Raras
Buscar doenças, sintomas, genes...
Síndrome Noonan com lentigos múltiplos
ORPHA:500CID-10 · Q87.1CID-11 · LD2F.1YDOENÇA RARA

Doença genética multissistêmica rara caracterizada por lentigos, cardiomiopatia hipertrófica, baixa estatura, deformidade pectus e características faciais dismórficas.

Mantido por Agente Raras·Colaborar como especialista →

Introdução

O que você precisa saber de cara

📋

Doença genética multissistêmica rara caracterizada por lentigos, cardiomiopatia hipertrófica, baixa estatura, deformidade pectus e características faciais dismórficas.

Pesquisas ativas
1 ensaio
2 total registrados no ClinicalTrials.gov
Publicações científicas
121 artigos
Último publicado: 2026 Mar 25

Escala de raridade

CLASSIFICAÇÃO ORPHANET · BRASIL 2024
<1 / 1 000 000
Ultra-rara
<1/50k
Muito rara
1/20k
Rara
1/10k
Pouco freq.
1/5k
Incomum
1/2k
Prevalência
0.0
Worldwide
Casos conhecidos
296
pacientes catalogados
Início
Neonatal
🏥
SUS: Cobertura mínimaScore: 35%
Centros em: PA, PR, SC, RS, ES +10CID-10: Q87.1
🇧🇷Dados SUS / DATASUS
PROCEDIMENTOS SIGTAP (5)
0202010503
Cariótipo — bandas G, Q ou Rgenetic_test
0202010600
Pesquisa de microdeleções/microduplicações por FISHlab_test
0202010694
Sequenciamento completo do exoma (WES)rehabilitation
0202010260
Dosagem de alfa-fetoproteína
0301070040
Atendimento em reabilitação — doenças raras
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Entender a doença

Do básico ao detalhe, leia no seu ritmo

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Sinais e sintomas

O que aparece no corpo e com que frequência cada sintoma acontece

Partes do corpo afetadas

❤️
Coração
14 sintomas
😀
Face
12 sintomas
🦴
Ossos e articulações
9 sintomas
🧬
Pele e cabelo
8 sintomas
🧠
Neurológico
7 sintomas
👂
Ouvidos
5 sintomas

+ 34 sintomas em outras categorias

Características mais comuns

90%prev.
Pele hiperextensível
Muito frequente (99-80%)
90%prev.
Deficiência auditiva neurossensorial
Muito frequente (99-80%)
90%prev.
Cardiomiopatia hipertrófica
Muito frequente (99-80%)
90%prev.
Sardas
Muito frequente (99-80%)
90%prev.
Anormalidade do sistema genital
Muito frequente (99-80%)
90%prev.
Múltiplas lentigens
Muito frequente (99-80%)
97sintomas
Muito frequente (16)
Frequente (16)
Ocasional (18)
Sem dados (47)

Os sintomas variam de pessoa para pessoa. Abaixo estão as 97 características clínicas mais associadas, ordenadas por frequência.

Pele hiperextensívelHyperextensible skin
Muito frequente (99-80%)90%
Deficiência auditiva neurossensorialSensorineural hearing impairment
Muito frequente (99-80%)90%
Cardiomiopatia hipertróficaHypertrophic cardiomyopathy
Muito frequente (99-80%)90%
SardasFreckling
Muito frequente (99-80%)90%
Anormalidade do sistema genitalAbnormality of the genital system
Muito frequente (99-80%)90%

Linha do tempo da pesquisa

Publicações por ano — veja quando o interesse científico cresceu
Anos de pesquisa1desde 2026
Total histórico121PubMed
Últimos 10 anos109publicações
Pico202214 papers
Linha do tempo
2026Hoje · 2026🧪 2015Primeiro ensaio clínico📈 2022Ano de pico
Publicações por ano (últimos 10 anos)

Encontrou um erro ou informação desatualizada? Sugira uma correção →

Genética e causas

O que está alterado no DNA e como passa nas famílias

Genes associados

3 genes identificados com associação a esta condição. Padrão de herança: Autosomal dominant.

RAF1RAF proto-oncogene serine/threonine-protein kinaseDisease-causing germline mutation(s) (gain of function) inAltamente restrito
FUNÇÃO

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

LOCALIZAÇÃO

CytoplasmCell membraneMitochondrionNucleus

VIAS BIOLÓGICAS (5)
IFNG signaling activates MAPKsCD209 (DC-SIGN) signalingStimuli-sensing channelsGP1b-IX-V activation signallingRap1 signalling
MECANISMO DE DOENÇA

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.

