14 results on '"Noonan Syndrome with Multiple Lentigines"'
Search Results
2. Compound heterozygosity for <scp>PTPN11</scp> variants in a subject with Noonan syndrome provides insights into the mechanism of <scp>SHP2</scp> ‐related disorders
- Author
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Marco Tartaglia, Simone Martinelli, Elías Cuesta-Llavona, Gianfranco Bocchinfuso, Luca Pannone, Julián Rodríguez-Reguero, Eliecer Coto, Inés Hernando, Rebeca Lorca, Giovanna Carpentieri, Juan Gómez, and Elisabetta Flex
- Subjects
LEOPARD syndrome ,Noonan syndrome ,phosphatase assay ,PTPN11 ,SHP2 ,Male ,Models, Molecular ,musculoskeletal diseases ,0301 basic medicine ,Heterozygote ,Protein Conformation ,Mutation, Missense ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,030105 genetics & heredity ,RASopathy ,Biology ,Compound heterozygosity ,LEOPARD Syndrome ,03 medical and health sciences ,Settore CHIM/02 ,Genetics ,medicine ,Humans ,Allele ,skin and connective tissue diseases ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Noonan Syndrome ,Genetic Variation ,Middle Aged ,medicine.disease ,Pedigree ,030104 developmental biology ,Amino Acid Substitution ,Mutation ,Noonan Syndrome with Multiple Lentigines - Abstract
The RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS-MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain-containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11. While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism.
- Published
- 2021
3. Noonan syndrome with multiple lentigines and prominent keratosis pilaris
- Author
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César Cosme Álvarez-Cuesta, Igor Vázquez-Osorio, Paula Fernández-Canga, and Eloy Rodríguez-Díaz
- Subjects
medicine.medical_specialty ,business.industry ,Mutation (genetic algorithm) ,Medicine ,Dermatology ,business ,medicine.disease ,Keratosis Pilaris ,Noonan Syndrome with Multiple Lentigines - Published
- 2019
4. A review of craniofacial and dental findings of the RASopathies
- Author
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Ophir D. Klein, Najla Alrejaye, Snehlata Oberoi, Alice F. Goodwin, and Haotian Cao
- Subjects
0301 basic medicine ,Port-Wine Stain ,030105 genetics & heredity ,Bioinformatics ,LEOPARD Syndrome ,Craniofacial Abnormalities ,Congenital ,Costello syndrome ,Ectodermal Dysplasia ,Ras/MAPK pathway ,2.1 Biological and endogenous factors ,Aetiology ,Heart Defects ,Pediatric ,Cafe-au-Lait Spots ,Costello Syndrome ,Noonan Syndrome ,craniofacial development ,Oral Surgery ,Noonan Syndrome with Multiple Lentigines ,Heart Defects, Congenital ,Neurofibromatosis 1 ,MAP Kinase Signaling System ,Orthodontics ,RASopathy ,Article ,Arteriovenous Malformations ,03 medical and health sciences ,Rare Diseases ,Genetics ,medicine ,Humans ,Dental/Oral and Craniofacial Disease ,Craniofacial ,Neurofibromatosis ,Germ-Line Mutation ,Legius syndrome ,business.industry ,Facies ,MAPK pathway ,malocclusion ,medicine.disease ,dental anomalies ,Capillaries ,Failure to Thrive ,030104 developmental biology ,Otorhinolaryngology ,Dentistry ,ras Proteins ,Congenital Structural Anomalies ,Noonan syndrome ,Surgery ,business ,Ras - Abstract
Objectives The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML or LEOPARD syndrome), neurofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1-like syndrome (NFLS or Legius syndrome) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the craniofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings. Methods Review of the literature. Results Each of the RASopathies reviewed, caused by mutations in genes that encode different proteins in the Ras pathway, have unique and overlapping craniofacial and dental characteristics. Conclusions Careful description of craniofacial and dental features of the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signalling in craniofacial development.
