LEOPARD Syndrome: An autosomal dominant disorder with an acronym of its seven features (LENTIGO; ELECTROCARDIOGRAM abnormalities; ocular HYPERTELORISM; PULMONARY STENOSIS; abnormal genitalia; retardation of growth; and DEAFNESS or SENSORINEURAL HEARING LOSS). This syndrome is caused by mutations of PTPN11 gene encoding the non-receptor PROTEIN TYROSINE PHOSPHATASE, type 11, and is an allelic to NOONAN SYNDROME. Features of LEOPARD syndrome overlap with those of NEUROFIBROMATOSIS 1 which is caused by mutations in the NEUROFIBROMATOSIS 1 GENES.Noonan Syndrome: A genetically heterogeneous, multifaceted disorder characterized by short stature, webbed neck, ptosis, skeletal malformations, hypertelorism, hormonal imbalance, CRYPTORCHIDISM, multiple cardiac abnormalities (most commonly including PULMONARY VALVE STENOSIS), and some degree of INTELLECTUAL DISABILITY. The phenotype bears similarities to that of TURNER SYNDROME that occurs only in females and has its basis in a 45, X karyotype abnormality. Noonan syndrome occurs in both males and females with a normal karyotype (46,XX and 46,XY). Mutations in a several genes (PTPN11, KRAS, SOS1, NF1 and RAF1) have been associated the the NS phenotype. Mutations in PTPN11 are the most common. LEOPARD SYNDROME, a disorder that has clinical features overlapping those of Noonan Syndrome, is also due to mutations in PTPN11. In addition, there is overlap with the syndrome called neurofibromatosis-Noonan syndrome due to mutations in NF1.Neurofibromatoses: A group of disorders characterized by an autosomal dominant pattern of inheritance with high rates of spontaneous mutation and multiple neurofibromas or neurilemmomas. NEUROFIBROMATOSIS 1 (generalized neurofibromatosis) accounts for approximately 95% of cases, although multiple additional subtypes (e.g., NEUROFIBROMATOSIS 2, neurofibromatosis 3, etc.) have been described. (From Neurochirurgie 1998 Nov;44(4):267-72)Protein Tyrosine Phosphatase, Non-Receptor Type 11: A subtype of non-receptor protein tyrosine phosphatases that contain two SRC HOMOLOGY DOMAINS. Mutations in the gene for protein tyrosine phosphatase, non-receptor type 11 are associated with NOONAN SYNDROME.Lentigo: Small circumscribed melanoses resembling, but differing histologically from, freckles. The concept includes senile lentigo ('liver spots') and nevoid lentigo (nevus spilus, lentigo simplex) and may also occur in association with multiple congenital defects or congenital syndromes (e.g., Peutz-Jeghers syndrome).Pulmonary Subvalvular Stenosis: Narrowing below the PULMONARY VALVE or well below it in the infundibuluar chamber where the pulmonary artery originates, usually caused by a defective VENTRICULAR SEPTUM or presence of fibrous tissues. It is characterized by restricted blood outflow from the RIGHT VENTRICLE into the PULMONARY ARTERY, exertional fatigue, DYSPNEA, and chest discomfort.Panthera: Genus in the family FELIDAE comprised of big felines including LIONS; TIGERS; jaguars; and the leopard.Felidae: The cat family in the order CARNIVORA comprised of muscular, deep-chested terrestrial carnivores with a highly predatory lifestyle.Syndrome: A characteristic symptom complex.Carnivora: An order of MAMMALS, usually flesh eaters with appropriate dentition. Suborders include the terrestrial carnivores Fissipedia, and the aquatic carnivores PINNIPEDIA.