EXPRESSÃO TECIDUAL(Ubíquo)
Músculo esquelético
152.2 TPM
Artéria tibial
139.4 TPM
Cérebro - Hemisfério cerebelar
134.9 TPM
Sangue
131.1 TPM
Ovário
129.4 TPM
OUTRAS DOENÇAS (9)
Noonan syndrome 5LEOPARD syndrome 2dilated cardiomyopathy 1NNNoonan syndrome
HGNC:9829UniProt:P04049
BRAFSerine/threonine-protein kinase B-rafDisease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

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)

LOCALIZAÇÃO

NucleusCytoplasmCell membrane

VIAS BIOLÓGICAS (4)
Spry regulation of FGF signalingParadoxical activation of RAF signaling by kinase inactive BRAFARMS-mediated activationSignalling to p38 via RIT and RIN
OUTRAS DOENÇAS (18)
Noonan syndrome 7LEOPARD syndrome 3melanoma, cutaneous malignant, susceptibility to, 1lung cancer
HGNC:1097UniProt:P15056
PTPN11Tyrosine-protein phosphatase non-receptor type 11Disease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

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

LOCALIZAÇÃO

CytoplasmNucleus

VIAS BIOLÓGICAS (10)
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)Spry regulation of FGF signalingRegulation of IFNA/IFNB signalingRegulation of IFNG signalingGPVI-mediated activation cascade
MECANISMO DE DOENÇA

LEOPARD syndrome 1

A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.

EXPRESSÃO TECIDUAL(Ubíquo)
Fibroblastos
111.4 TPM
Brain Spinal cord cervical c-1
108.7 TPM
Artéria tibial
90.4 TPM
Substância negra
83.1 TPM
Aorta
73.7 TPM
OUTRAS DOENÇAS (7)
juvenile myelomonocytic leukemiaNoonan syndrome 1metachondromatosisLEOPARD syndrome 1
HGNC:9644UniProt:Q06124

Medicamentos aprovados (FDA)

2 medicamentos encontrados nos registros da FDA americana.

💊 Norditropin (SOMATROPIN)
💊 SOGROYA (SOMAPACITAN-BECO)
Ver no DailyMed/FDA

Variantes genéticas (ClinVar)

985 variantes patogênicas registradas no ClinVar.

🧬 RAF1: NM_002880.4(RAF1):c.1458T>G (p.Asp486Glu) ()
🧬 RAF1: NM_002880.4(RAF1):c.1490G>A (p.Ser497Asn) ()
🧬 RAF1: GRCh37/hg19 3p26.3-14.3(chr3:2263690-55016039)x3 ()
🧬 RAF1: NM_002880.4(RAF1):c.1171A>G (p.Arg391Gly) ()
🧬 RAF1: NM_002880.4(RAF1):c.423+1G>T ()
Ver todas no ClinVar

Classificação de variantes (ClinVar)

Distribuição de 25 variantes classificadas pelo ClinVar.

21
3
1
Patogênica (84.0%)
VUS (12.0%)
Benigna (4.0%)
VARIANTES MAIS SIGNIFICATIVAS
PTPN11: NM_002834.5(PTPN11):c.934-59T>A [Likely pathogenic]
MAP2K2: NM_030662.4(MAP2K2):c.183A>T (p.Lys61Asn) [Conflicting classifications of pathogenicity]
PTPN11: NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu) [Pathogenic]
PTPN11: NM_002834.5(PTPN11):c.1517A>C (p.Gln506Pro) [Pathogenic]
PTPN11: NM_002834.5(PTPN11):c.1493G>T (p.Arg498Leu) [Pathogenic]

Vias biológicas (Reactome)

50 vias biológicas associadas aos genes desta condição.

