A Síndrome de Noonan (SN) é caracterizada por baixa estatura, dismorfismo facial típico e defeitos cardíacos congênitos.
Introdução
O que você precisa saber de cara
A Síndrome de Noonan (SN) é caracterizada por baixa estatura, dismorfismo facial típico e defeitos cardíacos congênitos.
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Escala de raridade
<1/50kMuito rara
1/20kRara
1/10kPouco freq.
1/5kIncomum
1/2k
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Sinais e sintomas
O que aparece no corpo e com que frequência cada sintoma acontece
Partes do corpo afetadas
+ 94 sintomas em outras categorias
Características mais comuns
Os sintomas variam de pessoa para pessoa. Abaixo estão as 267 características clínicas mais associadas, ordenadas por frequência.
Linha do tempo da pesquisa
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Genética e causas
O que está alterado no DNA e como passa nas famílias
Genes associados
17 genes identificados com associação a esta condição. Padrão de herança: Autosomal dominant, Autosomal recessive.
Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival (PubMed:16630891, PubMed:28289718, PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates the MAPK pathway activation (PubMed:16630891, PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). The formation of the SMP complex only occurs when MRAS is GTP-bound (PubMed:35768504, PubMed:358308
Cell membrane
Noonan syndrome 11
A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. NS11 inheritance is autosomal dominant.
Required for the assembly of dynein arms
Cell projection, cilium
Ciliary dyskinesia, primary, 39
A form of primary ciliary dyskinesia, a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia. Some patients exhibit randomization of left-right body asymmetry and situs inversus. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. CILD39 inheritance is autosomal recessive.
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, c
Cytoplasm, cytoskeleton, spindleNucleusCytoplasm, cytoskeleton, microtubule organizing center, centrosomeCytoplasmMembrane, caveolaCell junction, focal adhesion
Noonan syndrome 13
A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. NS13 inheritance is autosomal dominant. There is considerable variability in severity.
E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors (PubMed:10514377, PubMed:11896602, PubMed:14661060, PubMed:14739300, PubMed:15190072, PubMed:17509076, PubMed:18374639, PubMed:19689429, PubMed:21596750, PubMed:28381567, PubMed:40101708). Accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:10514377, Pu
CytoplasmCell membraneCell projection, ciliumGolgi apparatus
Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia
A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. Some have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS) (PubMed:30442762, PubMed:30442766, PubMed:30481304). Is a negative regulator of RAS-MAPK signaling that acts by controlling Ras levels and decreasing Ras association with membranes (PubMed:30442762, PubMed:30442766, PubMed:30481304)
Endomembrane systemRecycling endosomeGolgi apparatus
Glioma
Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.
Inhibitory regulator of the Ras-cyclic AMP pathway. Binds inositol tetrakisphosphate (IP4)
CytoplasmCytoplasm, perinuclear region
Key regulator of both differentiation and survival of T-lymphocytes during thymocyte development in mammals. Essential in controlling the responsiveness of hematopoietic stem cells to chemotactic signals by modulating the expression of the receptors CCR7 and CCR9, which direct the movement of progenitor cells from the bone marrow to the thymus (PubMed:27959755). Is a regulator of IL2 promoter and enhances IL2 expression in activated CD4(+) T-lymphocytes (PubMed:16809611). Tumor-suppressor that r
Nucleus
Immunodeficiency 49, severe combined
A form of severe combined immunodeficiency characterized by severe T-cell lymphopenia, no detectable T-cell receptor excision circles, no naive helper CD4+ T-cells, and impaired T-cell proliferative response. In addition to primary immunodeficiency, affected individuals manifest multiple abnormal systemic features, including severe delayed psychomotor development, intellectual disability, spastic quadriplegia, and craniofacial abnormalities.
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:20949621, PubMed:39809765). Plays an important role in the regulation of cell proliferation (PubMed:22711838, PubMed:23698361). Activates MAPK1/MAPK3 resulting in phosphorylation and ultimately degradation of GJA1 (By similarity). Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner (PubMed:24623306)
Cell membraneEndomembrane systemCytoplasm, cytosol
Leukemia, acute myelogenous
A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes.
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and
CytoplasmCell membraneMitochondrionNucleus
Noonan syndrome 5
A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity
Cell membraneGolgi apparatus membrane
Leukemia, juvenile myelomonocytic
An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages.
Promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3/ERK1 in response to EGF (PubMed:17339331). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (By similarity)
Fibromatosis, gingival, 1
A form of hereditary gingival fibromatosis, a rare condition characterized by a slow, progressive overgrowth of the gingiva. The excess gingival tissue can cover part of or the entire crown, and can result in diastemas, teeth displacement, or retention of primary or impacted teeth. GINGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common.
GTP-binding protein with GTPase activity, involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes (PubMed:31130282, PubMed:31130285, PubMed:39809765). Regulates craniofacial development (PubMed:31130282, PubMed:31130285)
Cell membraneGolgi apparatus membrane
Ovarian cancer
The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease.
Acts as guanine nucleotide exchange factor (GEF) for RAS proteins. Catalyzes the GDP-to-GTP exchange, resulting in an increase of the active GTP-bound form of HRAS (PubMed:20639119). Acts as a key modulator of PI3K-AKT signaling
Noonan syndrome 9
A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.
Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role in the postsynaptic responses of hippocampal neurons (PubMed:1508179)
NucleusCytoplasmCell membrane
Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus (PubMed:10655584, PubMed:14739280, PubMed:18559669, PubMed:18829466, PubMed:26742426, PubMed:28074573, PubMed:32184441). Positively regulates MAPK signal transduction pathway (PubMed:28074573). Dephosphorylates GAB1, ARHGAP35 and EGFR (PubMed:28074573). Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity
CytoplasmNucleus
LEOPARD syndrome 1
A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
GTP-binding protein with GTPase activity, likely involved in the regulation of MAPK signaling pathway and thereby controlling multiple cellular processes (PubMed:39809765). Regulates the organization of the actin cytoskeleton (PubMed:16537651, PubMed:18270267). With OSPBL3, modulates integrin beta-1 (ITGB1) activity (PubMed:18270267)
Cell membrane
Negatively regulates Ras signaling pathways and downstream activation of MAP kinases (PubMed:15683364, PubMed:34626534). Recruits and translocates NF1 to the cell membrane, thereby enabling NF1-dependent hydrolysis of active GTP-bound Ras to inactive GDP-bound Ras (PubMed:34626534). Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2 (By similarity). Inhibits TGFB-induced epithelial-to-mesenchymal trans
Cell membraneCytoplasmic vesicle, secretory vesicle membraneCytoplasm
Noonan syndrome 14
A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. NS14 inheritance is autosomal recessive.
Medicamentos e terapias
Mecanismo: Growth hormone receptor agonist
Mecanismo: HMG-CoA reductase inhibitor
Mecanismo: Insulin-like growth factor I receptor agonist
Variantes genéticas (ClinVar)
344 variantes patogênicas registradas no ClinVar.
Classificação de variantes (ClinVar)
Distribuição de 4,300 variantes classificadas pelo ClinVar.
Vias biológicas (Reactome)
125 vias biológicas associadas aos genes desta condição.
Diagnóstico
Os sinais que médicos procuram e os exames que confirmam
Tratamento e manejo
Remédios, cuidados de apoio e o que precisa acompanhar
Onde tratar no SUS
Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)
🇧🇷 Atendimento SUS — Síndrome Noonan
Centros de Referência SUS
24 centros habilitados pelo SUS para Síndrome Noonan
Centros para Síndrome Noonan
Detalhes dos centros
Hospital Universitário Prof. Edgard Santos (HUPES)
R. Dr. Augusto Viana, s/n - Canela, Salvador - BA, 40110-060 · CNES 0003808
Serviço de Referência
Hospital Infantil Albert Sabin
R. Tertuliano Sales, 544 - Vila União, Fortaleza - CE, 60410-794 · CNES 2407876
Serviço de Referência
Hospital de Apoio de Brasília (HAB)
AENW 3 Lote A Setor Noroeste - Plano Piloto, Brasília - DF, 70684-831 · CNES 0010456
Serviço de Referência
Hospital Estadual Infantil e Maternidade Alzir Bernardino Alves (HIABA)
Av. Min. Salgado Filho, 918 - Soteco, Vila Velha - ES, 29106-010 · CNES 6631207
Serviço de Referência
Hospital das Clínicas da UFG
Rua 235 QD. 68 Lote Área, Nº 285, s/nº - Setor Leste Universitário, Goiânia - GO, 74605-050 · CNES 2338424
Serviço de Referência
Hospital Universitário da UFJF
R. Catulo Breviglieri, Bairro - s/n - Santa Catarina, Juiz de Fora - MG, 36036-110 · CNES 2297442
Atenção Especializada
Hospital das Clínicas da UFMG
Av. Prof. Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte - MG, 30130-100 · CNES 2280167
Serviço de Referência
Hospital Universitário Julio Müller (HUJM)
R. Luis Philippe Pereira Leite, s/n - Alvorada, Cuiabá - MT, 78048-902 · CNES 2726092
Atenção Especializada
Hospital Universitário João de Barros Barreto
R. dos Mundurucus, 4487 - Guamá, Belém - PA, 66073-000 · CNES 2337878
Serviço de Referência
Hospital Universitário Lauro Wanderley (HULW)
R. Tabeliao Estanislau Eloy, 585 - Castelo Branco, João Pessoa - PB, 58050-585 · CNES 0002470
Atenção Especializada
Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)
R. dos Coelhos, 300 - Boa Vista, Recife - PE, 50070-902 · CNES 0000647
Serviço de Referência
Hospital Pequeno Príncipe
R. Des. Motta, 1070 - Água Verde, Curitiba - PR, 80250-060 · CNES 3143805
Serviço de Referência
Hospital Universitário Regional de Maringá (HUM)
Av. Mandacaru, 1590 - Parque das Laranjeiras, Maringá - PR, 87083-240 · CNES 2216108
Atenção Especializada
Hospital de Clínicas da UFPR
R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900 · CNES 2364980
Serviço de Referência
Hospital Universitário Pedro Ernesto (HUPE-UERJ)
Blvd. 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro - RJ, 20551-030 · CNES 2280221
Serviço de Referência
Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira (IFF/Fiocruz)
Av. Rui Barbosa, 716 - Flamengo, Rio de Janeiro - RJ, 22250-020 · CNES 2269988
Serviço de Referência
Hospital São Lucas da PUCRS
Av. Ipiranga, 6690 - Jardim Botânico, Porto Alegre - RS, 90610-000 · CNES 2232928
Serviço de Referência
Hospital de Clínicas de Porto Alegre (HCPA)
Rua Ramiro Barcelos, 2350 Bloco A - Av. Protásio Alves, 211 - Bloco B e C - Santa Cecília, Porto Alegre - RS, 90035-903 · CNES 2237601
Serviço de Referência
Hospital Universitário da UFSC (HU-UFSC)
R. Profa. Maria Flora Pausewang - Trindade, Florianópolis - SC, 88036-800 · CNES 2560356
Serviço de Referência
Hospital das Clínicas da FMUSP
R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo - SP, 05403-010 · CNES 2077485
Serviço de Referência
Hospital de Base de São José do Rio Preto
Av. Brg. Faria Lima, 5544 - Vila Sao Jose, São José do Rio Preto - SP, 15090-000 · CNES 2079798
Atenção Especializada
Hospital de Clínicas da UNICAMP
R. Vital Brasil, 251 - Cidade Universitária, Campinas - SP, 13083-888 · CNES 2748223
Serviço de Referência
Hospital de Clínicas de Ribeirão Preto (HCRP-USP)
R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto - SP, 14015-010 · CNES 2082187
Serviço de Referência
UNIFESP / Hospital São Paulo
R. Napoleão de Barros, 715 - Vila Clementino, São Paulo - SP, 04024-002 · CNES 2688689
Serviço de Referência
Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.