*  LEOPARD Syndrome Treatment & Management: Medical Care, Surgical Care, Consultations
Gorlin et al introduced the acronym LEOPARD as the name of the syndrome in 1969 to recall the main features of the disorder, as ... LEOPARD syndrome is a complex dysmorphogenetic disorder of variable penetrance and expressivity. ... encoded search term (LEOPARD%20Syndrome) and LEOPARD Syndrome What to Read Next on Medscape. Related Conditions and Diseases. * ... LEOPARD Syndrome with PTPN11 Gene Mutation Showing Six Cardinal Symptoms of LEOPARD. Ann Dermatol. 2011 May. 23(2):232-5. [ ...
  https://emedicine.medscape.com/article/1096445-treatment
*  LEOPARD Syndrome - Rare Disases - Condition | Our Health
Anyone diagnosed with LEOPARD syndrome?. Scientific literature from 50's till now only report about 300 people.. I probably got ... LEOPARD syndrome, although PTPN11 gene is negative for me.. Reply Follow This Thread Stop Following This Thread Flag this ...
  http://www.ourhealth.com/conditions/rare-disases/leopard-syndrome
*  LEOPARD syndrome
There are three types of LEOPARD syndrome, which are distinguished by their underlying genetic cause. LEOPARD syndrome type 1 ... "LEOPARD syndrome" (open studies are recruiting volunteers) and 1 "LEOPARD syndrome" studies with "all" status. Visit ... Noonan syndrome, Costello Syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair and Legius ... Do you know this syndrome? Leopard syndrome. Author(s): Flávio Heleno da Silva Queiroz Cançado, Luis Candido Pinto da Silva, ...
  http://www.diseaseinfosearch.org/LEOPARD+syndrome/4176
*  Free Science Flashcards about OPT Epithelial
benign cutaneous melanocytic hyperplasia not caused by sun-exposure; LEOPARD syndrome melasma. 'mask of pregnancy'; ... Plummer-Vinson syndrome. severe iron-deficiency anemia with increased risk for SCCA on pharynx. ... Muir-Torre syndrome. autosomal dominant disorder of sebaceous hyperplasia, malignancies and keratoacanthomas. ... BCCA that looks like nevus and there are usually multiple; part of nevoid basal cell carcinoma syndrome ...
  https://www.studystack.com/flashcard-2323951
*  CDKN3 Gene - GeneCards | CDKN3 Protein | CDKN3 Antibody
leopard syndrome. *capute-rimoin-konigsmark-esterly-richardson syndrome. *16638574. charcot-marie-tooth disease, type 4b1. * ... Diseases associated with CDKN3 include Hepatocellular Carcinoma and Bannayan-Riley-Ruvalcaba Syndrome. GO annotations related ...
  http://www.genecards.org/cgi-bin/carddisp.pl?gene=CDKN3
*  Cardiac Literature, including Myocardial Infarction, arrthymias, tachycardia, and angina sub-cluster 63
LEOPARD syndrome (LS, OMIM 151100) is a rare multiple congenital anomalies condition, mainly characterized by skin, facial and ... Congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome, is a very rare hereditary syndrome that is ... This syndrome is possibly due to an excess of catecholamines, and it is associated with emotional and physical stress ... ... LEOPARD is an acronym for the major features of this disorder, including multiple Lentigines, ECG conduction abnormalities, ...
  http://www.biomedsearch.com/cluster/1/Cardiac-Literature-including-Myocardial-Infarction-arrthymias-tachycardia-and-angina/sub-63-p9.html
*  Frontiers | Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery | Cell...
2010). Patient-specifi c induced pluripotent stem-cell derived models of LEOPARD syndrome. Nature 465, 808-812. doi: 10.1038/ ... There are many syndromes which are caused by the existence of one or more extra copies of a chromosome. Downs syndrome is one ... Down syndrome (DS) /trisomy 21 and the carrier state of Lesch-Nyhan syndrome (Park et al., 2008b). ... PTPN11 mutations in LEOPARD syndrome. J. Med. Genet. 39, 571-574. doi: 10.1136/jmg.39.8.571 ...
  https://www.frontiersin.org/articles/10.3389/fcell.2015.00002/full
*  SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton | Development
... the endogenous role for SHP-2 in heart development and its function in Noonan syndrome, AML, ALL, JMML and LEOPARD syndrome ... 2002). Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am. J. Hum. Genet. 71, 389-394. ... The Noonan syndrome-associated mutation SHP-2N308D leads to abnormal heart development in Xenopus. Noonan syndrome missense ... 2002). PTPN11 mutations in LEOPARD syndrome. J. Med. Genet. 39, 571-574. ...