Stimuli-sensing channels Rap1 signalling GP1b-IX-V activation signalling CD209 (DC-SIGN) signaling RAF activation MAP2K and MAPK activation Negative feedback regulation of MAPK pathway Negative regulation of MAPK pathway Signaling by moderate kinase activity BRAF mutants Signaling by high-kinase activity BRAF mutants Signaling by BRAF and RAF1 fusions Paradoxical activation of RAF signaling by kinase inactive BRAF Signaling downstream of RAS mutants Signaling by RAF1 mutants SHOC2 M1731 mutant abolishes MRAS complex function Gain-of-function MRAS complexes activate RAF signaling IFNG signaling activates MAPKs Spry regulation of FGF signaling Frs2-mediated activation ARMS-mediated activation Signalling to p38 via RIT and RIN Interleukin-6 signaling PI3K Cascade MAPK3 (ERK1) activation MAPK1 (ERK2) activation GPVI-mediated activation cascade Prolactin receptor signaling PIP3 activates AKT signaling Signaling by SCF-KIT GAB1 signalosome Downstream signal transduction PECAM1 interactions Tie2 Signaling Constitutive Signaling by Aberrant PI3K in Cancer Signaling by Leptin Co-inhibition by CTLA4 Co-inhibition by PD-1 Signal regulatory protein family interactions Netrin mediated repulsion signals Platelet sensitization by LDL Interleukin-3, Interleukin-5 and GM-CSF signaling PI-3K cascade:FGFR1 FRS-mediated FGFR1 signaling PI-3K cascade:FGFR2 FRS-mediated FGFR2 signaling FRS-mediated FGFR3 signaling PI-3K cascade:FGFR3 FRS-mediated FGFR4 signaling PI-3K cascade:FGFR4 Negative regulation of FGFR1 signaling

Diagnóstico

Os sinais que médicos procuram e os exames que confirmam

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Tratamento e manejo

Remédios, cuidados de apoio e o que precisa acompanhar

Pipeline de tratamentos
Pipeline regulatório — de medicamentos já aprovados a drogas em pesquisa exploratória.
·Pré-clínico2
Medicamentos catalogadosEnsaios clínicos· 0 medicamentos · 2 ensaios
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Onde tratar no SUS

Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)

🇧🇷 Atendimento SUS — Síndrome Noonan com lentigos múltiplos

Centros de Referência SUS

24 centros habilitados pelo SUS para Síndrome Noonan com lentigos múltiplos

Centros para Síndrome Noonan com lentigos múltiplos

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

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Infantil Albert Sabin

R. Tertuliano Sales, 544 - Vila União, Fortaleza - CE, 60410-794 · CNES 2407876

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital de Apoio de Brasília (HAB)

AENW 3 Lote A Setor Noroeste - Plano Piloto, Brasília - DF, 70684-831 · CNES 0010456

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

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

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

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

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Universitário da UFJF

R. Catulo Breviglieri, Bairro - s/n - Santa Catarina, Juiz de Fora - MG, 36036-110 · CNES 2297442

Atenção Especializada

Rota
Anomalias Congênitas

Hospital das Clínicas da UFMG

Av. Prof. Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte - MG, 30130-100 · CNES 2280167

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Julio Müller (HUJM)

R. Luis Philippe Pereira Leite, s/n - Alvorada, Cuiabá - MT, 78048-902 · CNES 2726092

Atenção Especializada

Rota
Anomalias Congênitas

Hospital Universitário João de Barros Barreto

R. dos Mundurucus, 4487 - Guamá, Belém - PA, 66073-000 · CNES 2337878

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Lauro Wanderley (HULW)

R. Tabeliao Estanislau Eloy, 585 - Castelo Branco, João Pessoa - PB, 58050-585 · CNES 0002470

Atenção Especializada

Rota
Anomalias Congênitas

Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)

R. dos Coelhos, 300 - Boa Vista, Recife - PE, 50070-902 · CNES 0000647

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Pequeno Príncipe

R. Des. Motta, 1070 - Água Verde, Curitiba - PR, 80250-060 · CNES 3143805

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital Universitário Regional de Maringá (HUM)

Av. Mandacaru, 1590 - Parque das Laranjeiras, Maringá - PR, 87083-240 · CNES 2216108

Atenção Especializada

Rota
Anomalias Congênitas

Hospital de Clínicas da UFPR

R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900 · CNES 2364980

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Pedro Ernesto (HUPE-UERJ)

Blvd. 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro - RJ, 20551-030 · CNES 2280221

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

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

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital São Lucas da PUCRS

Av. Ipiranga, 6690 - Jardim Botânico, Porto Alegre - RS, 90610-000 · CNES 2232928

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

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

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário da UFSC (HU-UFSC)

