Noonan Syndrome

name: Noonan Syndrome
creation_date: '2026-02-04T01:40:11Z'
updated_date: '2026-03-30T00:00:00Z'
description: >-
  Noonan syndrome is an autosomal dominant RASopathy caused by germline mutations
  in genes of the RAS-MAPK signaling pathway, most commonly PTPN11. It is characterized
  by distinctive facial features, short stature, congenital heart defects (particularly
  pulmonary valve stenosis and hypertrophic cardiomyopathy), and variable developmental
  delays.
  It is one of the most common genetic syndromes associated with congenital heart
  disease,
  with an estimated incidence of 1:1,000 to 1:2,500 live births.
category: Genetic
parents:
- RASopathy
- Congenital Heart Disease
disease_term:
  preferred_term: Noonan syndrome
  description: A RASopathy characterized by distinctive facial features, short
    stature, congenital heart defects, and variable developmental delays.
  term:
    id: MONDO:0018997
    label: Noonan syndrome
has_subtypes:
- name: Noonan Syndrome 1 (PTPN11-related)
  subtype_term:
    preferred_term: Noonan syndrome 1
    term:
      id: MONDO:0008104
      label: Noonan syndrome 1
  description: Most common form caused by PTPN11 mutations, accounting for
    approximately 50% of cases.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included 15 individuals with Noonan syndrome (nine with
      variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS...)
    explanation: >-
      This cohort confirms PTPN11-positive Noonan syndrome as the predominant
      molecular subtype.
- name: Noonan Syndrome with Multiple Lentigines
  subtype_term:
    preferred_term: Noonan syndrome with multiple lentigines
    term:
      id: MONDO:0007893
      label: Noonan syndrome with multiple lentigines
  description: Formerly known as LEOPARD syndrome, characterized by lentigines
    and hypertrophic cardiomyopathy.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two with Noonan syndrome with multiple lentigines (both with variants in PTPN11)


    explanation: >-
      Confirms Noonan syndrome with multiple lentigines as a related and
      clinically relevant subtype in modern RASopathy cohorts.
prevalence:
- population: Live births
  percentage: 1 in 1,000 to 1 in 2,500
  notes: >-
    Noonan syndrome is among the more common rare Mendelian syndromes and a
    leading syndromic cause of congenital heart disease.
  evidence:
  - reference: PMID:18047172
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Noonan syndrome, a genetic condition occurring in around 1 in 2,000 live births, was first described in 1968 by Dr Jacqueline Noonan, an American cardiologist, who noticed that patients attending her clinic often had similar features."
    explanation: This review provides a commonly cited live-birth frequency estimate for Noonan syndrome.
  - reference: PMID:10912404
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Background: Noonan syndrome is similar phenotypically to Turner syndrome, accounting for one in 1000-2500 live births."
    explanation: This paper supports the broader conventional birth-frequency range cited for Noonan syndrome.
pathophysiology:
- name: SHP2 Gain-of-Function Activation
  description: >-
    PTPN11 mutations destabilize the autoinhibitory interaction between the N-SH2
    and PTP domains, resulting in constitutively elevated phosphatase activity.
    SHP2 is a positive regulator of RAS-MAPK signaling and gain-of-function mutations
    lead to enhanced ERK activation.
  molecular_functions:
  - preferred_term: protein tyrosine phosphatase activity
    term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Enhanced SHP2 phosphatase activity promotes RAS activation and
      downstream ERK signaling.
    evidence:
    - reference: PMID:17143285
      reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and
        Noonan syndrome mutants enhance ERK activation ex vivo and in mice.
      explanation: >-
        Supports SHP2 gain-of-function as an upstream driver of ERK cascade
        hyperactivation in Noonan syndrome.
    - reference: PMID:11992261
      reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A gain of function was postulated as a mechanism for the disease.
      explanation: >-
        Provides direct Noonan/PTPN11 human-genetics evidence supporting
        gain-of-function SHP2 signaling upstream of ERK hyperactivation.