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Publicações mais relevantes
Mostrando amostra de 200 publicações de um total de 1.354
Novel Variants in PTPN11, NF1, RASA2, and MAP2K1: Expanding the Molecular Spectrum of RASopathies in a Turkish Cohort.
RASopathies are a group of genetically heterogeneous developmental disorders caused by germline variants affecting the RAS/MAPK signaling pathway. These disorders display overlapping clinical features and diverse molecular mechanisms. This study aimed to evaluate the clinical and molecular spectrum of patients diagnosed with RASopathies, with a particular focus on novel and rare variants. A retrospective, multicenter study was conducted on patients with clinically suspected RASopathy and diagnosed by targeted Next Generation Sequencing analysis between 2021 and 2024. Variants were classified according to ACMG criteria, and clinical data were reviewed for genotype-phenotype correlations. Among 23 patients (14 males, 9 females), 15 (65.2%) had Noonan syndrome, five (21.7%) Neurofibromatosis Type 1, two (8.7%) Cardio-facio-cutaneous syndrome, and one (4.3%) Neurofibromatosis-Noonan syndrome. The most frequent clinical findings were craniofacial dysmorphism (91.3%), musculoskeletal anomalies (82.6%), and cutaneous features (78.3%). A total of 24 heterozygous variants were identified in seven genes: PTPN11 (45.8%), NF1 (25%), LZTR1 (12.5%), and RASA2, SOS1, MAP2K1, and BRAF (each 4.2%). Four novel variants were detected (PTPN11 c.853 + 4A>G, RASA2 p.E71D, NF1 p.W784Mfs*10, MAP2K1 p.A106T). This study highlights the clinical and molecular heterogeneity of RASopathies and expands the variant spectrum with novel and rare pathogenic alterations. The identification of new variants, particularly in rarely implicated genes such as RASA2, underlines the diagnostic value of comprehensive NGS-based testing and the need for individualized, multidisciplinary clinical management.
Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.
Noonan syndrome (NS) is a common autosomal dominant disorder with considerable clinical heterogeneity. Mutations in the PTPN11 gene, encoding the SHP2 protein, constitute the most prevalent genetic cause of NS. Genetic sequencing of a pedigree exhibiting typical facial dysmorphism and short stature identified the same heterozygous PTPN11 variant (NM_001330437.2: c.923 A > G, p.Asn308Ser) in all seven affected individuals, co-segregating with the phenotype. Using a multi-level approach that integrated experimental structural analysis, molecular dynamics simulations, protein-protein interaction network analysis, quantitative phosphoproteomics, and functional validation in cellular models, we systematically elucidated the pathogenic mechanism of the p.Asn308Ser mutation. This revealed that the mutation disrupts critical hydrogen bonds and remodels the interaction network. This change enhances conformational heterogeneity and shifts the protein into an activated "open" state. Consequently, the mutation strengthens interactions with hub proteins, such as GRB2 and SRC, resulting in sustained RAS/MAPK activation. Phosphoproteomic analysis showed that the mutation induces extensive phosphorylation events, with differentially phosphorylated proteins significantly enriched in the nucleus, particularly in pathways related to chromatin organization and ATP-dependent chromatin remodeling. Further functional validation indicated that aberrantly activated ERK may phosphorylate chromatin remodeling complexes such as SWI/SNF, thereby directly connecting cytoplasmic signaling to aberrant epigenetic regulation in the nucleus. This study delineates the complete pathogenic axis of the PTPN11 p.Asn308Ser mutation, spanning atomic conformational changes and sustained signaling activation to aberrant nuclear chromatin remodeling. These findings extend the understanding of NS pathophysiology to the epigenetic level and provide a theoretical foundation for future interventions targeting both signaling pathways and chromatin states.
Unraveling the Impact of KRAS Accessory Proteins on Oncogenic Signaling Pathways.
The oncogene KRAS drives tumor growth by activating pathways such as MAPK and PI3K-AKT in a constitutive manner. Although direct KRAS inhibitors exist, they are often limited in clinical use due to therapeutic resistance and toxicity. Therefore, alternative combinatorial therapeutic strategies are urgently needed. This study examined the knockout of five KRAS-related proteins-galectin-3 (GAL3), phosphodiesterase delta (PDEδ), nucleophosmin (NPM1), IQ motif-containing GTPase-activating protein 1 (IQGAP1), and SHOC2-using CRISPR-Cas9 in adenocarcinoma cell lines harboring the KRAS(G12V) oncogenic mutation, as well as in the noncancerous HEK-293 cell line. These proteins act as critical modulators that regulate KRAS activity, cellular localization, and that of its downstream signaling components. We analyzed the downstream activation of ERK and AKT kinases and evaluated subsequent cancer cell proliferation. Knockout of GAL3 and PDEδ was highly effective, significantly reducing MAPK and PI3K-AKT pathway activity and substantially impairing cell proliferation. SHOC2 knockout selectively and potently disrupted MAPK activation, while NPM1 knockout resulted in the complex, reciprocal modulation of the two major pathways. Notably, knocking out IQGAP1 enhanced PI3K-AKT and mTORC2-AKT signaling without affecting the MAPK pathway. These distinct modulatory roles highlight the non-redundant functions of the accessory proteins. In conclusion, our findings establish GAL3 and PDEδ, two KRAS-associated proteins, as promising combinatorial drug targets. Targeting these modulators provides an effective alternative strategy to overcome resistance mechanisms and enhance the clinical utility of existing KRAS inhibitors.
Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort.