R. Profa. Maria Flora Pausewang - Trindade, Florianópolis - SC, 88036-800 · CNES 2560356

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital das Clínicas da FMUSP

R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo - SP, 05403-010 · CNES 2077485

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

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

Rota
Anomalias Congênitas

Hospital de Clínicas da UNICAMP

R. Vital Brasil, 251 - Cidade Universitária, Campinas - SP, 13083-888 · CNES 2748223

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

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

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

UNIFESP / Hospital São Paulo

R. Napoleão de Barros, 715 - Vila Clementino, São Paulo - SP, 04024-002 · CNES 2688689

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo
Sobre os centros SUS: Estes centros são habilitados pelo Ministério da Saúde como Serviços de Referência em Doenças Raras ou Serviços de Atenção Especializada. O atendimento é pelo SUS, com encaminhamento da rede de atenção básica.

Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.

Pesquisa ativa

Ensaios clínicos abertos e novidades científicas recentes

🟢 Recrutando agora

1 pesquisa recrutando participantes. Converse com seu médico sobre a possibilidade de participar.

Outros ensaios clínicos

2 ensaios clínicos encontrados, 1 ativos.

Distribuição por fase
Ver todos no ClinicalTrials.gov
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Publicações mais relevantes

Timeline de publicações
112 papers (10 anos)
#1

Clinical 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 Surgery2026 Mar 05

We characterized the clinical features of PTPN11-related deafness and evaluated the outcomes of cochlear implantation in affected patients. Whole-exome sequencing and bioinformatic analyses were performed in a cohort of 467 individuals with congenital sensorineural hearing loss to identify potential genetic etiologies. Four patients harboring PTPN11 variants were reviewed for their clinical characteristics and post-implantation auditory rehabilitation outcomes. PTPN11 variants were identified in four patients (Cases 1-4). A missense variant c.1391G > C (p.Gly464Ala) in exon 12 was detected in Case 1 and the recurrent variant c.836A > G (p.Tyr279Cys) in exon 7 was identified in Case 2. Both patients were diagnosed with Noonan syndrome with multiple lentigines. Missense variants c.1510A > G (p.Met504Val) in exon 13 and c.923A > G (p.Asn308Ser) in exon 8 were found in Cases 3 and 4, respectively; both were diagnosed with Noonan syndrome. Cases 1, 2, and 4 underwent cochlear implantation and demonstrated favorable postoperative auditory and speech outcomes. Our study provides a comprehensive characterization of auditory, speech and systemic phenotypes in PTPN11-related Noonan spectrum disorders and demonstrates that cochlear implantation is highly effective for severe-to-profound hearing loss. These findings emphasize the value of early genetic diagnosis and emphasize the importance of coordinated, interdisciplinary management.

#2

Noonan Syndrome With Multiple Lentigines Mimicking Obstructive Hypertrophic Cardiomyopathy Treated by Septal Myectomy.

JACC. Case reports2026 Feb 18

Noonan syndrome with multiple lentigines (NSML) is a rare RASopathy characterized by lentigines, craniofacial anomalies, and cardiac involvement. Hypertrophic cardiomyopathy (HCM) with left ventricular outflow tract obstruction is a frequent phenotype and may require interventional therapy. We present a 43-year-old woman with NSML and obstructive HCM. Despite optimized pharmacologic therapy and implantable cardioverter-defibrillator implantation, she developed progressive dyspnea and palpitations. Multidisciplinary heart team evaluation favored surgical septal myectomy with papillary muscle plasty, given unfavorable anatomy for alcohol septal ablation. Postoperative echocardiography showed marked gradient reduction and symptom relief. Approximately 5% to 10% of patients with HCM remain refractory to medical therapy. In phenocopies such as NSML, therapeutic decisions should be individualized. Surgical myectomy is a safe alternative when septal anatomy precludes alcohol septal ablation. Septal reduction therapies may be considered in NSML with left ventricular outflow tract obstruction. Heart team discussion is essential. Surgical myectomy can provide sustained functional improvement.

#3

Development and Treatment of Severe Lordoscoliosis in a Patient With Noonan Syndrome With Multiple Lentigines (NSML): A Case Report.