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All defects were missense, and several were recurrent. The vast majority
      of mutations altered amino acid residues located in or around the interacting
      surfaces of the N-SH2 and PTP domains"
    explanation: PTPN11 mutations cluster at the N-SH2/PTP interface, disrupting
      autoinhibition.

- name: SOS1-Mediated RAS-GTP Loading
  description: >-
    SOS1 gain-of-function mutations encode guanine nucleotide exchange factor
    variants with enhanced activity, increasing the rate of RAS-GDP to RAS-GTP
    conversion and amplifying downstream MAPK signaling.
  molecular_functions:
  - preferred_term: guanyl-nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Enhanced RAS-GTP loading directly amplifies RAF-MEK-ERK cascade
      activation.
    evidence:
    - reference: PMID:17143285
      reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Noonan syndrome-associated SOS1 mutations are hypermorphs encoding
        products that enhance RAS and ERK activation.
      explanation: >-
        Directly supports SOS1-driven amplification of ERK signaling.
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products
      that enhance RAS and ERK activation."
    explanation: SOS1 mutations are gain-of-function, enhancing RAS-GTP loading.

- name: RAF1 Kinase Hyperactivation
  description: >-
    RAF1 mutations, particularly those altering Ser259 and flanking residues,
    disrupt 14-3-3 binding and autoinhibition, resulting in constitutively
    elevated serine-threonine kinase activity and enhanced MEK phosphorylation.
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Hyperactive RAF1 directly phosphorylates MEK, amplifying ERK
      signaling.
    evidence:
    - reference: PMID:17603483
      reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ...have missense mutations in RAF1, which encodes a serine-threonine
        kinase that activates MEK1 and MEK2.
      explanation: >-
        Supports mechanistic linkage from RAF1 activation to downstream MEK/ERK
        cascade signaling.
  - target: Cardiomyocyte Hypertrophy
    description: RAF1 kinase hyperactivation is strongly associated with
      hypertrophic cardiomyopathy development.
    evidence:
    - reference: PMID:17603483
      reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings further implicate increased RAS signaling in pathological
        cardiomyocyte hypertrophy.
      explanation: >-
        Supports RAF1-mediated signaling as a proximal driver of cardiomyocyte
        hypertrophic remodeling.
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most mutations altered a motif flanking Ser259, a residue critical for
      autoinhibition of RAF1 through 14-3-3 binding."
    explanation: RAF1 mutations disrupt autoinhibitory 14-3-3 binding.

- name: RIT1-Mediated RAF Recruitment
  description: >-
    RIT1 gain-of-function mutations cause aberrant membrane localization and
    RAF recruitment, bypassing normal RAS regulation and driving excessive
    MAPK pathway activation.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Aberrant RIT1-mediated RAF recruitment amplifies downstream ERK
      signaling.
    evidence:
    - reference: DOI:10.1126/sciadv.adf4766
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Pathogenic RIT1 proteins promote mitogen-activated protein kinase
        (MAPK) hyperactivation; however, this mechanism remains poorly understood.
      explanation: >-
        Supports RIT1 mutant signaling as a direct contributor to MAPK/ERK
        hyperactivation.
  - target: Cardiomyocyte Hypertrophy
    description: RIT1 mutations are strongly associated with hypertrophic
      cardiomyopathy.
    evidence:
    - reference: PMID:23791108
      reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seventy percent of mutation-positive individuals presented with
        hypertrophic cardiomyopathy; this frequency is high relative to the
        overall 20% incidence in individuals with Noonan syndrome.
      explanation: >-
        Supports RIT1-associated signaling as strongly linked to hypertrophic
        myocardial phenotype.
  evidence:
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results demonstrate that gain-of-function mutations in RIT1 cause
      Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related
      genes."
    explanation: RIT1 gain-of-function mutations drive aberrant MAPK signaling.