The variety of genes associated with Noonan syndrome spectrum disorders (NSSD) is expanding, and real-life experience with its management is increasing; however, phenotypic differences among genotypes remain poorly defined. We aimed to assess clinical characteristics and response to growth hormone (GH) therapy in a genetically confirmed, single-country multicentre NSSD cohort. We included 101 patients with NSSD (56 males) from six centres: 76 with (likely) pathogenic PTPN11 variants, 7 with SOS1 variants, and 18 with other gene variations. All completed at least one year of GH therapy; 23 reached final height. Parental heights were below average (fathers: - 0.33 SDS [- 1.19; 0.39], p < 0.01; mothers: - 0.68 SDS [- 1.47; 0.12], p < 0.001; medians [IQR]). SOS1-NS patients were born earlier (gestational week 36 [31; 37]) compared to PTPN11-NS. Birth length (- 1.23 SDS [- 1.74; - 0.57]) was more reduced than weight (- 0.29 SDS [- 1.10; 0.54]; p < 0.0001); PTPN11-NS/SOS1-NS had the lowest birth weights (p < 0.05). GH was started at 6.4 years (3.8; 9.5), with baseline height-SDS - 2.92 (- 3.64; - 2.47). Median annual height-SDS increments were similar across genotypes: 0.61 (year 1; n = 101), 0.28 (year 2; n = 92), 0.21 (year 3; n = 77), 0.07 (year 4; n = 63), and 0.09 (year 5; n = 41), leading to height-SDS - 1.97 (- 2.81; - 1.42) after 5 years. Menarche occurred at age 15.7 (13.8; 17.2) years (n = 13), and final height-SDS (available in 23 patients) reached - 1.68 (- 2.65; - 0.41). Conclusions Growth restriction in NSSD begins prenatally, especially in PTPN11-NS and SOS1-NS. GH therapy was associated with improved height SDS, with the largest height gains observed before puberty. Earlier treatment initiation may therefore be beneficial for growth outcomes. What is Known: • Noonan syndrome spectrum disorders (NSSD) are genetically heterogeneous, with pathogenic variants in the PTPN11 and SOS1 genes being most prevalent. Phenotypic differences among genotypes remain poorly defined. • Short stature is a key NSSD feature. Growth hormone (GH) therapy is beneficial, but prior studies lacked genetic justification or had limited sample sizes. What is New: • We analysed perinatal data and real-life GH outcomes in 101 genetically confirmed NSSD cases. • SOS1-NS was linked to prematurity. Birth length was more reduced than weight across genotypes; PTPN11/SOS1 cases had the lowest birth weights. GH therapy was associated with an increase in height SDS from - 2.92 to - 1.97 (median) following 5 years, and to - 1.68 in those with final height.
Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2-RAS-PP1C complex. MRAS forms a high-affinity SHOC2-MRAS-PP1C (SMP) complex, while canonical RAS isoforms (KRAS, HRAS, NRAS) form analogous but lower-affinity assemblies. Yet, cancers driven by oncogenic KRAS, HRAS, or NRAS remain strongly SHOC2-dependent, suggesting that these weaker complexes contribute to tumorigenesis. To elucidate how canonical RAS proteins form lower-affinity ternary complexes, the cryo-EM structure of the SHOC2-KRAS-PP1C (SKP) complex stabilized by Noonan syndrome mutations is described. The SKP architecture is similar to the SMP complex but forms fewer contacts and buries less surface area due to the absence of MRAS-specific structural features in KRAS that enhance complex stability. RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. These RAS inhibitors do not affect SMP formation because they do not bind MRAS. Since MRAS is upregulated in resistance to KRAS inhibition, we characterize a MRAS mutant capable of binding MRTX1133. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.
Publicações recentes
Targeting Interleukin-8-Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome.
Clinical and Genetic Characterization of Noonan Syndrome in a Colombian Pediatric Cohort.
A Phase II Basket Trial of Vosoritide in Children with RASopathies, ACAN and NPR2 Deficiency.
Sleep disorders in genetic syndromes associated with congenital heart disease: A comprehensive review.
Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses.
📚 EuropePMC1.472 artigos no totalmostrando 196
Complex Genetic Architecture in RASopathies: Constitutional PTPN11 and Mosaic RIT1 Pathogenic Variants Underlying Severe Noonan Syndrome With Adult-Onset Acute Myeloid Leukemia.
American journal of medical genetics. Part AHypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review.
Prenatal diagnosisPulmonary Hypertension in Pediatric Patients with Noonan Syndrome Undergoing Cardiac Catheterization.
Pediatric cardiologyLargely preserved vestibular function despite severe-to-profound hearing loss in Noonan syndrome spectrum disorders.
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck SurgeryDe Novo RRAS2 Pathogenic Variant in a Fetus With Bilateral Radial Ray and Multisystem Anomalies.
Prenatal diagnosisNovel Variants in PTPN11, NF1, RASA2, and MAP2K1: Expanding the Molecular Spectrum of RASopathies in a Turkish Cohort.
Clinical geneticsPhosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciencesThe 9th International RASopathies Symposium.
American journal of medical genetics. Part AOptimizing Diagnostic Accuracy of Clinical Red Flags in RASopathies.
American journal of medical genetics. Part APatient and caregiver perspectives on neurodevelopmental and mental health care for RASopathies.
Therapeutic advances in rare diseaseNatural history of coronary aneurysms associated with Noonan's syndrome.
Journal of cardiology casesClinical phenotypes and cochlear implant outcomes in patients with PTPN11-associated noonan spectrum disorders: Insights from a genetically screened cohort.
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck SurgeryPTPN11-related Noonan syndrome predisposes to multifocal low-grade CNS tumors harboring FGFR1 variants.
Journal of neuro-oncologyOssification of Mandibular Central Giant Cell Granuloma (CGCG) in Neurofibromatosis Type 1 Patients.
Cancer diagnosis & prognosisOnce-weekly somapacitan in children with Noonan syndrome: randomized controlled phase 3 trial.
European journal of endocrinologyIrreversible blindness induced by vitamin A deficiency in a child with avoidant/restrictive food intake disorder secondary to Noonan syndrome.
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienneAutomated bone age assessment in rare pediatric growth disorders: a comparative study using Deeplasia.