Cureus2026 Jan

Noonan syndrome with multiple lentigines (NSML) is an allelic variant of Noonan syndrome (NS), which can exhibit multisystemic features, including sensorineural hearing loss (SNHL) and skeletal anomalies. We report on a patient with this rare condition who developed an uncommon syndromic feature of severe lordoscoliosis requiring surgical intervention, whose comorbidities complicated the perioperative course, including the preclusion of magnetic resonance imaging (MRI) and relative contraindication to transcranial motor evoked potentials (TcMEPs). We discuss the use of preoperative computed tomography (CT) and somatosensory evoked potentials (SSEPs) in facilitating the consent process for surgery where MRI and TcMEPs are impracticable, as well as the intraoperative measures taken to minimise complications in this case. We also highlight the importance of multispecialty, multidisciplinary involvement in the management of such patients. In this patient whose severe lordoscoliosis led to persistent back pain and airway compression, posterior spinal fusion achieved satisfactory deformity correction and excellent clinical outcome, which was maintained at follow-up.

#4

Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.

Molecular syndromology2026 Feb

RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk. This retrospective study analyzed the medical records regarding clinical and molecular data from 2018 to 2024 in a single center for rare diseases of individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques. Twenty-four patients were enrolled with an even sex ratio distribution and ages ranging from 1 month to 16 years at first evaluation. The main reason for referral was diagnostic assessment due to a combination of dysmorphic features (24/24; 100%), growth deficiency (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart disease (13/24; 54.1%). Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS, besides one with variants in both LZTR1 and SOS1), two with Noonan syndrome with multiple lentigines (both with variants in PTPN11), two with Neurofibromatosis-Noonan (NF1), two with cardiofaciocutaneous syndrome (BRAF), and one each with Noonan syndrome-like with loose anagen hair (PPP1CB), Noonan syndrome-like (CBL), and Costello syndrome (HRAS); one individual presented with a double diagnosis of Noonan and Klinefelter syndromes. Three pairs of unrelated patients presented recurrent variants in the PTPN11 gene, partially concordant in phenotypic correlation among the pairs but not fully concordant compared to previously described cases in the literature. Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the A2ML1 gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the LZTR1 gene and c.1A>G in the NF1 gene are variants for the first time associated with features of Noonan syndrome.

#5

Dysregulated TGFβ-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve Stenosis.

bioRxiv : the preprint server for biology2026 Jan 20

Pulmonary valve stenosis (PVS) is the most common congenital heart defect in Noonan syndrome (NS) and related RASopathies, yet the molecular mechanisms linking pathogenic variants to the valve pathology remain poorly defined. Here, we utilized a human iPSC-based valve differentiation platform to generate the cardiac valve cell lineages-including fibrosa and spongiosa valve interstitial cell (VIC) subtypes. CRISPR-edited iPSCs harboring NS gain-of-function RAS/MAPK and Noonan syndrome with multiple lentigines (NSML) dominant-negative RAS/MAPK variants exhibited early defects in mesodermal and endocardial specification in all genotypes. Additionally, NS-iPSC endocardial cells exhibited defects in endothelial-to-mesenchymal transition (EndMT) specifically towards fibrosa VICs, which was most pronounced in PTPN11 N308D (N308D) cells. Single-cell transcriptomics revealed widespread dysregulation of extracellular matrix (ECM) programs in N308D fibrosa VICs, including increased expression of collagens and proteoglycans, as well as dysregulation of multiple genes involved in ECM remodeling. We also detected activation of RAS-MAPK, TGFβ, and fibrosis-associated pathways in our transcriptional dataset. Mass spectrometry-based phosphoproteomics confirmed coordinated increases in ERK, PKC, and stress-related kinases, as well as enhanced activity of the TGFβ receptor. Functionally, N308D fibrosa VICs exhibited exaggerated upregulation of ECM genes in the presence of TGFβ2 ligand, suggesting that these cells are hypersensitive to TGFβ stimulation. Furthermore, we demonstrated that this pathological ECM-program occurs independently of BAMBI, a negative regulator of TGFβ signaling that was found to be decreased in N308D fibrosa VICs. Lastly, we performed histopathological analyses of stenotic pulmonary valves from two NS infants, which demonstrated marked overproduction and disorganization of ECM, mirroring the findings from our iPSC-based disease model. Together, our data reveal a central mechanism where NS-associated alleles sensitize fibrosa VICs to TGFβ, which leads to aberrant downstream signaling and drives the pathological ECM program in NS-associated PVS.

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📚 EuropePMC44 artigos no totalmostrando 109

2026

Clinical 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 Surgery
2026

Noonan Syndrome With Multiple Lentigines Mimicking Obstructive Hypertrophic Cardiomyopathy Treated by Septal Myectomy.