- name: LZTR1-Mediated RAS Proteostasis Defect
  description: >-
    Loss of LZTR1-mediated RAS proteostasis through CRL3 E3 ligase
    increases RAS-family protein levels (including MRAS, RIT1, and KRAS)
    and MAPK signaling. Dominant LZTR1 mutations act in a dominant-negative
    manner to disrupt ubiquitination and degradation of RAS proteins.
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
  - preferred_term: regulation of proteolysis
    term:
      id: GO:0030162
      label: regulation of proteolysis
  downstream:
  - target: ERK Cascade Hyperactivation
    description: Accumulated RAS proteins lead to increased basal MAPK
      signaling.
    evidence:
    - reference: PMID:39352760
      reference_title: "Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Multi-omics analysis revealed that the mitogen-activated protein kinase
        (MAPK) signaling pathway was activated in the LVs of mutant mice.
      explanation: >-
        Demonstrates MAPK pathway activation downstream of dominant-negative
        LZTR1 dysfunction.
  evidence:
  - reference: PMID:39352760
    reference_title: "Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiomyocyte size and the expression of RAS subfamily members, including
      MRAS and RIT1, were significantly increased in the left ventricles (LVs)
      of mutant male mice.
    explanation: >-
      Supports LZTR1 loss-of-function effects on RAS-family proteostasis and
      downstream tissue-level cardiac phenotypes.

- name: ERK Cascade Hyperactivation
  description: >-
    Convergent point where all upstream RAS-MAPK pathway defects lead to
    sustained ERK1/2 phosphorylation and hyperactivation. This affects
    cell proliferation, differentiation, and survival during embryonic
    development and postnatal life.
  biological_processes:
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: regulation of ERK1 and ERK2 cascade
    term:
      id: GO:0070372
      label: regulation of ERK1 and ERK2 cascade
  downstream:
  - target: Cardiac Valve Morphogenesis Defects
    description: Perturbed ERK signaling alters endocardial-mesenchymal
      transition during valve development.
    evidence:
    - reference: PMID:11992261
      reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ...pulmonic stenosis was more prevalent among the group of subjects with
        NS who had PTPN11 mutations than it was in the group without them
        (70.6% vs. 46.2%; P<.01)...
      explanation: >-
        Supports a mechanistic link from upstream RAS-MAPK dysregulation to
        abnormal cardiac valve development outcomes in Noonan syndrome.
  - target: Cardiomyocyte Hypertrophy
    description: Sustained ERK signaling promotes hypertrophic growth and fetal
      gene reprogramming.
    evidence:
    - reference: DOI:10.1126/sciadv.adf4766
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        ...we show that pathway inhibition alleviates cardiac hypertrophy in a
        mouse model of RIT1 mutant Noonan syndrome.
      explanation: >-
        Reversibility of hypertrophy with MAPK-pathway inhibition supports ERK
        cascade hyperactivation as a proximal hypertrophic driver.
  - target: Cortical Layer Development Abnormalities
    description: >-
      Sustained RAS-MAPK signaling perturbs cortical neuronal lineage patterning
      and synaptic maturation programs in Noonan syndrome models.
    evidence:
    - reference: GEO:GSE213798
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ...single-cell transcriptomic analysis represented increment of EN
        population and overexpression of cortical layer markers in NS-COs.
      explanation: >-
        Supports a downstream neurodevelopmental consequence of pathway
        dysregulation in NS-derived cortical organoid models.
  - target: Lymphatic Structural Abnormalities
    description: >-
      RAS-MAPK pathway overactivation contributes to clinically severe lymphatic
      anomalies in Noonan syndrome.
    evidence:
    - reference: DOI:10.3389/fped.2025.1475143
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most are dominant gain-of-function variants that cause an overactivation
        of the RAS/MAPK signaling pathway leading to uncontrolled cell
        proliferation in many organs and systems.
      explanation: >-
        Supports pathway overactivation as an upstream driver for systemic,
        including lymphatic, NS manifestations.
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and
      Noonan syndrome mutants enhance ERK activation ex vivo and in mice.
    explanation: >-
      Supports ERK cascade hyperactivation as a convergent signaling consequence
      of NS-associated upstream mutations.