  http://dev.biologists.org/content/139/5/948
*  Nevus of Ota disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials
leopard syndrome 9.8. 22. cerebritis 9.8. 23. retinitis 9.8. 24. meningeal melanoma 9.8. ... mirror polydactyly-vertebral segmentation-limbs defects syndrome 9.2. BAP1 BRAF TP53 40. dubin-johnson syndrome 9.2. BAP1 BRAF ... Phakomatosis pigmentovascularis type IIb: A case with Klippel-TrenA!unay syndrome and extensive dermal melanocytosis as nevus ...
  http://www.malacards.org/card/nevus_of_ota
*  Search of: Recruiting, Not yet recruiting, Available Studies | 'Craniofacial Abnormalities' - List Results - ClinicalTrials.gov
Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes. *Noonan Syndrome. *LEOPARD Syndrome ... Klippel-Feil Syndrome Alliance. American MEN Support. Kleine-Levin Syndrome. All Things Kabuki. WSS Foundation. BIVA. ABDA. ... Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome. *Noonan Syndrome ... Kabuki Syndrome Network. Kawasaki Disease Foundation. Klippel-Feil Syndrome Freedom. Leiomyosarcoma Direct Research. MSS ...
  https://clinicaltrials.gov/search/open/condition=%22Craniofacial+Abnormalities%22
*  Search of: 'noonan syndrome' - List Results - ClinicalTrials.gov
Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes. *Noonan Syndrome. *LEOPARD Syndrome ... Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome. *Noonan Syndrome ... Effect of MAXOMAT ® on the Growth of Small Children to NOONAN's Syndrome. *Noonan Syndrome ... Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome. * ...
  https://clinicaltrials.gov/ct2/results?cond=%22noonan+syndrome%22&show_rss=Y&sel_rss=new14
*  PMCMP - Clinical: Postmortem Cardiomyopathy Panel
... syndrome, and multiple lentigines syndrome (formerly called LEOPARD syndrome). Noonan syndrome and related disorders (also ... Noonan/CFC/LEOPARD syndrome RAF1 V-RAF-1 murine leukemia viral oncogene homolog 1 AD Noonan/LEOPARD syndrome RBM20 RNA-binding ... sudden infant death syndrome (SIDS), long QT syndrome (LQTS), sick sinus syndrome (SSS), autosomal dominant (AD), autosomal ... There are a number of disorders with significant phenotypic overlap with Noonan syndrome, including Costello syndrome, ...
  https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/65560
*  PMNSR - Clinical: Postmortem Noonan and Related Panel
Noonan/CFC/LEOPARD syndrome RAF1 V-raf-1 murine leukemia viral oncogene homolog 1 AD Noonan/LEOPARD syndrome SHOC2 Suppressor ... Noonan-like syndrome disorder HRAS V-HA-RAS Harvey rat sarcoma viral oncogene homolog AD Costello syndrome KRAS V-KI-RAS ... Postmortem diagnosis of Noonan syndrome or a related disorder may assist in confirmation of the cause of death, as well as risk ... Costello syndrome, which is characterized by coarse facies, short stature, distinctive hand posture and appearance, severe ...
  https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/65562
*  In Vitro Uses of Human Pluripotent Stem Cell-Derived Cardiomyocytes | SpringerLink
2010). Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature, 465(7299), 808-812. doi: ... 2011). Modelling the long QT syndrome with induced pluripotent stem cells. Nature, 471(7337), 225-229.PubMedGoogle Scholar ... Bokil, N. J., Baisden, J. M., Radford, D. J., & Summers, K. M. (2010). Molecular genetics of long QT syndrome. Molecular ... 2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. The New England Journal of Medicine, 363(15 ...
  https://link.springer.com/article/10.1007%2Fs12265-012-9376-5
*  BRAF (gene) - Wikipedia
In GeneReviews Gelb, Bruce D; Tartaglia, Marco (2010-11-16). LEOPARD Syndrome. NBK1383. In GeneReviews "BRAF gene". NCI ... Allanson, Judith E; Roberts, Amy E (2011-08-04). Noonan Syndrome. NBK1124. In Pagon RA, Bird TD, Dolan CR, et al., eds. (1993 ... Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental ... Check date values in: ,date= (help) Rauen, Katherine A (2012-09-06). Cardiofaciocutaneous Syndrome. NBK1186. ...
  https://en.wikipedia.org/wiki/BRAF_(gene)
*  Tyrosine-protein phosphatase non-receptor elisa and antibody
Disease: Juvenile Myelomonocytic Leukemia; Leopard Syndrome 1; Metachondromatosis; Noonan Syndrome 1. PTPN11 ELISA Kit. PTPN11 ...
