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Journal of Cardiothoracic and Vascular... Oct 2014LEOPARD syndrome is a rare congenital disease that can manifest with cardiac anomalies, multiple lentigines, ocular hypertelorism, growth retardation, and deafness. The...
OBJECTIVES
LEOPARD syndrome is a rare congenital disease that can manifest with cardiac anomalies, multiple lentigines, ocular hypertelorism, growth retardation, and deafness. The purpose of this case series was to review the most prominent comorbidities associated with LEOPARD syndrome, and describe perioperative outcomes in a series of patients undergoing anesthesia.
DESIGN
Retrospective case series review
SETTING
Tertiary care institution
PARTICIPANTS
Patients diagnosed with LEOPARD syndrome who underwent surgical procedures requiring anesthesia at this institution.
INTERVENTION
The medical and anesthesia records of patients with LEOPARD syndrome were reviewed. Demographic information, clinical features of LEOPARD syndrome, comorbidities, intraoperative and postoperative events and complications were recorded. A systematic literature review also was conducted.
MEASUREMENTS AND MAIN RESULTS
Nine patients with LEOPARD syndrome underwent 49 procedures under general anesthesia (n = 40) or monitored anesthesia care (n = 9). The majority of operations were related to correction of cardiac anomalies (n = 20). The most common cardiac malformations were ventricular septal hypertrophy and pulmonary (or subpulmonary) stenosis, and major perioperative complications were related to severe arrhythmias and/or cardiac decompensation.
CONCLUSIONS
Dominant pathology associated with perioperative complications in patients with LEOPARD syndrome is related to cardiac disease. A large proportion of patients with this condition have ventricular septal hypertrophy, which tends to progress with age; therefore, these patients undergoing anesthesia should have recent cardiologist evaluation.
Topics: Adult; Anesthesia; Anesthetics; Female; Humans; Intraoperative Complications; LEOPARD Syndrome; Male; Middle Aged; Retrospective Studies; Ultrasonography
PubMed: 24461361
DOI: 10.1053/j.jvca.2013.09.015 -
Pediatric Neurology Jul 2009We report on a 2-year-old boy with facial dysmorphism, multiple lentigines, and hypertrophic cardiomyopathy. Mutation analyses of the patient and his mother revealed a...
We report on a 2-year-old boy with facial dysmorphism, multiple lentigines, and hypertrophic cardiomyopathy. Mutation analyses of the patient and his mother revealed a Y279G mutation in exon 7 of the PTPN11 gene. The presence of LEOPARD syndrome was confirmed by a genetic study and clinical phenotypes. Since age 18 months, the patient had manifested frequent seizures that were poorly controlled by multiple anticonvulsants. Neurologic examinations indicated severe developmental delay and sensorineural deafness. Brain imaging demonstrated open-lip schizencephaly in the right frontoparietal area. Central nervous system anomalies are rarely reported in this disease. To the best of our knowledge, this is the first report of LEOPARD syndrome with associated schizencephaly. Psychomotor retardation is not uncommon in LEOPARD syndrome. We advocate brain-imaging studies of patients with LEOPARD syndrome and neurologic abnormalities such as developmental delay or epilepsy.
Topics: Abdomen; Brain; Child, Preschool; DNA Mutational Analysis; Diagnosis, Differential; Humans; LEOPARD Syndrome; Magnetic Resonance Imaging; Male; Malformations of Cortical Development; Mothers; Mutation, Missense; Neurologic Examination; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Thorax
PubMed: 19520282
DOI: 10.1016/j.pediatrneurol.2009.02.015 -
American Journal of Human Genetics Feb 2006Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS),...
Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.
Topics: Adult; Amino Acid Sequence; Cohort Studies; Female; Germ-Line Mutation; Humans; Intracellular Signaling Peptides and Proteins; LEOPARD Syndrome; Leukemia; Male; Mutation; Noonan Syndrome; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases
PubMed: 16358218
DOI: 10.1086/499925 -
Cutis Apr 1996
Review
Topics: Abnormalities, Multiple; Diagnosis, Differential; Genitalia; Heart Diseases; Humans; Lentigo; Syndrome
PubMed: 8727768
DOI: No ID Found -
Journal of Pediatric Genetics Dec 2020LEOPARD syndrome (LS) is a rare autosomal dominant disorder that is characterized by multiple lentigines and various congenital anomalies. The clinical diagnosis of LS...
LEOPARD syndrome (LS) is a rare autosomal dominant disorder that is characterized by multiple lentigines and various congenital anomalies. The clinical diagnosis of LS requires molecular confirmation. The most frequently reported mutations in LS patients are in the protein tyrosine phosphatase nonreceptor type 11 gene, . Herein, we report the cases of three family members from two generations who are affected by LS and all carry the mutation c.836A > G (p.Tyr279Cys), identified by next-generation sequencing, while exhibiting different phenotypes.