- name: Cortical Layer Development Abnormalities
  description: >-
    NS-derived cortical organoid models show abnormal excitatory-neuron layer
    specification and reduced synaptic connectivity, consistent with
    neurodevelopmental pathway disruption.
  downstream:
  - target: Global Developmental Delay
    description: >-
      Perturbed cortical development and connectivity likely contributes to
      delayed neurodevelopmental trajectories.
    evidence:
    - reference: GEO:GSE213798
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Collectively, our findings suggest that perturbed cortical layer
        identity and impeded neuronal connectivity account for the neurological
        manifestations of NS.
      explanation: >-
        Supports mechanistic linkage from cortical developmental defects to
        global developmental phenotypes in NS.
  - target: Mild Intellectual Disability
    description: >-
      Abnormal cortical-layer identity and synaptic organization can contribute
      to persistent cognitive impairment in a subset of patients.
    evidence:
    - reference: GEO:GSE213798
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Collectively, our findings suggest that perturbed cortical layer
        identity and impeded neuronal connectivity account for the neurological
        manifestations of NS.
      explanation: >-
        Supports a biologically plausible causal route to intellectual and
        learning phenotypes in Noonan syndrome.
  evidence:
  - reference: GEO:GSE213798
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ...EN subpopulation co-expressing upper layer marker SATB2 and deep layer
      maker CTIP2 was enriched in NS-COs during the cortical development.
    explanation: >-
      Provides direct transcriptomic evidence of abnormal cortical layering in
      NS-derived organoid models.

- name: Lymphatic Structural Abnormalities
  description: >-
    Noonan syndrome can include severe central and peripheral lymphatic
    abnormalities that produce clinically significant fluid and lymphatic-flow
    complications.
  downstream:
  - target: Lymphedema
    description: >-
      Structural and flow abnormalities in lymphatic channels manifest clinically
      as peripheral or generalized lymphedema.
    evidence:
    - reference: PMID:38618951
      reference_title: "Central conducting lymphatic anomaly: from bench to bedside."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CCLA...may present with nonimmune fetal hydrops, chylothorax, chylous
        ascites, or lymphedema.
      explanation: >-
        Supports lymphedema as a downstream clinical consequence of central
        lymphatic structural pathology.
  evidence:
  - reference: DOI:10.3389/fped.2025.1475143
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Albeit phenotypically heterogeneous, NS can be associated with severe
      cardiovascular and lymphatic anomalies, potentially lethal during infancy,
      neonatal and fetal periods.
    explanation: >-
      Supports the presence of clinically severe lymphatic disease as part of
      the Noonan syndrome pathophysiologic spectrum.

- name: Cardiac Valve Morphogenesis Defects
  description: >-
    In endocardial and valvular tissues, perturbed ERK signaling alters
    endocardial-mesenchymal transition and valve morphogenesis, underlying
    pulmonary valve stenosis, the most common cardiac defect in Noonan syndrome.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition involved in endocardial
      cushion formation
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  - preferred_term: heart valve morphogenesis
    term:
      id: GO:0003179
      label: heart valve morphogenesis
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  locations:
  - preferred_term: pulmonary valve
    term:
      id: UBERON:0002146
      label: pulmonary valve
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pulmonic stenosis was more prevalent among the group of subjects with
      NS who had PTPN11 mutations than it was in the group without them (70.6% vs.
      46.2%; P<.01)"
    explanation: Demonstrates that pulmonary valve stenosis is highly associated
      with PTPN11 mutations in Noonan syndrome.
  downstream:
  - target: Pulmonary Valve Stenosis
    description: >-
      Valve morphogenesis defects in the pulmonary outflow tract manifest as
      dysplastic pulmonary valve stenosis.
    evidence:
    - reference: PMID:11992261
      reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ...pulmonic stenosis was more prevalent among the group of subjects with
        NS who had PTPN11 mutations than it was in the group without them
        (70.6% vs. 46.2%; P<.01)...
      explanation: >-
        Supports direct phenotypic consequence of valvulogenesis defects as
        pulmonary valve stenosis.
