SHP2 expression was effectively prevented by reducing AKT1 protein. This demonstrates that AKT1 plays an important role in the underlying pathomechanism. Furthermore, the functional rescue was associated with an increase in the capillary-to-cardiomyocyte ratio and normalization of capillary density per tissue area in the compound mutant offspring. We therefore speculate that limited oxygen supply to the hypertrophied cardiomyocytes may contribute to the functional decline observed in our mouse model of NSML-associated HCM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Noonan syndrome with multiple lentigines (NSML) is primarily caused by mutations in the nonreceptor protein tyrosine phosphatase SHP2 and associated with congenital heart disease in the form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Our goal was to elucidate the cellular mechanisms underlying the development of HCM caused by the Q510E mutation in SHP2. NSML patients carrying this mutation suffer from a particularly severe form of HCM. Drawing parallels to other, more common forms of HCM, we hypothesized that altered Ca(2+) homeostasis and/or sarcomeric mechanical properties play key roles in the pathomechanism. We used transgenic mice with cardiomyocyte-specific expression of Q510E-SHP2 starting before birth. Mice develop neonatal onset HCM with increased ejection fraction and fractional shortening at 4-6 wk of age. To assess Ca(2+) handling, isolated cardiomyocytes were loaded with fluo-4. Q510E-SHP2 expression increased Ca(2+) transient amplitudes during excitation-contraction coupling and increased sarcoplasmic reticulum Ca(2+) content concurrent with increased expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase. In skinned cardiomyocyte preparations from Q510E-SHP2 mice, force-velocity relationships and power-load curves were shifted upward. The peak power-generating capacity was increased approximately twofold. Transmission electron microscopy revealed that the relative intracellular area occupied by sarcomeres was increased in Q510E-SHP2 cardiomyocytes. Triton X-100-based myofiber purification showed that Q510E-SHP2 increased the amount of sarcomeric proteins assembled into myofibers. In summary, Q510E-SHP2 expression leads to enhanced contractile performance early in disease progression by augmenting intracellular Ca(2+) cycling and increasing the number of power-generating sarcomeres. This gives important new insights into the cellular pathomechanisms of Q510E-SHP2-associated HCM., (Copyright © 2015 the American Physiological Society.)

Aims: A variety of human inherited heart diseases affect the normal functions of cardiomyocytes (CMs), endothelial cells (ECs), or smooth muscle cells (SMCs). To study human heart disease and generate cardiac cells for basic and translational research, an efficient strategy is needed for production of cardiac lineages from human stem cells. In the present study, a highly reproducible method was developed that can simultaneously enrich a large number of CMs and cardiac SMCs and ECs from human induced pluripotent stem (iPS) cells with high purity., Methods and Results: Human multipotent cardiovascular progenitor cells were generated from human iPS cells, followed by selective differentiation of the multipotent cardiovascular progenitor cells into CMs, ECs, and SMCs. With further fluorescence-activated cell sorting, each of the three cardiovascular cell types could be enriched with high purity (>90%). These enriched cardiovascular cells exhibited specific gene expression signatures and normal functions when assayed both in vitro and in vivo. Moreover, CMs purified from iPS cells derived from a patient with LEOPARD syndrome, a disease characterized by cardiac hypertrophy, showed the expected up-regulated expression of genes associated with cardiac hypertrophy., Conclusions: Overall, our technical advance provides the means for generating a renewable resource of pure human cardiovascular cells that can be used to dissect the mechanisms of human inherited heart disease and for the future development of drug and cell therapeutics for heart disease.

LEOPARD syndrome (LS) is a rare hereditary disorder, characterised mainly by skin, facial and cardiac abnormalities. We report on the case of a six-year-old Djiboutian with typical features of LS. Multiple cardiovascular problems are described, including pulmonary infundibular, valvular and supra-valvular stenosis. A favourable course was observed after successful cardiac surgery. This is the first reported case of LS from the horn of Africa.

A connection between LEOPARD syndrome (a rare autosomal dominant disorder) and autism spectrum disorders (ASDs) may exist. Of four related individuals (father and three sons) with LEOPARD syndrome, all patients exhibited clinical symptoms consistent with ASDs. Findings included aggressive behavior and impairment of social interaction, communication, and range of interests. The coexistence of LEOPARD syndrome and ASDs in the related individuals may be an incidental familial event or indicative that ASDs is associated with LEOPARD syndrome. There have been no other independent reports of the association of LEOPARD syndrome and ASDs. Molecular and biochemical mechanisms that may suggest a connection between LEOPARD syndrome and ASDs are discussed., (Copyright © 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