JACC. Case reports
2026

Development and Treatment of Severe Lordoscoliosis in a Patient With Noonan Syndrome With Multiple Lentigines (NSML): A Case Report.

Cureus
2026

Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.

Molecular syndromology
2026

Dysregulated TGFβ-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve Stenosis.

bioRxiv : the preprint server for biology
2026

Neuropathic 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 A
2025

Molecular and Clinical Profiles of Patients with RASopathies: Targeted Next-Generation Sequencing Panel Results and Identification of 14 Novel Disease-Causing Variants.

Molecular syndromology
2025

Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study.

Molecular autism
2025

Executive and Social Functioning in Children and Adolescents With Noonan Syndromes: Cognition and Behavior.

JAACAP open
2025

SHP2 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 America
2025

Everolimus therapy in an infant with Noonan syndrome with multiple lentigines.

Annals of pediatric cardiology
2025

[Hypertrophy of the lumbosacral nerve roots in Noonan syndrome with multiple lentigines: a case report].

Rinsho shinkeigaku = Clinical neurology
2025

RASopathies. Part II: Cutaneous and extracutaneous manifestations.

Journal of the American Academy of Dermatology
2025

RASopathies. Part I: Genetics and therapeutic considerations.

Journal of the American Academy of Dermatology
2025

Rapamycin treatment for progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines.

Kardiologia polska
2025

[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 surgery
2025

Case Report: A rare case of Noonan syndrome with multiple lentigines manifesting as cardiac enlargement.

Frontiers in cardiovascular medicine
2024

Genomic 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 sciences
2024

Orbital and Lumbosacral Plexiform Neurofibroma with PTPN11 Mutation: A Form of the RASopathy.

Cureus
2024

Atypical left-ventricular hypertrophy with apical aneurysm in leopard syndrome.

The international journal of cardiovascular imaging
2024

SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis.

Nature communications
2024

Paternally Inherited Noonan Syndrome Caused by a PTPN11 Variant May Exhibit Mild Symptoms: A Case Report and Literature Review.

Genes
2024

A novel variant in PTPN11, c.1277A>G p.(His426Arg), in a patient with Noonan syndrome with multiple lentigines.

Clinical and experimental dermatology
2024

MEK Inhibition for RASopathy-Associated Hypertrophic Cardiomyopathy: Clinical Application of a Basic Concept.

The Canadian journal of cardiology
2024

Coexisting PTPN11 and TNNT2 mutations in noonan syndrome with multiple lentigines.

QJM : monthly journal of the Association of Physicians
2024

[Translated article] Noonan Syndrome With Multiple Lentigines.

Actas dermo-sifiliograficas
2023

Case report: Distinctive cardiac features and phenotypic characteristics of Noonan syndrome with multiple lentigines among three generations in one family.

Frontiers in cardiovascular medicine
2023

Hypertrophic cardiomyopathy in an adult patient with Noonan syndrome with multiple lentigines.

Clinical case reports
2023

Lessons From a Genotype-Phenotype Study About the Clinical Spectrum of Hypertrophic Cardiomyopathy Associated With Noonan Syndrome With Multiple Lentigines and PTPN11-Mutations.

Circulation. Genomic and precision medicine
2023

A rare mutation in a patient with Noonan syndrome with multiple lentigines.

JAAD case reports
2023

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines.

Circulation. Genomic and precision medicine
2022

Dermatological manifestations, management, and care in RASopathies.

American journal of medical genetics. Part C, Seminars in medical genetics
2022

New prospectives on treatment opportunities in RASopathies.

American journal of medical genetics. Part C, Seminars in medical genetics
2022

Clinical overview on RASopathies.

American journal of medical genetics. Part C, Seminars in medical genetics
2022

The heart in RASopathies.

American journal of medical genetics. Part C, Seminars in medical genetics
2022

Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2.

Frontiers in cell and developmental biology
2022

Effects of Noonan Syndrome-Germline Mutations on Mitochondria and Energy Metabolism.

Cells
2022

Cognitive Phenotype and Psychopathology in Noonan Syndrome Spectrum Disorders through Various Ras/MAPK Pathway Associated Gene Variants.

Journal of clinical medicine
2022

Epilepsy in a cohort of children with Noonan syndrome and related disorders.