- name: Cardiomyocyte Hypertrophy
  description: >-
    In cardiomyocytes, sustained ERK signaling (and intersecting AKT/mTOR activity)
    promotes hypertrophic growth and fetal gene reprogramming, leading to
    hypertrophic cardiomyopathy, particularly in patients with RAF1 and RIT1 mutations.
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed
      hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among
      individuals with Noonan syndrome in general."
    explanation: Demonstrates strong association between RAF1 mutations and HCM,
      implicating the kinase pathway in cardiac hypertrophy.
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy percent of mutation-positive individuals presented with hypertrophic
      cardiomyopathy; this frequency is high relative to the overall 20% incidence
      in individuals with Noonan syndrome."
    explanation: RIT1 mutations are strongly associated with hypertrophic
      cardiomyopathy.
  downstream:
  - target: Hypertrophic Cardiomyopathy
    description: >-
      Persistent cardiomyocyte hypertrophic remodeling yields clinical
      hypertrophic cardiomyopathy.
    evidence:
    - reference: PMID:17603483
      reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%)
        showed hypertrophic cardiomyopathy (HCM)...
      explanation: >-
        Supports direct connection from hypertrophic cardiomyocyte remodeling to
        overt HCM phenotype in NS.
phenotypes:
- category: Craniofacial
  name: Hypertelorism
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  description: >-
    Widely spaced eyes are a characteristic facial feature of Noonan syndrome.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 22-year-old woman presented with typical dysmorphic features of NS,
      including...hypertelorism...
    explanation: >-
      Supports hypertelorism as part of the characteristic craniofacial
      phenotype in clinically diagnosed Noonan syndrome.
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  description: >-
    Downward slanting of the eye openings is a common facial feature.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main facial features of NS are hypertelorism with down-slanting
      palpebral fissures, ptosis and low-set posteriorly rotated ears with a
      thickened helix.
    explanation: >-
      Review evidence explicitly identifies down-slanting palpebral fissures
      as a main facial feature in Noonan syndrome.
- category: Craniofacial
  name: Ptosis
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  description: >-
    Drooping of the upper eyelids is frequently observed.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main facial features of NS are hypertelorism with down-slanting
      palpebral fissures, ptosis and low-set posteriorly rotated ears with a
      thickened helix.
    explanation: >-
      Review evidence explicitly identifies ptosis as a core facial feature in
      Noonan syndrome.
- category: Craniofacial
  name: Low-set Ears
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  description: >-
    Posteriorly rotated, low-set ears are characteristic.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 22-year-old woman presented with typical dysmorphic features of NS,
      including...low-set posteriorly rotated ears...
    explanation: >-
      Case-based clinical evidence supports low-set/posteriorly rotated ears
      as a characteristic facial finding in Noonan syndrome.
- category: Craniofacial
  name: Webbed Neck
  phenotype_term:
    preferred_term: Webbed neck
    term:
      id: HP:0000465
      label: Webbed neck
  description: >-
    Excess skin on the lateral neck creating a webbed appearance.
  frequency: FREQUENT
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 22-year-old woman presented with typical dysmorphic features of NS,
      including...a broad neck.
    explanation: >-
      Supports cervical dysmorphology in Noonan syndrome and is consistent with
      common webbed/broad neck clinical descriptions.
- category: Cardiovascular
  name: Pulmonary Valve Stenosis
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  description: >-
    Dysplastic pulmonary valve stenosis is the most common cardiac defect, occurring
    in approximately 50-60% of patients. Associated with PTPN11 and SOS1 genotypes.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pulmonic stenosis was more prevalent among the group of subjects with
      NS who had PTPN11 mutations than it was in the group without them (70.6% vs.
      46.2%; P<.01)"
    explanation: Confirms high prevalence of pulmonary stenosis in Noonan
      syndrome, especially with PTPN11 mutations.