A 47-year-old man was referred because of an acute anterolateral ST-segment elevation myocardial infarction. Coronary angiography showed marked ectasia of the coronary arteries, with no obstructive lesions. Ventriculography strongly suggested severe left ventricular hypertrophy, later confirmed by cardiovascular magnetic resonance imaging. Complete clinical investigation showed that the patient also had multiple lentigines, ocular hypertelorism, and deafness. These associations led to the diagnosis of LEOPARD (Lentigines, Electrocardiographic anomalies, Ocular hypertelorism, Pulmonary stenosis, Anomalies of the genitalia, Retarded growth, and Deafness [sensorineural]) syndrome. Although uncommon, LEOPARD syndrome is important to recognize because it can be associated with serious adverse cardiac events, particularly in patients with severe left ventricular hypertrophy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A case of acute predominantly axonal motor and sensory neuropathy (AMSAN) is reported in a 16-year-old boy with LEOPARD syndrome (the acronym represents lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness). The presentation was atypical for acute motor and sensory axonal neuropathy, in that this patient had progression of symptoms of more than 4 weeks and there were signs of reinnervation in the acute phase. Treatment response to intravenous immunoglobulins was excellent. In patients with LEOPARD syndrome and acute neuropathies, treatment with intravenous immunoglobulins should be considered., (Copyright 2010 Elsevier Inc. All rights reserved.)

Noonan syndrome (NS) and the clinically overlapping disorders cardio-facio-cutaneous syndrome, LEOPARD syndrome, Costello syndrome and Neurofibromatosis-Noonan syndrome share the clinical features of short stature, the same spectrum of congenital heart defects, and a similar pattern of craniofacial anomalies. It is now known that all these disorders are caused by mutations in components of the RAS-MAPK signaling pathway. This pathway was previously known for its involvement in tumorigenesis. This article reviews the current knowledge on underlying genetic alterations and possible pathogenetic mechanisms responsible for NS and related disorders. It discusses the relationship between a group of developmental disorders and oncogenes. Potential future treatment prospects are based on the possibility of inhibiting RAS-MAPK signaling by pharmaceuticals., (2009 S. Karger AG, Basel.)

Background: Several clinical and echocardiographic studies describe morphological and functional findings in patients with hypertrophic cardiomyopathy. Less is known regarding morphological and functional characteristics of the left ventricular hypertrophy found in the setting of the Noonan and LEOPARD syndromes., Objective: To compare non-invasively the morphological and functional findings potentially affecting symptoms and clinical outcome in children with hypertrophic cardiomyopathy as opposed to Noonan and LEOPARD syndromes., Patients and Methods: We studied by echo-Doppler 62 children with left ventricular hypertrophy, dividing them into two subgroups matched for age and body surface area. The first group, of 45 patients with a mean age of 7.5 +/- 5.2 years and body surface area of 0.9 +/- 0.44 mq, had idiopathic hypertrophic cardiomyopathy. The second group, of 17 patients, all had left ventricular hypertrophy in the setting of Noonan or LEOPARD syndromes. Their mean age was 6.6 +/- 5 years, and body surface area was 0.8 +/- 0.36 mq. In all patients, we assessed the left ventricular maximal mural thickness, expressed as a Z-score, along with any obstructions in the left and right ventricular outflow tracts. In addition, to define left ventricular diastolic function, we used mitral flow and pulsed Tissue Doppler to record the Ea, Aa, Ea/Aa, E/Ea indexes in the apical 4-chamber view at the lateral corner of the mitral annulus. We also measured the diameters of the coronary arteries in the diastolic frame., Results: Compared to those with hypertrophic cardiomyopathy, those with syndromic left ventricular hypertrophy showed a significantly increased Z-score for mural thickness, and a higher prevalence of obstruction in the left ventricular outflow tract. In addition, the patients with Noonan or LEOPARD syndromes showed a significantly decrease of Ea and increase of Aa, with a decreased Ea/Aa ratio, all suggestive of left ventricular abnormal relaxation. Moreover, the E/Ea ratio was significantly increased in these patients. The presence of right ventricular hypertrophy, mainly associated with dynamic obstruction in the outflow tract, was detected in only 5 of the 17 patients with Noonan or LEOPARD syndromes, as was dilation of the coronary arteries., Conclusions: Compared to children with hypertrophic cardiomyopathy, those with left ventricular hypertrophy in the setting of Noonan or LEOPARD syndromes show more ventricular hypertrophy and diastolic dysfunction, due to both abnormal relaxation and reduced compliance. They also exhibit an increased prevalence of obstruction of the left ventricular outflow tract, along with dynamic obstruction of the right ventricular outflow tract and dilated coronary arteries. These morphological and functional findings could explain the different symptoms and clinical events, and potentially define the more appropriate therapeutic options in children with left ventricular hypertrophy of different aetiology.