- Published
- 2017
5. Choroidal abnormalities in café-au-lait syndromes: a new differential diagnostic tool?
- Author
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Hilde Brems, Catherine Cassiman, Karel Van Keer, Ingele Casteels, Ellen Plasschaert, Eric Legius, Kathia Dubron, and Julie Jacob
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Genetic counseling ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Café au lait spot ,Genetics ,medicine ,Neurofibromatosis ,Genetics (clinical) ,Legius syndrome ,business.industry ,Nodule (medicine) ,medicine.disease ,Dermatology ,eye diseases ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,030221 ophthalmology & optometry ,sense organs ,Choroid ,Differential diagnosis ,medicine.symptom ,business ,Noonan Syndrome with Multiple Lentigines - Abstract
The best known cafe-au-lait syndrome is neurofibromatosis type 1 (NF1). Legius syndrome (LS) is another, rarer syndrome with cafe-au-lait macules (CALMs). In young patients their clinical picture is often indistinguishable. We investigated the presence of choroidal abnormalities in syndromes with CALMs as a candidate tool for a more efficient diagnosis. Thirty-four patients with NF1 (14 with a truncating mutation, 14 with a non-truncating mutation and 6 with unknown mutation) and 11 patients with LS. All patients underwent an ophthalmological examination. Infrared images were performed. Choroidal nodules were diagnosed in 65% of the NF1 group. About 71% of NF1 patients with a truncating mutation and 50% of patients with a non-truncating mutation were found to have nodules. Choroidal nodules were seen in 18% of the LS patients, never more than one nodule/eye was detected in this group. Choroidal nodules are more abundantly present in NF1 genotypes with truncating mutations. In contrast, the number of choroidal nodules in LS is comparable with their presence in healthy individuals. Especially at an early age, when the clinical picture is incomplete, the detection of choroidal nodules is of diagnostic value, and helps in an appropriate genetic counselling and follow-up. These results support the suggestion to include choroidal nodules to the diagnostic criteria for NF1.
- Published
- 2016
6. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway
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Kim M. Keppler-Noreuil, Abby Sandler, Chiara Leoni, Karlyne M. Reilly, Bronwyn Kerr, Frank McCormick, Anne Goriely, David Neal Franz, Amy E. Roberts, Scott R. Plotkin, Karen W. Gripp, Michael Fisher, Bruce R. Korf, Brigitte C. Widemann, Pinar Bayrak-Toydemir, Kathryn C. Chatfield, Annette Bakker, Karin S. Walsh, Brage S. Andresen, Emma Burkitt-Wright, Florent Elefteriou, Antonio Y. Hardan, Katherine A. Rauen, Bruce D Gelb, Dawn H. Siegel, Ype Elgersma, Lisa Schill, Lisa Schoyer, David A. Stevenson, and Neurosciences
- Subjects
MAPK/ERK pathway ,Clinical Sciences ,Ras/MAPK ,ras Proteins/genetics ,experimental models ,RASopathy ,Article ,Capital Financing ,Congenital ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Costello syndrome ,Genetics ,medicine ,cancer ,Humans ,Family ,Neurofibromatosis ,rare disorders ,Intersectoral Collaboration ,Genetics (clinical) ,Pediatric ,Legius syndrome ,clinical trials ,Clinical Trials as Topic ,business.industry ,Ras mapk ,Neurosciences ,Mitogen-Activated Protein Kinases/genetics ,medicine.disease ,MAPK ,Inborn ,Genetic Diseases ,030220 oncology & carcinogenesis ,ras Proteins ,Genetic Diseases, Inborn/diagnosis ,Cancer research ,Congenital Structural Anomalies ,Noonan syndrome ,Mitogen-Activated Protein Kinases ,business ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines ,Ras ,Signal Transduction - Abstract
The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. (c) 2016 Wiley Periodicals, Inc.
- Published
- 2016
7. Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy
- Author
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Blaine L. Hart, Karen S. SantaCruz, Carol L. Clericuzio, and Geoffrey D. McWilliams
- Subjects
Adult ,Male ,Risk ,Oncology ,medicine.medical_specialty ,Adolescent ,Childhood leukemia ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,Humans ,Medicine ,Child ,Genetics (clinical) ,DNET ,Brain Neoplasms ,Human Growth Hormone ,business.industry ,Dysembryoplastic Neuroepithelial Tumor ,Noonan Syndrome ,Cancer ,medicine.disease ,Neoplasms, Neuroepithelial ,PTPN11 ,Developmental disorder ,Endocrinology ,030220 oncology & carcinogenesis ,Noonan syndrome ,Female ,business ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk.
- Published
- 2015
8. Malignancy in Noonan syndrome and related disorders
- Author
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Dina J. Zand, Marshall L. Summar, Patroula Smpokou, and Kenneth N. Rosenbaum
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business.industry ,RASopathy ,medicine.disease ,Malignancy ,Cardiofaciocutaneous syndrome ,Bioinformatics ,LEOPARD Syndrome ,Costello syndrome ,Genetics ,medicine ,Cancer research ,Noonan syndrome ,Neurofibromatosis ,business ,Genetics (clinical) ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome (NS) and related disorders, such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, and Costello syndrome, constitute an important group of developmental malformation syndromes with variable clinical and molecular features. Their underlying pathophysiologic mechanism involves dysregulation of the Ras/mitogen-activated protein kinase signaling pathway, an essential mediator of developmental and growth processes in the prenatal and postnatal setting. Malignant tumor development is an important complication encountered in other RASopathies, such as neurofibromatosis type 1, but the neoplastic risks and incidence of malignant tumors are less clearly defined in NS and related disorders of the Noonan spectrum. Malignant tumor development remains an important complication variably seen in the RASopathies and, thus, a clear understanding of the underlying risks is essential for appropriate clinical care in this patient population. This review discusses previously published reports of malignancies in individuals with RASopathies of the Noonan spectrum.