Frontiers in endocrinologyAtrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy.
JACC. Case reportsNoonan Syndrome With Multiple Lentigines Mimicking Obstructive Hypertrophic Cardiomyopathy Treated by Septal Myectomy.
JACC. Case reportsDevelopment and Treatment of Severe Lordoscoliosis in a Patient With Noonan Syndrome With Multiple Lentigines (NSML): A Case Report.
CureusGenotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.
Molecular syndromologyPaediatric Retinal Detachment in a Patient With Coexistent Stickler and Noonan Syndromes: The Importance of a Multidisciplinary Approach.
CureusDysregulated TGFβ-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve Stenosis.
bioRxiv : the preprint server for biologyIncidence and severity of SARS-CoV-2 infection and vaccine BNT162 side effects in children and adolescents with Noonan Syndrome: a national multicentric study.
Frontiers in pediatricsUnraveling the Impact of KRAS Accessory Proteins on Oncogenic Signaling Pathways.
CellsAdvancing Obstetric Care: The Role of Targeted Next-Generation Sequencing in Pregnancies with Structurally Normal Fetuses.
Journal of the Chinese Medical Association : JCMANoonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort.
European journal of pediatricsNeuropathic Pain and Enlarged Nerves in Adult Noonan Syndrome and Noonan Syndrome With Multiple Lentigines: Health-Related Quality of Life and Neurologic Symptoms.
American journal of medical genetics. Part AStructure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
Nature communicationsNovel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report.
MedicineDomain-specific phenotypic profiles in RAF1-related Noonan syndrome.
European journal of human genetics : EJHGMolecular and Clinical Profiles of Patients with RASopathies: Targeted Next-Generation Sequencing Panel Results and Identification of 14 Novel Disease-Causing Variants.
Molecular syndromologyNoonan Syndrome Spectrum Disorders Predispose to Systemic Lupus Erythematosus: Case Report and Critical Review of the Literature.
American journal of medical genetics. Part AUnderstanding Molecular Basis of PTPN11-Related Diseases.
ArXivVentricular arrhythmia and Noonan syndrome with leucine zipperlike transcription regulator 1 mutations: expanding the phenotype with a case report and review of the literature.
Cardiology in the youngSirolimus for Recurrent Chylothorax and Edema in an Infant with Noonan Syndrome after Resolved Hydrops Fetalis: A Case Report.
AJP reportsCBL-Mutated Juvenile Myelomonocytic Leukaemia With Loss of Heterozygosity on 11q Detected by Microarray: Not Always Such a Favourable Outcome.
International journal of laboratory hematologyGenetic insights and diagnostic challenges in inherited bone marrow failure syndromes: a comprehensive study from a low middle-income country.
Expert review of hematologyEvaluating the Genetic Overlap Between Congenital Heart Disease and Neuroblastoma Risk.
Pediatric blood & cancerReal-World Evidence of Treatment Patterns and Costs of Turner Syndrome and Noonan Syndrome in the USA.
Hormone research in paediatricsProtein domain-specific genotype-phenotype correlation study of neurofibromatosis type 1.
Scientific reportsPhenotypic Analysis of Embryos in a Noonan Syndrome Model Mouse With the Rit1 A57G Mutation.
Molecular genetics & genomic medicinePulmonary hypertension in patients with Noonan syndrome.
The European respiratory journalClinical characteristics of 41 children with hypertrophic cardiomyopathy: A single-center retrospective study.
The Journal of international medical researchNovel use of placental growth hormone in managing intrauterine growth restriction in Noonan syndrome.
Annals of medicine and surgery (2012)Heterogeneity of Orodental Features in a Family with Noonan Syndrome.
International journal of molecular sciencesModified Nuss procedure versus Ravitch in concurrent repair of pectus deformity and open-heart surgery.
Asian cardiovascular & thoracic annalsClinical Spectrum of Noonan Syndrome-Associated Myeloproliferative Disorder.
American journal of hematologyTherapeutic Response to Myosin Inhibitor Therapy in Noonan Syndrome-Associated Obstructive Hypertrophic Cardiomyopathy.
JACC. Case reportsM-Ras distinct activation scenarios: A mechanistic outlook and targeting.
Computational and structural biotechnology journalLupus vorax: A rare case of facial tuberculosis in a patient with Noonan syndrome.
IDCasesDiagnostic Value of Exome Sequencing in Isolated Polyhydramnios.
Prenatal diagnosisTargeted fetal NGS panel reveals genetic conditions in sonographically normal fetuses: Insights from a large cohort study.
PloS oneEndoCompass Project: Research Roadmap for Growth Disorders.
Hormone research in paediatricsAnesthetic Μanagement of an Emergency Craniotomy in a Patient With Noonan Syndrome: A Case Report.
CureusPrevalence of neurodevelopmental and psychiatric disorders in Noonan syndrome: a systematic review and meta-analysis.
European journal of pediatricsBiventricular Surgical Approach in Noonan Syndrome With Hypertrophic Obstructive Cardiomyopathy.
JACC. Case reportsLong-term effectiveness and safety of daily growth hormone therapy in Japanese children with Noonan syndrome: a post-marketing surveillance study.
Endocrine journalAnalysis of the clinical features of neurocristopathy-related hearing loss and how these relate to outcomes after cochlear implantation.
Scientific reportsTransdiagnostic similarities and distinctions in brain networks associated with autistic social impairments: a prospective cohort study.
Molecular autismDeficiency of anterior pituitary hormones in Noonan syndrome and its impact on response to growth hormone therapy.
World journal of clinical pediatricsCurrent opinions on Noonan syndrome and RASopathies.
Current opinion in pediatricsOptic nerve changes in PTPN11-related Noonan syndrome.
Oman journal of ophthalmologyClinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum.
Diagnostics (Basel, Switzerland)Germline Predisposition to Pediatric Lymphoid Malignancies: Genetic Tumor Syndromes Identified in a Single-Center Study.