European journal of pediatrics
2022

Targeting SHP2 phosphatase in hematological malignancies.

Expert opinion on therapeutic targets
2022

Cochlear Implantation in Noonan Syndrome With and Without Multiple Lentigines: A Case Report and Systematic Review.

Otology &amp; neurotology open
2023

An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies.

Cardiovascular drugs and therapy
2022

RASopathies: Dermatologists' viewpoints.

Indian journal of dermatology, venereology and leprology
2022

The RASopathies: Biology, genetics and therapeutic options.

Advances in cancer research
2022

Natural history of left ventricular hypertrophy in infants of diabetic mothers.

International journal of cardiology
2021

Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state.

Computational and structural biotechnology journal
2021

Dermatologic manifestations of pediatric cardiovascular diseases: Skin as a reflection of the heart.

Pediatric dermatology
2023

OPTIC DISK COLOBOMA AND CONTRALATERAL OPTIC DISK PIT MACULOPATHY TREATED BY VITRECTOMY IN A PATIENT WITH NOONAN SYNDROME WITH MULTIPLE LENTIGINES.

Retinal cases &amp; brief reports
2021

Noonan Syndrome with Multiple Lentigines and PTPN11 Mutation: A Case with Intracerebral Hemorrhage.

Molecular syndromology
2022

Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines.

Cardiovascular drugs and therapy
2021

Noonan Syndrome With Multiple Lentigines: Subtle Key Skin Clues to the Diagnosis.

Actas dermo-sifiliograficas
2021

Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2-related disorders.

Clinical genetics
2021

Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines.

Pediatric research
2020

Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.

Cell
2020

Targeting a Pathogenic Cysteine Mutation: Discovery of a Specific Inhibitor of Y279C SHP2.

Biochemistry
2021

Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms.

Journal of medical genetics
2020

Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines.

JCI insight
2020

Melanoma in Noonan Syndrome With Multiple Lentigines (Leopard Syndrome): A New Case.

Actas dermo-sifiliograficas
2020

Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts.

Annals of oncology : official journal of the European Society for Medical Oncology
2020

Legius Syndrome and its Relationship with Neurofibromatosis Type 1.

Acta dermato-venereologica
2020

Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1.

Molecular genetics &amp; genomic medicine
2020

Café au Lait Macules and Associated Genetic Syndromes.

Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates &amp; Practitioners
2019

Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina.

Archivos argentinos de pediatria
2019

[Case report and diagnosis of Noonan syndrome with multiple lentigines with deafness as its main clinical feature].

Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery
2019

Pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: the multifaceted consequences of PTPN11 mutations.

Orphanet journal of rare diseases
2020

Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation.

Journal of biomolecular structure &amp; dynamics
2019

Noonan syndrome with multiple lentigines and prominent keratosis pilaris.

Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG
2019

Out-of-hospital cardiac arrest and survival in a patient with Noonan syndrome and multiple lentigines: a case report.

Journal of medical case reports
2019

RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis.

American journal of medical genetics. Part A
2019

Pathogenesis of Growth Failure in Rasopathies.

Pediatric endocrinology reviews : PER
2019

Clinical Manifestations of Noonan Syndrome and Related Disorders.

Pediatric endocrinology reviews : PER
2019

First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics.

American journal of medical genetics. Part A
2019

Genetic landscape of RASopathies in Chinese: Three decades' experience in Hong Kong.

American journal of medical genetics. Part C, Seminars in medical genetics
2019

Generation of an induced pluripotent stem cell line (TRNDi003-A) from a Noonan syndrome with multiple lentigines (NSML) patient carrying a p.Q510P mutation in the PTPN11 gene.

Stem cell research
2018

Widespread keratosis pilaris in a patient with Noonan syndrome with multiple lentigines.

International journal of dermatology
2018

Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.

American journal of medical genetics. Part A
2018

The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway.

Endocrine reviews
2018

RAS signalling in energy metabolism and rare human diseases.

Biochimica et biophysica acta. Bioenergetics
2018

Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner.

Science signaling
2018

Patient with confirmed LEOPARD syndrome developing multiple melanoma.

Dermatology practical &amp; conceptual
2018

Neurocutaneous Disorders.

Continuum (Minneapolis, Minn.)
2018

Noonan syndrome with multiple lentigines and associated craniosynostosis.

Clinical and experimental dermatology
2017

Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders.