PubMed: 32765928
DOI: 10.1055/s-0039-3400226 -
Frontiers in Cardiovascular Medicine 2023As binary switches, RAS proteins switch to an ON/OFF state during signaling and are on a leash under normal conditions. However, in RAS-related diseases such as cancer... (Review)
Review
As binary switches, RAS proteins switch to an ON/OFF state during signaling and are on a leash under normal conditions. However, in RAS-related diseases such as cancer and RASopathies, mutations in the genes that regulate RAS signaling or the RAS itself permanently activate the RAS protein. The structural basis of this switch is well understood; however, the exact mechanisms by which RAS proteins are regulated are less clear. RAS/MAPK syndromes are multisystem developmental disorders caused by germline mutations in genes associated with the RAS/mitogen-activated protein kinase pathway, impacting 1 in 1,000-2,500 children. These include a variety of disorders such as Noonan syndrome (NS) and NS-related disorders (NSRD), such as cardio facio cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML, also known as LEOPARD syndrome). A frequent manifestation of cardiomyopathy (CM) and hypertrophic cardiomyopathy associated with RASopathies suggest that RASopathies could be a potential causative factor for CM. However, the current supporting evidence is sporadic and unclear. RASopathy-patients also display a broad spectrum of congenital heart disease (CHD). More than 15 genes encode components of the RAS/MAPK signaling pathway that are essential for the cell cycle and play regulatory roles in proliferation, differentiation, growth, and metabolism. These genes are linked to the molecular genetic pathogenesis of these syndromes. However, genetic heterogeneity for a given syndrome on the one hand and alleles for multiple syndromes on the other make classification difficult in diagnosing RAS/MAPK-related diseases. Although there is some genetic homogeneity in most RASopathies, several RASopathies are allelic diseases. This allelism points to the role of critical signaling nodes and sheds light on the overlap between these related syndromes. Even though considerable progress has been made in understanding the pathophysiology of RASopathy with the identification of causal mutations and the functional analysis of their pathophysiological consequences, there are still unidentified causal genes for many patients diagnosed with RASopathies.
PubMed: 37529712
DOI: 10.3389/fcvm.2023.1176828 -
Molecular Syndromology Oct 2012The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type...
The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations.
PubMed: 23239957
DOI: 10.1159/000342251 -
Anais Brasileiros de Dermatologia 2017Hypertrophic cardiomyopathy is known as Leopard syndrome, which is a mnemonic rule for multiple lentigines (L), electrocardiographic conduction abnormalities (E), ocular...
Hypertrophic cardiomyopathy is known as Leopard syndrome, which is a mnemonic rule for multiple lentigines (L), electrocardiographic conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), abnormalities of genitalia (A), retardation of growth (R), and deafness (D). We report the case of a 12-year-old patient with some of the abovementioned characteristics: hypertelorism, macroglossia, lentigines, hypospadias, cryptorchidism, subaortic stenosis, growth retardation, and hearing impairment. Due to this set of symptoms, we diagnosed Leopard syndrome.
Topics: Child; Humans; LEOPARD Syndrome; Male; Phenotype
PubMed: 28225973
DOI: 10.1590/abd1806-4841.20174505 -
Pediatric Dermatology 2008Lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retarded growth, and deafness syndrome (multiple...
Lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retarded growth, and deafness syndrome (multiple lentigines syndrome) is most often characterized by multiple lentigines and cardiac conduction defects. Café noir spot is a term proposed, by analogy to café au lait spots, for the larger and darkly pigmented patches that are frequently observed in patients with this syndrome. Although presumed by some authors to represent lentigines, the histologic features of café noir spots have not been well documented in the literature. Only two previous cases have been reported in which a biopsy of the café noir spots than melanocytic nevi. We describe the histologic characteristics of seven café noir spots in six patients with lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retarded growth, and deafness syndrome. Three lesions represented melanocytic nevi (one with dysplastic features), and four were compatible with lentigo simplex. These findings help our understanding of the histologic spectrum of pigmented lesions in lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retarded growth, and deafness syndrome.
Topics: Adolescent; Adult; Child; Female; Humans; LEOPARD Syndrome; Lentigo; Male; Middle Aged; Nevus, Pigmented; Skin; Skin Pigmentation
PubMed: 18789084
DOI: 10.1111/j.1525-1470.2008.00734.x -
Clinical Genetics Feb 2007Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal... (Review)
Review
Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies and a predisposition to develop neoplasia, both benign and malignant. CS is caused by activating germline mutations in HRAS and belongs to an exciting class of genetic syndromes that are caused by perturbation of function through the Ras pathway. Some of these other syndromes include Noonan syndrome, LEOPARD syndrome, neurofibromatosis 1 and cardio-facio-cutaneous syndrome. Ras is a critical signaling hub in the cell and is activated by receptor tyrosine kinases, G-protein-coupled receptors, cytokine receptors and extracellular matrix receptors. The downstream effectors of Ras are many and control vital cellular functions including cell cycle progression, cell survival, motility, transcription, translation and membrane trafficking. Understanding the genetic etiology of CS is the first step in gaining insight to the role Ras plays in human development, cellular signaling and cancer pathogenesis.
Topics: Abnormalities, Multiple; Craniofacial Abnormalities; Diagnosis, Differential; Ectodermal Dysplasia; Failure to Thrive; Genes, ras; Genotype; Germ-Line Mutation; Humans; Intellectual Disability; Models, Biological; Neoplasms; Phenotype; Proto-Oncogene Proteins p21(ras); Signal Transduction; Syndrome
PubMed: 17250658
DOI: 10.1111/j.1399-0004.2007.00743.x