Clinical laboratoryHomozygous LZTR1 Variant Lacking the Second BTB Domain Associated With Bone Marrow Failure and Multiple Congenital Anomalies Distinct From Those of Noonan Syndrome.
Clinical geneticsAnesthetic Management During Post-tonsillectomy Hemorrhage in a Child With Noonan Syndrome: A Case Report.
CureusFive Years of Combined Newborn Screening Quantifying TREC and KREC in Switzerland.
The journal of allergy and clinical immunology. In practicePathogenesis of Noonan syndrome is modulated by NOC2L, a novel interactor of LZTR1 leading to impaired p53 signalling.
The Journal of clinical endocrinology and metabolismLangerhans Cell Histiocytosis in Cardiofaciocutaneous Syndrome.
American journal of medical genetics. Part AHeart transplantation in special patient populations.
JHLT openRas-related protein 2 limits vascular smooth muscle cell phenotypic switching and abdominal aortic aneurysm development.
Nature communicationsMultivessel Cerebral Occlusion in Noonan Syndrome.
StrokeNon-RASopathy Genetic Syndromes Identified as the Molecular Cause of Disease in Patients Previously Diagnosed With Noonan Syndrome.
American journal of medical genetics. Part AMultidisciplinary Treatment of Patients With Noonan Syndrome: A Consensus Statement.
JAMA network openOut of Sync? Rare Genetic Disease and the Chronopolitics of Care.
Sociology of health & illnessExpanding the Genetic Landscape of RASopathies: Significance of Including NF1 in Targeted Panels.
Molecular syndromologyPRKAG2 Syndrome Presenting With Fetal Sinus Bradycardia and Pulmonary Valve Stenosis as Initial Manifestations.
Prenatal diagnosisGenotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study.
Molecular autismCentral Conducting Lymphatic Abnormalities in Noonan Syndrome Identified Using SPECT/CT Lymphoscintigraphy.
Nuklearmedizin. Nuclear medicineCavitary Lung Abscess Secondary to a Tracheal Bronchus: A Pediatric Patient With Noonan Syndrome.
CureusNoonan syndrome and autoimmune hepatitis: patient report and literature review.
Journal of pediatric endocrinology & metabolism : JPEMT1w/T2w ratio suggests reduced intracortical myelin content in youth with RASopathies.
medRxiv : the preprint server for health sciencesTransdiagnostic similarities and distinctions in brain networks associated with ASD symptoms: A prospective cohort study.
medRxiv : the preprint server for health sciencesAnesthetic implications of elective cesarean section in a parturient with Noonan syndrome and complex cardiomyopathy: A case report.
Saudi journal of anaesthesiaNoonan Syndrome With Complex Pulmonary Stenosis at High Altitude: Impact of Delayed Diagnosis.
JACC. Case reportsNoonan syndrome with PTPN11 gene variant presenting as isolated short stature: a case report.
Translational pediatricsClinical and molecular analysis of seventy-one fetal cases with RASopathies.
European journal of obstetrics, gynecology, and reproductive biologyPrenatal diagnosis of a familial heterozygous pathogenic variant in the PTPN11 gene (c.1510A>G, p.M504V) in a fetus with increased nuchal translucency and pleural effusion and a mother carrier with atypical Noonan syndrome.
Taiwanese journal of obstetrics & gynecologyFirst Transcatheter Pulmonary Valve Replacement in Tanzania: Feasibility of Advanced Cardiac Interventions in Resource-Limited Settings.
JACC. Case reportsExecutive and Social Functioning in Children and Adolescents With Noonan Syndromes: Cognition and Behavior.
JAACAP openPercutaneous Thoracic Duct Externalization and Autotransfusion in Patients With Lymphatic Failure Due to Elevated Central Venous Pressure.
Circulation. Cardiovascular interventionsNoonan Syndrome and Rett Syndrome in An 8-Year-Old Girl With A Tectal Neoplasm.
JCEM case reportsImatinib For Treatment of Multifocal Maxillofacial Giant Cell Lesions: A Case Series.
Journal of pediatric hematology/oncologySHP2 genetic variants in NSML-associated RASopathies disrupt the PZR-IRX transcription factor signaling axis.
Proceedings of the National Academy of Sciences of the United States of AmericaCase Report: Chylopericardium after Heart Transplantation due to Lymphatic Malformation in a Patient With Noonan Syndrome.
Transplantation proceedingsMirror syndrome and placental ectopic liver in association with de novo SOS1 variant.
European journal of medical geneticsA child with tuberous sclerosis having Novel NRAS gene mutation.
Journal of family medicine and primary careEverolimus therapy in an infant with Noonan syndrome with multiple lentigines.
Annals of pediatric cardiologyPZR: Advances in research from cellular signaling Hub to emerging therapeutic targets.
Cellular signallingSubcortical shape alterations in children with Noonan syndrome spectrum: insights into genotype-phenotype associations.
Cerebral cortex (New York, N.Y. : 1991)Oral Health and Dental Management Strategies in Noonan Syndrome: A Case Report.
Iranian endodontic journalEncephalocraniocutaneous lipomatosis-a neuroradiological perspective.
Pediatric radiologyA Noonan Syndrome Mimicking Acute Coronary Syndrome.
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidirNon-Immune Hydrops Fetalis, Multifocal Chorangiomatosis, and Noonan Syndrome 8.
Congenital anomaliesIncreased Prevalence of Psychiatric Disorders in Children with RASopathies: Comparing NF1, Noonan Syndrome Spectrum Disorder, and the General Population.
GenesExpanding the Phenotypic Spectrum Associated with DPH5-Related Diphthamide Deficiency.
Genes[Hypertrophy of the lumbosacral nerve roots in Noonan syndrome with multiple lentigines: a case report].
Rinsho shinkeigaku = Clinical neurologySequencing validates deep learning models for EHR-based detection of Noonan syndrome in pediatric patients.
NPJ genomic medicineCochlear Implantation in a Patient With Noonan Syndrome and Enlarged Cochlear Apertures.