BMC medical genomics
2017

Heterozygous deletion of AKT1 rescues cardiac contractility, but not hypertrophy, in a mouse model of Noonan Syndrome with Multiple Lentigines.

Journal of molecular and cellular cardiology
2017

Noonan syndrome with multiple lentigines with PTPN11 (T468M) gene mutation accompanied with solitary granular cell tumor.

The Journal of dermatology
2017

Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype.

American journal of medical genetics. Part A
2017

A review of craniofacial and dental findings of the RASopathies.

Orthodontics &amp; craniofacial research
2017

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy.

PloS one
2017

Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11.

International journal of pediatric otorhinolaryngology
2018

Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype.

Clinical genetics
2017

Modeling RASopathies with Genetically Modified Mouse Models.

Methods in molecular biology (Clifton, N.J.)
2016

Molecular screening strategies for NF1-like syndromes with café-au-lait macules (Review).

Molecular medicine reports
2017

Choroidal abnormalities in café-au-lait syndromes: a new differential diagnostic tool?

Clinical genetics
2016

Cardiac Manifestations and Associations with Gene Mutations in Patients Diagnosed with RASopathies.

Pediatric cardiology
2016

RASopathies: Presentation at the Genome, Interactome, and Phenome Levels.

Molecular syndromology
2016

Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines.

The Journal of clinical investigation
2016

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders.

Neurobiology of learning and memory
2016

Multiple giant cell lesions in a patient with Noonan syndrome with multiple lentigines.

European journal of medical genetics
2016

The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway.

American journal of medical genetics. Part A
2016

Hypertrophic neuropathy in Noonan syndrome with multiple lentigines.

American journal of medical genetics. Part A
2016

Recent advances in RASopathies.

Journal of human genetics
2015

Cardiomyopathies in Noonan syndrome and the other RASopathies.

Progress in pediatric cardiology
2016

Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy.

American journal of medical genetics. Part A
2015

SHP2 sails from physiology to pathology.

European journal of medical genetics
2016

Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines.

Journal of medical genetics
2015

Copy number variants including RAS pathway genes-How much RASopathy is in the phenotype?

American journal of medical genetics. Part A
2015

Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines.

American journal of physiology. Heart and circulatory physiology
2015

Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog.

American journal of medical genetics. Part A
2015

Malignancy in Noonan syndrome and related disorders.

Clinical genetics

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Ordenadas pelo número de sintomas em comum.

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.

  1. Clinical 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 Surgery· 2026· PMID 41786942mais citado
  2. Noonan Syndrome With Multiple Lentigines Mimicking Obstructive Hypertrophic Cardiomyopathy Treated by Septal Myectomy.
    JACC. Case reports· 2026· PMID 41709793mais citado
  3. Development and Treatment of Severe Lordoscoliosis in a Patient With Noonan Syndrome With Multiple Lentigines (NSML): A Case Report.
    Cureus· 2026· PMID 41694882mais citado
  4. Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.
    Molecular syndromology· 2026· PMID 41675685mais citado
  5. Dysregulated TGF&#x3b2;-ERK Signaling Drives Aberrant Extracellular Matrix Production in Noonan Syndrome-Associated Pulmonary Valve Stenosis.
    bioRxiv : the preprint server for biology· 2026· PMID 41648231mais citado
  6. Cancer risk in adults with pathogenic germline variants in RAS/MAPK genes using genomic ascertainment.
    Genet Med· 2026· PMID 41904680recente

Bases de dados e fontes oficiais

Identificadores e referências canônicas usadas para montar este verbete.

  1. ORPHA:500(Orphanet)
  2. MONDO:0007893(MONDO)
  3. GARD:1100(GARD (NIH))
  4. Variantes catalogadas(ClinVar)
  5. Busca completa no PubMed(PubMed)
  6. Q1798016(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

Síndrome Noonan com lentigos múltiplos
Compêndio · Raras BR

Síndrome Noonan com lentigos múltiplos

ORPHA:500 · MONDO:0007893
Prevalência
<1 / 1 000 000
Casos
296 casos conhecidos
Herança
Autosomal dominant
CID-10
Q87.1 · Síndromes com malformações congênitas associadas predominantemente com nanismo
CID-11
Ensaios
1 ativos
Início
Neonatal
Prevalência
0.0 (Worldwide)
MedGen
UMLS
C0175704
EuropePMC
Wikidata
Papers 10a
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