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Global Pediatric Health 2019RASopathy is caused by dysfunction in the pathway, and include syndromes like Noonan syndrome (NS), NS with multiple lentigines (formerly known as Leopard syndrome),...
RASopathy is caused by dysfunction in the pathway, and include syndromes like Noonan syndrome (NS), NS with multiple lentigines (formerly known as Leopard syndrome), cardiofaciocutaneous (CFC), Legius syndrome, capillary malformation-arteriovenous malformation, neurofibromatosis type 1, and Costello syndrome. When counted together, RASopathies affect 1/1000 live births, and are characterized by cardiovascular manifestations, short stature, developmental delay, renal, urogenital, skin/skeletal abnormalities, and dysmorphic appearance. NS-one of the most common RASopathies-occurs in 1/1000 to 1/2500 live births. On the other hand, the frequency of CFC is unknown, but it is one of the rarest RASopathies, with estimates of only a few hundred cases worldwide. However, its phenotype overlaps with that of NS. In this case series, we describe 5 patients with a clinical and genetic diagnosis of RASopathy-either NS or CFC-all of whom were also diagnosed with isolated sagittal synostosis (ISS). Medical records from ophthalmology, cardiology, plastic surgery, medical genetics, cleft craniofacial, and neurosurgery were used to determine patient history. In our cohort, late presentation of ISS was the predominant form of ISS presentation. We hope this report further characterizes the burgeoning relationship between RASopathy and ISS. Furthermore, these findings support including sagittal synostosis among the presenting features in the clinical phenotype of RASopathies. Ethical approval was obtained from the university's institutional review board.
PubMed: 31192281
DOI: 10.1177/2333794X19846774 -
Familial Cancer Sep 2011Cutaneous markers of systemic disease are vital for clinicians to recognize. This chapter outlines familial lentiginosis syndromes that include Peutz-Jeghers syndrome,... (Review)
Review
Cutaneous markers of systemic disease are vital for clinicians to recognize. This chapter outlines familial lentiginosis syndromes that include Peutz-Jeghers syndrome, Carney Complex, the PTEN hamartomatous syndromes, and LEOPARD/Noonan syndrome. The inheritance of these syndromes is autosomal dominant; they also share characteristic skin findings that offer a clue to their recognition and treatment. We will discuss the clinical presentation of these disorders, with a focus on the dermatological manifestations, and will provide an update on the molecular mechanisms involved. Recognition of cutaneous markers associated with these rare familial cancer syndromes provides the opportunity to pursue early surveillance for malignancies, as well as genetic counseling.
Topics: Diagnosis, Differential; Humans; Lentigo; Peutz-Jeghers Syndrome
PubMed: 21538076
DOI: 10.1007/s10689-011-9446-x -
Acta Dermato-venereologica Jan 2024
Topics: Humans; LEOPARD Syndrome; Melanoma; Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11
PubMed: 38189222
DOI: 10.2340/actadv.v104.14720 -
American Journal of Medical Genetics.... Aug 2018Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies)....
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.
Topics: Amiodarone; Arrhythmias, Cardiac; Calcium; Cardiomyopathy, Hypertrophic; Costello Syndrome; Digoxin; Female; Humans; Infant; Infant, Newborn; LEOPARD Syndrome; Male; Noonan Syndrome; Propranolol; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); SOS1 Protein; Tachycardia, Ectopic Atrial; ras Proteins
PubMed: 30055033
DOI: 10.1002/ajmg.a.38854 -
LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity.Proceedings of the National Academy of... Oct 2014LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of...
LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.
Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Body Composition; Cell Differentiation; Diet; Disease Models, Animal; Energy Metabolism; Insulin; LEOPARD Syndrome; Lentivirus; Lipolysis; MAP Kinase Kinase Kinase 1; Male; Mice; Mice, Transgenic; Mutation; Obesity; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Recombination, Genetic; Thinness
PubMed: 25288766
DOI: 10.1073/pnas.1406107111 -
Transboundary and Emerging Diseases Sep 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of seven coronaviruses known to infect humans. Different from other concerned coronavirus and...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of seven coronaviruses known to infect humans. Different from other concerned coronavirus and influenza viruses, SARS-CoV-2 has a higher basic reproduction number and thus transmits more efficiently among hosts. Testing animals for SARS-CoV-2 may help decipher virus reservoirs, transmission and pathogenesis. Here, we report the first detection of SARS-CoV-2 in three snow leopards (Panthera uncia) in a zoo in Kentucky in 2020, the first year of the pandemic. Sequence analysis revealed that snow leopard SARS-CoV-2 strains were non-variant B.1.2 lineage and closely correlated with human strains. One snow leopard shed SARS-CoV-2 in faeces up to 4 weeks. Based on clinical signs and viral shedding periods and levels in the three snow leopards, animal-to-animal transmission events could not be excluded. Further testing of SARS-CoV-2 in animals is needed.
Topics: Animals; COVID-19; Humans; Pandemics; Panthera; SARS-CoV-2
PubMed: 35698174
DOI: 10.1111/tbed.14625 -
Veterinary World Oct 2021The recent coronavirus disease (COVID-19) outbreak is one of its kind in the history of public health that has created a major global threat. The causative agent, severe... (Review)
Review
The recent coronavirus disease (COVID-19) outbreak is one of its kind in the history of public health that has created a major global threat. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a zoonotic source and hence, reverse zoonosis (disease transmission from humans to animals) increases the risk and rate of SARS-CoV-2 infection. Serological and molecular analyses and experimental infection studies have identified SARS-CoV-2 infection in several animal species in various countries. Different domestic and wild animals, including cats, dogs, tigers, lions, puma, snow leopard, minks, and pet ferrets, are infected naturally with SARS-CoV-2, mostly through suspected human to animal transmission. In addition, in vivo experimental inoculation studies have reported the susceptibility of cats, ferrets, hamsters, Egyptian fruit bats, and non-human primates to the virus. These experimentally infected species are found to be capable of virus transmission to co-housed animals of the same species. However, SARS-CoV-2 showed poor replication in livestock species such as pigs, chickens, and ducks with no detection of viral RNA after the animals were deliberately inoculated with the virus or exposed to the infected animals. As the pets/companion animals are more susceptible to COVID-19, the infection in animals needs an in-depth and careful study to avoid any future transmissions. The one health approach is the best inter-disciplinary method to understand the consequences of viral spread and prevention in novel host populations for the betterment of public health. Further in this review, we will explain in detail the different natural and experimentally induced cases of human to animal SARS-CoV-2 infection.
PubMed: 34903944
DOI: 10.14202/vetworld.2021.2817-2826 -
Cells Apr 2020P-related protein (PZR), a Noonan and Leopard syndrome target, is a member of the transmembrane Immunoglobulin superfamily. Its cytoplasmic tail contains two...
P-related protein (PZR), a Noonan and Leopard syndrome target, is a member of the transmembrane Immunoglobulin superfamily. Its cytoplasmic tail contains two immune-receptor tyrosine-based inhibitory motifs (ITIMs), implicated in adhesion-dependent signaling and regulating cell adhesion and motility. PZR promotes cell migration on the extracellular matrix (ECM) molecule, fibronectin, by interacting with SHP-2 (Src homology-2 domain-containing protein tyrosine phosphatase-2), a molecule essential for skeletal development and often mutated in Noonan and Leopard syndrome patients sharing overlapping musculoskeletal abnormalities and cardiac defects. To further explore the role of PZR, we assessed the expression of PZR and its ITIM-less isoform, PZRb, in human bone marrow mesenchymal stromal cells (hBM MSC), and its ability to facilitate adhesion to and spreading and migration on various ECM molecules. Furthermore, using siRNA knockdown, confocal microscopy, and immunoprecipitation assays, we assessed PZR and PZRb interactions with β1 integrins. PZR was the predominant isoform in hBM MSC. Migrating hBM MSCs interacted most effectively with fibronectin and required the association of PZR, but not PZRb, with the integrin, VLA-5(α5β1), leading to modulation of focal adhesion kinase phosphorylation and vinculin levels. This raises the possibility that dysregulation of PZR function may modify hBM MSC migratory behavior, potentially contributing to skeletal abnormalities.
Topics: Carrier Proteins; Cell Movement; Fibronectins; Humans; Integrin alpha5beta1; Mesenchymal Stem Cells; Phosphoproteins; Signal Transduction; Tyrosine
PubMed: 32365526
DOI: 10.3390/cells9051100 -
Developmental Cell May 2010The tyrosine phosphatase SHP2 (PTPN11) regulates cellular proliferation, survival, migration, and differentiation during development. Germline mutations in PTPN11 cause...
The tyrosine phosphatase SHP2 (PTPN11) regulates cellular proliferation, survival, migration, and differentiation during development. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, which have overlapping clinical features. Paradoxically, Noonan syndrome mutations increase SHP2 phosphatase activity, while LEOPARD syndrome mutants are catalytically impaired, raising the possibility that SHP2 has phosphatase-independent roles. By comparing shp2-deficient zebrafish embryos with those injected with mRNA encoding LEOPARD syndrome point mutations, we identify a phosphatase- and Erk-dependent role for Shp2 in neural crest specification and migration. We also identify an unexpected phosphatase- and Erk-independent function, mediated through its SH2 domains, which is evolutionarily conserved and prevents p53-mediated apoptosis in the brain and neural crest. Our results indicate that previously enigmatic aspects of LEOPARD syndrome pathogenesis can be explained by the combined effects of loss of Shp2 catalytic function and retention of an SH2 domain-mediated role that is essential for neural crest cell survival.
Topics: Animals; Cell Differentiation; Cell Division; Cell Movement; Cell Survival; Gastrula; Germ-Line Mutation; Humans; LEOPARD Syndrome; Neural Crest; Neural Tube; Noonan Syndrome; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; RNA, Messenger; Transcription, Genetic; Zebrafish
PubMed: 20493809
DOI: 10.1016/j.devcel.2010.03.009 -
Journal of Cardiology Cases Feb 2013LEOPARD syndrome is a phenotypic expression of mutations in several genes: PTPN11, RAF1, and BRAF. All these genes are responsible for Ras/MARK signaling pathway, which...
LEOPARD syndrome is a phenotypic expression of mutations in several genes: PTPN11, RAF1, and BRAF. All these genes are responsible for Ras/MARK signaling pathway, which are important for cell cycle regulation, differentiation, growth, and aging. Mutations result in anomalies of skin, skeletal, and cardiovascular systems. The LEOPARD syndrome means lentigines, electrocardiographic conducting abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, and deafness. Mutations affect tyrosine proteases, which are included in the signal pathway between the cell membrane and the nucleus. This rare autosomal dominant disorder is characterized by high variability of clinical manifestations. Usually only lentigines are common. Clinical diagnosis is based on lentigines and 2 other symptoms; in cases without lentigines - 3 symptoms and at least one affected first-line relative. Herein, we report the case of 17-year-old male who had idiopathic hypertrophic cardiomyopathy with left ventricular obstruction, and supraventricular and ventricular extasystoles, class IVa, left bundle branch block, as a life-threatening manifestation of LEOPARD syndrome. For the treatment of cardiac manifestations of this syndrome, the patient underwent two interventions: (1) mitral valve replacement by mechanical valve Optiform number 27 with surgical resection of left ventricular outflow tract and subaortic membrane excision; (2) implantable cardioverter-defibrillator therapy. < Explain the abbreviation L.E.O.P.A.R.D. (Lentigines, Electrocardiographic conducting abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth, and Deafness). Suspect the signs of L.E.O.P.A.R.D.-syndrome. Realize the etiology. Evaluate probability of this congenital disease on the ground of the clinical manifestations and laboratory data. Measure the significance for health of changes of organs and systems. Choose the main and dangerous manifestation of L.E.O.P.A.R.D.-syndrome. Select the best way for treatment such patients.>.
PubMed: 30533116
DOI: 10.1016/j.jccase.2012.10.006