- Published
- 2015
9. Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: Palliative treatment with a rapamycin analog
- Author
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Reinhard Kandolf, Susanne von Gerlach, Martin Zenker, Bruce D. Gelb, K. Behnke-Hall, Josef Thul, Anne Schänzer, Dietmar Schranz, Boyan K. Garvalov, Tushiha Logeswaran, Maria I. Kontaridis, Andreas Hahn, Jessica Lauriol, and Nuray Böğürcü
- Subjects
Male ,medicine.medical_specialty ,Palliative care ,medicine.medical_treatment ,DNA Mutational Analysis ,Mutation, Missense ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Article ,Muscle hypertrophy ,Internal medicine ,LEOPARD Syndrome ,Genetics ,medicine ,Humans ,Everolimus ,cardiovascular diseases ,Genetic Association Studies ,Genetics (clinical) ,Heart transplantation ,Base Sequence ,business.industry ,Myocardium ,Palliative Care ,Hypertrophic cardiomyopathy ,Cardiomyopathy, Hypertrophic ,medicine.disease ,Brain natriuretic peptide ,Endocrinology ,Heart failure ,Disease Progression ,cardiovascular system ,Cardiology ,Heart Transplantation ,business ,Immunosuppressive Agents ,Noonan Syndrome with Multiple Lentigines ,medicine.drug - Abstract
Noonan syndrome with multiple lentigines (NSML) frequently manifests with hypertrophic cardiomyopathy (HCM). Recently, it was demonstrated that mTOR inhibition reverses HCM in NSML mice. We report for the first time on the effects of treatment with a rapamycin analog in an infant with LS and a malignant form of HCM. In the boy, progressive HCM was diagnosed during the first week of life and diagnosis of NSML was established at age 20 weeks by showing a heterozygous Q510E mutation in the PTPN11 gene. Immunoblotting with antibodies against pERK, pAkt, and pS6RP in fibroblasts demonstrated reduced RAS/MAPK and enhanced Akt/mTOR pathway activities. Because of the patient’s critical condition, everolimus therapy was started at age 24 weeks and continued until heart transplantation at age 36 weeks. Prior to surgery, heart failure improved from NYHA stage IV to II and brain natriuretic peptide values decreased from 9600 to
- Published
- 2015
10. A novel heterozygousMAP2K1mutation in a patient with Noonan syndrome with multiple lentigines
- Author
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Eriko Nishi, Yoshimitsu Fukushima, Seiji Mizuno, Yuka Nanjo, Tomoki Kosho, Tetsuya Niihori, Yoichi Matsubara, and Yoko Aoki
- Subjects
Male ,Heterozygote ,medicine.medical_specialty ,Adolescent ,DNA Mutational Analysis ,MAP Kinase Kinase 2 ,Molecular Sequence Data ,MAP Kinase Kinase 1 ,LEOPARD Syndrome ,Internal medicine ,Genetics ,medicine ,Humans ,Missense mutation ,Precocious puberty ,Amino Acid Sequence ,Hypertelorism ,Genetics (clinical) ,business.industry ,Facies ,medicine.disease ,Dermatology ,Hypotonia ,PTPN11 ,Phenotype ,Endocrinology ,Amino Acid Substitution ,Mutation ,Sensorineural hearing loss ,medicine.symptom ,business ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome with multiple lentigines (NSML), formerly referred to as LEOPARD syndrome, is a rare autosomal-dominant condition, characterized by multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness. To date, PTPN11, RAF1, and BRAF have been reported to be causal for NSML. We report on a 13-year-old Japanese boy, who was diagnosed with NSML. He was found to have a novel heterozygous missense variant (c.305A > G; p.E102G) in MAP2K1, a gene mostly causal for cardio-facio-cutaneous syndrome (CFCS). He manifested fetal macrosomia, and showed hypotonia and poor sucking in the neonatal period. He had mild developmental delay, and multiple lentigines appearing at approximately age 3 years, as well as flexion deformity of knees bilaterally, subtle facial characteristics including ocular hypertelorism, sensorineural hearing loss, and precocious puberty. He lacked congenital heart defects or hypertrophic cardiomyopathy, frequently observed in patients with NSML, mostly caused by PTPN11 mutations. He also lacked congenital heart defects, characteristic facial features, or intellectual disability, frequently observed in those with CFCS caused by MAP2K1 or MAP2K2 mutations. This may be the first patient clinically diagnosed with NSML, caused by a mutation in MAP2K1. © 2014 Wiley Periodicals, Inc.