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  description: >-
    Left ventricular hypertrophy occurring in approximately 20% of patients overall,
    but up to 70-95% in those with RAF1 or RIT1 mutations. Can be present
    at birth or develop during infancy.
  frequency: FREQUENT
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed
      hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among
      individuals with Noonan syndrome in general."
    explanation: RAF1 mutations are strongly associated with HCM.
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy percent of mutation-positive individuals presented with hypertrophic
      cardiomyopathy; this frequency is high relative to the overall 20% incidence
      in individuals with Noonan syndrome."
    explanation: RIT1 mutations confer high risk of hypertrophic cardiomyopathy.
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypertrophic cardiomyopathy was less prevalent among those with PTPN11
      mutations (5.9% vs. 26.2%; P<.005)"
    explanation: PTPN11 mutations are associated with lower HCM risk compared to
      other NS genes.
- category: Cardiovascular
  name: Atrial Septal Defect
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  description: >-
    Atrial septal defects occur in 6-10% of individuals with Noonan syndrome.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41718520
    reference_title: "Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An infant presented with a large secundum atrial septal defect
      complicating NS-HCM.
    explanation: >-
      Supports atrial septal defect as a documented structural cardiac
      manifestation in Noonan syndrome.
- category: Growth
  name: Short Stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  description: >-
    Postnatal growth retardation resulting in adult height typically at or below the
    third percentile for the general population. Linked to RAS/MAPK effects on GH
    signaling and chondrocyte differentiation.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41577878
    reference_title: "Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Short stature is a key NSSD feature.
    explanation: >-
      Large multicenter Noonan-spectrum cohort data support short stature as a
      prevalent and clinically significant growth phenotype.
- category: Musculoskeletal
  name: Pectus Deformity
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  description: >-
    Chest wall deformities including pectus excavatum and pectus carinatum are common.
  frequency: FREQUENT
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of other congenital heart malformations, short stature,
      pectus deformity, cryptorchidism, and developmental delay did not differ between
      the two groups."
    explanation: Pectus deformity is recognized as a common feature across
      genotypes.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    Undescended testes in males is a common finding.
  frequency: FREQUENT
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of other congenital heart malformations, short stature,
      pectus deformity, cryptorchidism, and developmental delay did not differ between
      the two groups."
    explanation: Cryptorchidism is recognized as a common feature across Noonan
      syndrome genotypes.
- category: Hematologic
  name: Bruising Susceptibility
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  description: >-
    Coagulation defects including factor XI deficiency and platelet dysfunction,
    leading to easy bruising and prolonged bleeding after surgery or trauma.
  frequency: FREQUENT
  evidence:
  - reference: PMID:24444506
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have characteristic facial features that evolve
      with age; a broad, webbed neck; increased bleeding tendency; and a high
      incidence of congenital heart disease, failure to thrive, short stature,
      feeding difficulties, sternal deformity, renal malformation, pubertal
      delay, cryptorchidism, developmental or behavioral problems, vision
      problems, hearing loss, and lymphedema.
    explanation: >-
      This clinical review supports bleeding tendency/easy bruising as a common
      hematologic phenotype in Noonan syndrome.
- category: Neurologic
  name: Peripheral Neuropathy
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  description: >-
    Adult Noonan syndrome and Noonan syndrome with multiple lentigines can
    include neuropathic pain and objective peripheral nerve involvement, with
    enlarged nerves and impaired quality of life in symptomatic individuals.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41560462
    reference_title: "Neuropathic Pain and Enlarged Nerves in Adult Noonan Syndrome and Noonan Syndrome With Multiple Lentigines: Health-Related Quality of Life and Neurologic Symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients reported somatosensory symptoms consistent with peripheral
      neuropathy...electrodiagnostic testing was consistent with peroneal
      neuropathy in one patient.
    explanation: >-
      Supports peripheral neuropathy as a clinically meaningful neurologic
      manifestation in adults with Noonan-spectrum disorders.