Germline mutations in PTPN11 gene cause Noonan syndrome and the clinically similar LEOPARD syndrome (LS). LS is a rare congenital developmental disorder characterized by multiple lentigines, cardiac abnormalities, facial dysmorphism, retardation of growth, and deafness. Mutations in exons 7 and 12 of the PTPN11 gene can be identified in nearly 90% of patients with LS. PTPN11 gene encodes for an ubiquitously expressed protein tyrosine phosphatase SHP-2 involved in a variety of intracellular signaling processes in development and hematopoiesis. Somatic PTPN11 mutations contribute to leukemogenesis in children with hematologic malignancies including juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplasia. Two cases of leukemia (acute myeloid leukemia) have been reported in children with LS. The authors describe for the first time a girl with genetically confirmed LEOPARD syndrome presenting with common acute lymphoblastic leukemia.

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548-555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465-468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652-662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413-427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42-48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038-1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet, 2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294-296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis.

The LEOPARD syndrome is a complex of multisystemic congenital abnormalities characterized by lentiginosis, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness (sensorineural). Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located on chromosome 12q24.1, have been identified in 88% of patients with LEOPARD syndrome. A missense mutation (836-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in this patient and his mother with LEOPARD syndrome. This mutation is one of the two recurrent mutations most often associated with the syndrome. Leukemia has not previously been reported in patients with LEOPARD syndrome. The authors describe a 13-year-old boy diagnosed with both LEOPARD syndrome and acute myelomonocytic leukemia (AML-M4).

The multiple lentigines/LEOPARD syndrome (ML/LS) is a rare and complex genetic syndrome. It is an autosomal dominant disorder with a variable expressivity. The syndrome is mainly characterised by growth retardation, multiple lentigines, and congenital heart diseases with electrocardiographic anomalies, dysmorphia of the face and deafness. The incidence of this pathology is still unknown and a familial inheritance is present in 70% of cases. Some of the ML/LS clinical features are the same as those of the Noonan syndrome (NS), such as congenital cardiac abnormalities, dysmorphia and growth retardation. NS and ML/LS are caused by allele mutations of the PTPN11 gene. We report the case of a 3-year-old girl, who was observed for the presence of widespread lentigines, a 1/6-protosystolic murmur at the mesocardium and growth retardation. The diagnosis of ML/LS was made and thus a molecular analysis of the PTPN11 gene was carried out, directly sequencing the codifying region. The molecular analysis revealed a missense mutation (A836G) in hexone 7 (TYR279CYS) of the PTPNII gene. This mutation is has been observed, at present, in a few cases of ML/LS and Noonan syndrome.

This review summarizes PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutations and genotype-phenotype correlations in Noonan syndrome (NS) and LEOPARD syndrome (LS). PTPN11 mutations have been identified in approximately 40% of NS patients and in >80% of LS patients. Since the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities. The type of mutations is diverse in NS and limited in LS, and is almost mutually exclusive between NS and LS. Clinical assessment in NS patients implies that cardiovascular anomalies and hematologic abnormalities are predominant in mutation positive patients, hypertrophic cardiomyopathy is predominant in mutation negative patients, and growth deficiency, mental retardation, and minor somatic anomalies are similar between the two groups of patients. Phenotypic evaluation in LS patients suggests that a hypertrophic cardiomyopathy rather than an electrocardiographic conduction abnormality is characteristic of PTPN11 mutation positive patients.

LEOPARD syndrome is a neuroectodermal disorder presumed to result from an abnormality in neural crest cells. The acronym 'LEOPARD' is derived from the clinical features which include multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, and deafness. Given the multisystem nature of the disease process, several issues may affect the perioperative care of these patients. Of primary importance are associated conditions of the cardiovascular system including congenital heart disease, conduction disturbances, and progressive hypertrophic obstructive cardiomyopathy. The authors present a 4-year old boy who presented for anaesthetic care for repair of a ventricular septal defect and pulmonary valvotomy for congenital pulmonary stenosis. The potential perioperative implications of LEOPARD syndrome are discussed.

LEOPARD syndrome is a rare congenital disease characterized by seven features. Besides the original clinical manifestations, hypertrophic cardiomyopathy was reported as an additional laboratory finding recently. We gave general anesthesia to a child of this syndrome, and encountered ECG changes during emergence from anesthesia. The diagnosis was made in her infancy, and had been receiving beta-blocker treatment ever since. The preoperative examination showed remarkable right axis deviation in ECG, and asymmetric ventricular septal hypertrophy in echocardiography. After the operation, several kinds of arrhythmia (i.e. atrioventricular junctional rhythm, atrioventricular dissociation, etc), were observed and they continued for a few minutes. Careful planning for the perioperative management of this syndrome is mandatory. The cardiomyopathy must be examined beforehand. We made an effort to prevent the extreme changes of pre- and after-load during the general anesthesia.