  https://www.mybiosource.com/protein_family.php?root=tyrosine-protein-phosphatase-non-receptor
*  authors:"Giuseppe Limongelli" - Search | Paperity
LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies Apr 2014 , BMC Medical Genetics, Claudia Santoro, ... Oesophagus perforation mimicking an acute chest pain syndrome Mar 2015 , Internal and Emergency Medicine, Giovambattista ... Here, we describe a child initially diagnosed with Neurofibromatosis-Noonan syndrome. The follow-up of the proband, the ...
  http://paperity.org/search/?q=authors%3A%22Giuseppe+Limongelli%22
*  cardiofaciocutaneous syndrome [Lymphedema People]
Legius syndrome, LEOPARD syndrome, Noonan syndrome, Costello syndrome and cardiofaciocutaneous (CFC) syndrome. While the ... These syndromes, known as rasopathies, include Noonan syndrome, Costello syndrome, neurofibromatosis-1, LEOPARD syndrome, ... MAP2K1-Related Cardiofaciocutaneous Syndrome, MAP2K2-Related Cardiofaciocutaneous Syndrome, Noonan syndrome, Costello syndrome ... Cardiofaciocutaneous syndrome (CFC). Related Terms: Cardio-facio-cutaneous syndrome, CFC syndrome, Facio-cardio-cutaneous ...
  http://lymphedemapeople.com/wiki/doku.php?id=cardiofaciocutaneous_syndrome
*  Phospho anti-SHP2 (S576) antibody (ab17940) | Abcam
Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:151100]. It is an autosomal dominant disorder ... Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:163950]. Noonan syndrome (NS) is a disorder characterized ... JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome ... Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which ...
  http://www.abcam.com/shp2-phospho-s576-antibody-ab17940.html
*  3p7z - Proteopedia, life in 3D
Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat. 1996;8(1):51-6. PMID:8807336 ... JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome ... Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A. 2005 ... Nystrom AM, Ekvall S, Allanson J, Edeby C, Elinder M, Holmstrom G, Bondeson ML, Anneren G. Noonan syndrome and ...
  http://proteopedia.org/wiki/index.php/3p7z
*  Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome
PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006;281:6785-6792. [ ... Missense mutations in PTPN11 have previously been identified in patients with Noonan, Noonan-like, and LEOPARD syndromes, as ... Mutations in PTPN11 were not found in other cartilage tumor syndromes, including Ollier disease and Maffucci syndrome. We are ... as in the Multiple Osteochondroma syndrome (MO). In a hybrid syndrome, called metachondromatosis (MC), patients develop tumors ...
  http://pubmedcentralcanada.ca/pmcc/articles/PMC3077396/?lang=en-ca
*  UK and Ireland Natural History Bloggers: New Member
Home - On a ridge above the Himalayan hamlet of Ulley a snow leopard walks through deep snow. The asiatic ibex on the next ... Now...where was I? Oh yes - rhynchokinesis - otherwise known as handy-bendy-beak syndrome. I have touch... 6 years ago ...
  http://uknhb.blogspot.co.uk/2016/03/new-member_11.html
*  Brood X - Zooillogix
After 17 years of patiently waiting underground, Brood X has begun to emerge with a vengeance, eager to populate our planet with their infernal buzzing (we actually like it). It may sound like the plot for War of the Worlds, but it is actually much more benign and very real. This spring and summer, cicadas will emerge in the billions from their underground burrows to begin a frantic and inelegant mating ritual. Who wouldn't want to cut to the chase after 17 years living in the dirt? For a few short weeks, the shrimp-sized insects create a cacophony of sound that can be heard quite clearly in urban and suburban environments alike. Cicadas are sometimes called locusts, but are unrelated to true locusts, which are grasshoppers. They are actually closely related to the more adorable leaf-hoppers and spittle bugs ...
  http://scienceblogs.com/zooillogix/2007/05/03/brood-x/
*  Lake Worth Veterinarian, Lake Worth Animal Clinic, Lake Worth TX 76135 :: Newsletter Library
At Lake Worth Animal Clinic our mission and our promise is to provide the best possible and most compassionate medical care to your pet.
  http://lakeworthanimalclinic.net/index.php?package=newsletter&action=show_archive&year=2017&month=8

(1/34) LEOPARD syndrome: a new polyaneurysm association and an update on the molecular genetics of the disease.

LEOPARD syndrome, one of many cardiocutaneous syndromes, is an acronym for some of the obvious manifestations of the disease, such as lentigines or ocular hypertelorism. The synonymous name progressive cardiomyopathic lentiginosis better indicates the morbid cardiac features that patients with the syndrome have. A patient with LEOPARD syndrome is presented. He had recurrent upper extremity aneurysms requiring multiple operations and finally PTFE reinforced venous grafts to prevent further aneurysmal degeneration. He has multiple other peripheral aneurysms, thus far asymptomatic. His diagnosis of LEOPARD syndrome was confirmed on a genetic basis. Review of the literature reveals no previous reports of severe aneurysmal disease in these patients.  (+info)

(2/34) A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome.

Noonan (NS) and multiple lentigines/LEOPARD syndromes (LS) have proved to be associated with distinct PTPN11 mutations. Noonan-like/multiple giant cell lesion syndrome (NLS) is a rare disease, characterised by short stature, facial dysmorphisms, congenital heart defect (CHD) and central giant cell lesions. PTPN11 gene mutations have been reported in a single NLS family and two sporadic patients. Here we report a patient with a complex phenotype progressing throughout the years from NS at birth towards LS and NLS. PTPN11 gene analysis disclosed a novel missense mutation (Ala461Thr) in exon 12, affecting the consensus sequence of the SHP2-active site. This observation joins together NS and LS to NLS into a unique genetic defect, broadening the clinical and molecular spectrum of PTPN11-related disorders.  (+info)

(3/34) LEOPARD syndrome and hypertrophic obstructive cardiomyopathy: a case report.

The LEOPARD syndrome is a rare, autosomal dominant multisystemic disorder characterized by lentiginosis, ocular hypertelorism, abnormal genitalia, growth retardation, sensorineural deafness, and cardiac and electrocardiographic abnormalities. Although it is not cited, hypertrophic cardiomyopathy is often associated with the disease. In this study, we present a nine-year-old boy with LEOPARD syndrome and hypertrophic obstructive cardiomyopathy.  (+info)

(4/34) Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

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.  (+info)

(5/34) PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.

Multiple lentigines/LEOPARD syndrome (LS) is a rare, autosomal dominant disorder characterized by Lentigines, Electrocardiogram abnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Like the more common Noonan syndrome (NS), LS is caused by germ line missense mutations in PTPN11, encoding the protein-tyrosine phosphatase Shp2. Enzymologic, structural, cell biological, and mouse genetic studies indicate that NS is caused by gain-of-function PTPN11 mutations. Because NS and LS share several features, LS has been viewed as an NS variant. We examined a panel of LS mutants, including the two most common alleles. Surprisingly, we found that in marked contrast to NS, LS mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinase-mediated signaling. Molecular modeling and biochemical studies suggest that LS mutations contort the Shp2 catalytic domain and result in open, inactive forms of Shp2. Our results establish that the pathogenesis of LS and NS is distinct and suggest that these disorders should be distinguished by mutational analysis rather than clinical presentation.  (+info)

(6/34) Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1.

LEOPARD (LS) and Noonan (NS) are overlapping syndromes associated with distinct mutations of SHP-2. Whereas NS mutations enhance SHP-2 catalytic activity, we show that the activity of three representative LS mutants is undetectable when assayed using a standard protein tyrosine phosphatase (PTP) substrate. A different assay using a specific SHP-2 substrate confirms their decreased PTP activity, but also reveals a significant activity of the T468M mutant. In transfected cells stimulated with epidermal growth factor, the least active LS mutants promote Gab1/PI3K binding, validating our in vitro data. LS mutants thus display a reduced PTP activity both in vitro and in transfected cells.  (+info)

(7/34) Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction.

Noonan syndrome is a relatively common, genetically heterogeneous Mendelian trait with a pleiomorphic phenotype. Prior to the period covered in this review, missense mutations in PTPN11 had been found to account for nearly 50% of Noonan syndrome cases. That gene encodes SHP-2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway. Noonan syndrome-associated PTPN11 mutations are gain-of-function, with most disrupting SHP-2's activation-inactivation mechanism. Here, we review recent information that has elucidated further the types and effects of PTPN11 defects in Noonan syndrome and compare them to the related, but specific, missense PTPN11 mutations causing other diseases including LEOPARD syndrome and leukemias. These new data derive from biochemical and cell biological studies as well as animal modeling with fruit flies and chick embryos. The discovery of KRAS missense mutation as a minor cause of Noonan syndrome and the pathogenetic mechanisms of those mutants is discussed. Finally, the elucidation of gene defects underlying two phenotypically related disorders, Costello and cardio-facio-cutaneous syndromes is also reviewed. As these genes also encode proteins relevant for RAS-MAPK signal transduction, all of the syndromes discussed in this article now can be understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.  (+info)

(8/34) Noonan syndrome and related disorders: alterations in growth and puberty.

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.  (+info)