- Published
- 2014
11. Widespread keratosis pilaris in a patient with Noonan syndrome with multiple lentigines
- Author
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Vehap Topcu, Seda Purnak, Elçin Kadan, Başak Yalçin, and Busranur Cavdarli
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Genetic counseling ,MEDLINE ,Dermatology ,medicine.disease ,Keratosis Pilaris ,030207 dermatology & venereal diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,business ,Noonan Syndrome with Multiple Lentigines ,Genetic testing - Published
- 2018
12. Noonan syndrome with multiple lentigines with PTPN11 (T468M) gene mutation accompanied with solitary granular cell tumor
- Author
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Si Hyung Lee and Seh Hyun Park
- Subjects
0301 basic medicine ,Granular cell tumor ,business.industry ,Dermatology ,General Medicine ,Gene mutation ,medicine.disease ,LEOPARD Syndrome ,PTPN11 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,business ,Noonan Syndrome with Multiple Lentigines - Published
- 2017
13. Medulloblastoma in a patient with thePTPN11p.Thr468Met mutation
- Author
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Peter D. Turnpenny, John Short, Bruce Castle, Julia Rankin, and C. Oliver Hanemann
- Subjects
Adult ,Male ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Cardiofaciocutaneous syndrome ,Polymerase Chain Reaction ,LEOPARD Syndrome ,Young Adult ,Costello syndrome ,Internal medicine ,Genetics ,medicine ,Humans ,Neurofibromatosis ,neoplasms ,Genetics (clinical) ,Legius syndrome ,Medulloblastoma ,business.industry ,DNA ,Middle Aged ,medicine.disease ,nervous system diseases ,stomatognathic diseases ,Phenotype ,Endocrinology ,Mutation ,Noonan syndrome ,business ,Noonan Syndrome with Multiple Lentigines - Abstract
Medulloblastoma is the commonest brain tumor in childhood and in a minority of patients is associated with an underlying genetic disorder such as Gorlin syndrome or familial adenomatous polyposis. Increased susceptibility to certain tumors, including neuroblastoma and some hematological malignancies, is recognized in disorders caused by mutations in genes encoding components of the RAS signaling pathway which include Noonan syndrome, Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome), Costello syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, and Neurofibromatosis type 1 (NF1), collectively termed RASopathies. Although an association between medulloblastoma and NF1 has been reported, this tumor has not previously been reported in other RASopathies. We present a patient with NSML caused by the recurrent PTPN11 mutation c.1403C > T (p.Thr468Met) in whom medulloblastoma was diagnosed at age 10 years. Medulloblastoma could therefore be part of the tumor spectrum associated with this disorder.
- Published
- 2013
14. Developmental Syndromes of Ras/ <scp>MAPK</scp> Pathway Dysregulation
- Author
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Alexsandra C. Malaquias and A. A. L. Jorge
- Subjects
Legius syndrome ,Genetics ,MAPK/ERK pathway ,Costello syndrome ,medicine ,Noonan syndrome ,RASopathy ,Biology ,medicine.disease ,Cardiofaciocutaneous syndrome ,LEOPARD Syndrome ,Noonan Syndrome with Multiple Lentigines - Abstract
The term RASopathies designates a group of developmental syndromes caused by germline mutations in genes that encode proteins of the Ras/mitogen-activated protein kinase (MAPK) signalling pathway. Ras/MAPK pathway controls several biological functions, such as cell proliferation, migration, differentiation and apoptosis. Similar molecular mechanisms disturbing the Ras/MAPK pathway were described in the RASopathies, including Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome-like disorder with loose anagen hair, CBL mutation-associated syndrome, Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1 and Legius syndrome. Even though these syndromes share some overlapping features, genotype–phenotype correlations are well established for each of these, supporting the idea that they represent clinically distinct disorders. Owing to the similar mechanism encompassing Ras/MAPK germline and somatic mutations, Ras/MAPK pathway components have been considered a potential therapeutic target for RASopathies by promoting pathway modulation or small-molecule inhibition. Key Concepts: Ras/MAPK is one of the most well-known signalling pathways and plays an important role in critical cellular functions to normal development. RASopathies are a group of medical genetic disorders caused by gain-of-function germline mutations in components of the Ras/MAPK signalling pathway. Although the RASopathies may share clinically overlapping features, they also exhibit some individual ones that support the concept that they are distinct disorders. Ras/MAPK germline mutations are similar to somatic mutations when associated with cancer, but they tend to be weakly activating. Noonan syndrome is a frequent autosomal dominant disorder characterised by facial dysmorphisms, heart defects, short stature and learning disabilities. The best clinical practice for each RASopathy could be defined if its genotype–phenotype correlation is understood. Keywords: cardiofaciocutaneous syndrome; Costello syndrome; Legius syndrome; LEOPARD syndrome; neurofibromatosis; Noonan syndrome; Ras/MAPK; RASopathies; signal transduction pathway
- Published
- 2014
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