- category: Lymphatic
  name: Lymphedema
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  description: >-
    Peripheral lymphedema and central conducting lymphatic anomalies occur in a
    substantial minority. ERK/SOX18 signaling axis is implicated in lymphatic dysplasia.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24444506
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected individuals have characteristic facial features that evolve
      with age; a broad, webbed neck; increased bleeding tendency; and a high
      incidence of congenital heart disease, failure to thrive, short stature,
      feeding difficulties, sternal deformity, renal malformation, pubertal
      delay, cryptorchidism, developmental or behavioral problems, vision
      problems, hearing loss, and lymphedema.
    explanation: >-
      Supports lymphedema as a recognized clinical manifestation in Noonan
      syndrome.
- category: Developmental
  name: Global Developmental Delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Mild cognitive impairment and motor delays are common, with learning disabilities
    in approximately 25% of individuals.
  frequency: FREQUENT
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of other congenital heart malformations, short stature,
      pectus deformity, cryptorchidism, and developmental delay did not differ between
      the two groups."
    explanation: Developmental delay is a recognized feature across Noonan
      syndrome genotypes.
- category: Developmental
  name: Mild Intellectual Disability
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  description: >-
    Approximately 15-35% of individuals have mild intellectual disability.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to one fourth of affected individuals have mild intellectual
      disability, and language impairments in general are more common in NS
      than in the general population.
    explanation: >-
      GeneReviews reports mild intellectual disability in a substantial minority
      of individuals with Noonan syndrome.
- category: Feeding
  name: Feeding Difficulties in Infancy
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  description: >-
    Many infants experience feeding difficulties and failure to thrive in early life.
  frequency: FREQUENT
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other associated features are webbed neck, chest deformity, mild
      intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding
      tendency and lymphatic dysplasias.
    explanation: >-
      Supports poor feeding in infancy as a common early-life manifestation in
      Noonan syndrome.
genetic:
- name: PTPN11
  gene_term:
    preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  association: Pathogenic Variants
  frequency: VERY_FREQUENT
  notes: >-
    Most commonly mutated gene, accounting for approximately 50-60% of cases.
    Encodes SHP2 phosphatase. Gain-of-function mutations destabilize the
    autoinhibited conformation leading to increased phosphatase activity.
    Associated with pulmonary stenosis but lower HCM risk.
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic
      or familial NS."
    explanation: Confirms PTPN11 mutations account for approximately half of
      Noonan syndrome cases.
- name: SOS1
  gene_term:
    preferred_term: SOS1
    term:
      id: hgnc:11187
      label: SOS1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Accounts for 10-20% of PTPN11-negative cases (approximately 10% overall).
    Encodes a RAS guanine nucleotide exchange factor. Gain-of-function mutations
    enhance RAS-GTP loading.
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified missense mutations in SOS1, which encodes an essential
      RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases
      of Noonan syndrome without PTPN11 mutation."
    explanation: SOS1 mutations are a significant cause of PTPN11-negative
      Noonan syndrome.
- name: RAF1
  gene_term:
    preferred_term: RAF1
    term:
      id: hgnc:9829
      label: RAF1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Accounts for 3-17% of cases. Strongly associated with hypertrophic cardiomyopathy
    (up to 95% of patients with RAF1 mutations have HCM).
  evidence:
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 of 231 individuals with Noonan syndrome without known mutations (corresponding
      to 3% of all affected individuals)...have missense mutations in RAF1"
    explanation: RAF1 mutations account for approximately 3% of Noonan syndrome.
- name: RIT1
  gene_term:
    preferred_term: RIT1
    term:
      id: hgnc:10023
      label: RIT1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Accounts for approximately 5-10% of cases. Associated with high incidence of
    hypertrophic cardiomyopathy (70% of mutation-positive individuals).
  evidence:
  - reference: PMID:23791108
    reference_title: "Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a total of nine missense, nonsynonymous mutations in RIT1...in
      17 of 180 individuals (9%) with Noonan syndrome"
    explanation: RIT1 mutations account for approximately 9% of cases without
      mutations in other known genes.