The LaryngoscopeTargeted Therapy for Complex Lymphatic Anomalies in Patients with Noonan Syndrome and Related Disorders.
International journal of molecular sciencesAbernethy malformation (Type II) presenting in a 6-day-old boy with Noonan syndrome: a case report.
BMC pediatricsRIT1 Drives Oncogenic Transformation and Is an Actionable Target in Lung Adenocarcinoma.
Cancer researchSFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.
EMBO molecular medicineMultiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.
bioRxiv : the preprint server for biologyAdvancing edge-based clustering and graph embedding for biological network analysis: a case study in RASopathies.
Briefings in bioinformaticsAssessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing.
NPJ genomic medicineComplete commissural agenesis in a child with Noonan-like syndrome with loose anagen hair 2.
NeurogeneticsRAF1 mutation expands the cardiac phenotypic spectrum of Noonan syndrome: A case report.
World journal of cardiologyRole of Histopathology of Skin Lesions in Diagnosing MAP2K1-Positive Cardiofaciocutaneous Syndrome.
The American Journal of dermatopathologySerum Markers of Bone Turnover and Bone Remodeling in Children with Noonan Syndrome: Genotype-Phenotype Correlation.
GenesBroad Electrocardiogram Syndromes Spectrum: From Common Emergencies to Particular Electrical Heart Disorders-Part II.
Diagnostics (Basel, Switzerland)Experience with etilefrine in refractory non-traumatic chylothorax: a case report.
Cardiology in the young[Analysis of clinical characteristics and NF1 gene variants in a child with Neurofibroma-Noonan syndrome].
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical geneticsReview of 40 genes causing congenital myasthenic syndromes.
Journal of human geneticsRASopathies. Part II: Cutaneous and extracutaneous manifestations.
Journal of the American Academy of DermatologyProtein-losing enteropathy and multiple vasculature dysplasia in LZTR1-related Noonan syndrome: A case report and review of literature.
World journal of gastroenterologyRASopathies. Part I: Genetics and therapeutic considerations.
Journal of the American Academy of DermatologyEosinophilic gastroenteritis in a 14-year-old patient with Noonan syndrome with a PTPN11 variation: a case report.
Journal of medical case reportsSecond Trimester Ultrasound Diagnosis of External Hydrocephalus in Two Fetuses with Noonan Syndrome-Case Report Series.
Journal of clinical medicineUrethral Polyp: A Rare Cause of Urethral Obstruction in Newborns and Children with Special Needs-A Case Series.
Archivos espanoles de urologiaBiallelic SH2B3 germline variants are associated with a neonatal myeloproliferative disease and multisystemic involvement.
European journal of human genetics : EJHGSevere Nerve Enlargement in SOS2-Related Noonan Syndrome.
American journal of medical genetics. Part ARecurrent cellulitis associated with lymphoedema in Noonan syndrome: case reports with RIT1 variants and literature review.
Human genome variationRapamycin treatment for progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines.
Kardiologia polskaTargeting cardiomyopathies associated with RASopathies: the role of mitogen-activated protein kinase inhibitors and therapeutic challenges.
Pharmacogenetics and genomicsIrritability in children with RASopathies, insights into emotional dysregulation and social impairment.
European child & adolescent psychiatryACTC1 Variants Result in Isolated and Syndromic Cardiac Phenotypes.
Clinical geneticsTruncating Variants in RREB1 Cause a Novel RASopathy Syndrome of Congenital Heart Disease, Genitourinary Malformations, and Developmental Delay.
American journal of medical genetics. Part AAn Efficient Protocol to Assess ERK Activity Modulation in Early Zebrafish Noonan Syndrome Models via Live FRET Microscopy and Immunofluorescence.
Journal of visualized experiments : JoVECo-Occurrence of Dysembryoplastic Neuroepithelial Tumor and Hodgkin Lymphoma in a Patient with Noonan Syndrome and Mutation in the PTPN11 Gene.
Hormone research in paediatricsDeciphering the structural and dynamic effects of SHP2-E76 mutations: mechanistic insights into oncogenic activation.
BMC chemistryMolecular Dynamics Simulations of the SPRED2Leu100Pro EVH-1 Domain Complexed with the GAP-Related Domain of Neurofibromin.
International journal of molecular sciencesNoonan Syndrome and Heart Failure in a Postpartum Patient.
CureusChiari 1 malformation in patient with Noonan syndrome: A case report and review of literature.
Surgical neurology internationalExpanding the genetic spectrum of short rib polydactyly syndrome: Novel DYNC2H1 variants and functional insights.
BoneOsteosarcoma Arising in Noonan Syndrome/RASopathy Complex: First Case Report.
Head and neck pathologyUpdate on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review.
International journal of molecular sciencesQuantitative T1 Mapping Indicates Elevated White Matter Myelin in Children With RASopathies.
Biological psychiatryMissense and truncated variants in ERF in individuals with a Noonan-like phenotype without craniosynostosis.
Scientific reportsRare missense variants in FNDC1 are associated with severe adolescent idiopathic scoliosis.
Journal of medical geneticsInfant with Known Dandy-Walker Malformation and Poor Feeding Found to Have Additional Diagnosis.
AJP reportsNeurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review.
Orphanet journal of rare diseasesEfficacy of Sirolimus in Treating Refractory Lymphatic Malformation in Noonan Syndrome: A Case Study.
JCEM case reportsModified "Posterior Cervical Lift" Correction of Webbed Neck Deformity.
Plastic and reconstructive surgery. Global open[A rare placental lesion: Intraparenchymal hepatic heterotopia].
Annales de pathologieA Novel Description of Immunodeficiency and Immune Dysregulation in a 14-Year-Old Girl with Noonan Syndrome 13.
Journal of clinical immunologyRVOT Stenting and Trametinib in an Infant With Noonan Syndrome, Pulmonary Stenosis, and Hypertrophic Cardiomyopathy.
JACC. Case reportsFirst steps toward building natural history of diseases computationally: Lessons learned from the Noonan syndrome use case.
American journal of human geneticsIncidental Discovery of Complications of Cryptorchidism During Laparoscopic Inguinal Hernia Surgery.
Case reports in surgeryCardiovascular aspects of Noonan syndrome and related disorders.
Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.VGene signatures and genotype-phenotype correlations of sensorineural hearing loss in Noonan syndrome and related RASopathies.
Scientific reportsLong-Term Efficacy and Safety of Growth Hormone in Children Suffering from Short Stature in China (CGLS): An Open-Label, Multicenter, Prospective and Retrospective, Observational Study.
Advances in therapySignaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses.
bioRxiv : the preprint server for biologyAssessment of Fetal Posterior Fossa Anomalies at 11-13+6 Gestational Weeks in the Midsagittal Cranial Plane by Three-Dimensional Multiplanar Sonography: A Prospective Study.
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in MedicinePlastic Bronchitis in Noonan Syndrome: Further Evidence Suggesting a Higher Risk of Lymphatic Abnormalities in Individuals Harboring Variants in PTPN11 Residue p.Phe285.
Molecular syndromologyRASopathies and Cardiac Complications: Insights into Mechanisms, Diagnosis, and Innovative Treatments.
Current cardiology reviewsCardiac MRI Characteristics of Noonan Syndrome Associated With Hypertrophic Cardiomyopathy and Congenital Heart Disease.
Korean journal of radiologyEtiologies of Early-Onset Hearing Impairment in Rwanda.
GenesImpact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy.
JACC. Basic to translational scienceA familial modeling framework for advancing precision medicine for children with neuropsychiatric disorders.
Developmental medicine and child neurologyNoonan Syndrome Associated with a Patent Foramen Ovale.
The Nigerian postgraduate medical journal[Clinical characteristics analysis of children with Noonan-like syndrome with loose anagen hair].
Zhonghua er ke za zhi = Chinese journal of pediatricsGenetic Insights Into Recurrent Granular Cell Tumours in an Adolescent: The Role of Cytology and Next-Generation Sequencing in the Diagnosis of RASopathies.
Cytopathology : official journal of the British Society for Clinical CytologyEvaluation of information flows in the RAS-MAPK system using transfer entropy measurements.
eLifeTrametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome.
Frontiers in pediatrics[Perioperative management of cochlear implantation and analysis on the influencing factors of efficacy in patients diagnosed as hereditary syndromic hearing loss].
Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgeryHeart Transplantation Outcomes in Pediatric Patients with Noonan Syndrome: An Institutional Case Series.
Pediatric cardiologyNoonan syndrome and parasternal pericardiocentesis.
Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart FoundationNoonan Syndrome, Cancer Risk, and Growth Hormone Treatment.
Journal of clinical research in pediatric endocrinologyAberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models.
The Journal of clinical investigationHealth outcomes and drug utilisation in children with Noonan syndrome: a European cohort study.
Orphanet journal of rare diseasesGermline Variants in Pediatric Cancer : Based on Oncogenic Pathways.
Journal of Korean Neurosurgical SocietyHypertrophic cardiomyopathy combined with renal and adrenal aplasia in a male with Noonan syndrome from RAF1 variant.
ESC heart failureHypertrophic cardiomyopathy: prevalence of disease-specific red flags.
European heart journalCase Report: A rare case of Noonan syndrome with multiple lentigines manifesting as cardiac enlargement.
Frontiers in cardiovascular medicineImpact of pubertal timing on growth progression and final height in subjects affected by RASopathies.
Frontiers in endocrinologyBeyond the postmortem diagnosis of hypertrophic cardiomyopathy: a genetic approach guided by clinical and morphological features in Noonan syndrome.
Revista espanola de cardiologia (English ed.)Endoscopic Mitral Surgery in Noonan Syndrome-Case Report and Considerations.
Journal of clinical medicineGH Therapy in Non-Growth Hormone-Deficient Children.
Children (Basel, Switzerland)[Growth and development patterns of Noonan syndrome and advances in the treatment of short stature].
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatricsLong-acting growth hormones: innovations in treatment and guidance on patient selection in pediatric growth hormone deficiency.
Annals of pediatric endocrinology & metabolismLongitudinal outcomes in Noonan syndrome.
Genetics in medicine : official journal of the American College of Medical GeneticsGenomic ascertainment to quantify prevalence and cancer risk in adults with pathogenic and likely pathogenic germline variants in RASopathy genes.
medRxiv : the preprint server for health sciencesSevere coronary artery ectesia in a paediatric patient with Noonan syndrome presenting for transcatheter pulmonary valve placement.
Cardiology in the youngIrritability in Children with Rasopathies, Insights into Emotional Dysregulation and Social Skills Impairments.
Research squareAssociações
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Referências e fontes
Bases de dados externas citadas neste artigo
Publicações científicas
Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.
- Novel Variants in PTPN11, NF1, RASA2, and MAP2K1: Expanding the Molecular Spectrum of RASopathies in a Turkish Cohort.
- Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences· 2026· PMID 41843963mais citado
- Unraveling the Impact of KRAS Accessory Proteins on Oncogenic Signaling Pathways.
- Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort.
- Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
- Targeting Interleukin-8-Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome.
- Clinical and Genetic Characterization of Noonan Syndrome in a Colombian Pediatric Cohort.
- A Phase II Basket Trial of Vosoritide in Children with RASopathies, ACAN and NPR2 Deficiency.
- Sleep disorders in genetic syndromes associated with congenital heart disease: A comprehensive review.
- Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses.
Bases de dados e fontes oficiais
Identificadores e referências canônicas usadas para montar este verbete.
- ORPHA:648(Orphanet)
- MONDO:0018997(MONDO)
- GARD:10955(GARD (NIH))
- Variantes catalogadas(ClinVar)
- Busca completa no PubMed(PubMed)
- Artigo Wikipedia(Wikipedia)
- Q1543446(Wikidata)
Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.
Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar