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Pathogenic Variants
  frequency: VERY_RARE
  notes: >-
    Rare cause, less than 2% of cases. Germline activating variants often cause
    more severe phenotype with significant neurodevelopmental involvement.
  evidence:
  - reference: PMID:17143285
    reference_title: "Germline gain-of-function mutations in SOS1 cause Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KRAS mutations account for <5% of cases of Noonan syndrome"
    explanation: KRAS mutations are a rare cause of Noonan syndrome.
- name: LZTR1
  gene_term:
    preferred_term: LZTR1
    term:
      id: hgnc:6742
      label: LZTR1
  association: Pathogenic Variants
  frequency: OCCASIONAL
  notes: >-
    Can cause both autosomal dominant and autosomal recessive forms.
    Acts as a CUL3 adaptor controlling RAS proteostasis through ubiquitination.
    Dominant mutations act in a dominant-negative manner.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included 15 individuals with Noonan syndrome...one each
      in LZTR1, A2ML1, and MRAS...
    explanation: >-
      Supports LZTR1 as a clinically observed Noonan syndrome genotype in
      contemporary molecular cohorts.
- name: MRAS
  gene_term:
    preferred_term: MRAS
    term:
      id: hgnc:7227
      label: MRAS
  association: Pathogenic Variants
  frequency: RARE
  notes: >-
    Emerging Noonan syndrome gene associated with variable expressivity, including
    adult-onset hypertrophic cardiomyopathy in recent reports.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included 15 individuals with Noonan syndrome...one each
      in LZTR1, A2ML1, and MRAS...
    explanation: >-
      Supports MRAS as a rare but clinically confirmed contributor to Noonan syndrome.
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a heterozygous MRAS c.203C>T
      (p.Thr68Ile) mutation...supporting the diagnosis of MRAS-associated
      Noonan syndrome.
    explanation: >-
      Case-level molecular confirmation supports pathogenic MRAS-associated
      Noonan syndrome with cardiac involvement.
inheritance:
- name: Autosomal Dominant
  description: Most cases follow autosomal dominant inheritance with variable
    expressivity. Approximately 30-75% of cases are de novo mutations.
  evidence:
  - reference: PMID:11992261
    reference_title: "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations were found in 54 of 119 (45%) unrelated individuals with
      sporadic or familial NS.
    explanation: >-
      Supports autosomal dominant inheritance with both familial transmission
      and de novo/sporadic occurrence.
- name: Autosomal Recessive
  description: >-
    A subset of Noonan syndrome is inherited in an autosomal recessive manner,
    particularly in LZTR1-associated disease.
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NS caused by pathogenic variants in LZTR1 can be inherited in either an
      autosomal dominant or an autosomal recessive manner.
    explanation: >-
      Supports autosomal recessive inheritance in LZTR1-associated Noonan
      syndrome.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Multigene RASopathy molecular testing is central to confirming Noonan
    syndrome and separating it from phenotypically overlapping RASopathies.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This retrospective study analyzed...individuals diagnosed with Noonan
      syndrome and related disorders previously submitted to diagnostic molecular
      analysis through next-generation sequencing techniques.
    explanation: >-
      Supports molecular testing as a practical diagnostic discriminator in
      suspected Noonan-spectrum disorders.
- name: Clinical whole-exome sequencing
  description: >-
    Whole-exome sequencing can establish diagnosis in atypical or less common
    genotypes, including MRAS-associated Noonan syndrome.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: MAXO:0009004
      label: clinical whole-exome sequencing
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a heterozygous MRAS c.203C>T
      (p.Thr68Ile) mutation...supporting the diagnosis of MRAS-associated
      Noonan syndrome.
    explanation: >-
      Demonstrates diagnostic utility of exome sequencing in genetically
      heterogeneous Noonan syndrome.
- name: Echocardiography
  description: >-
    Echocardiography is a key diagnostic assessment for structural defects and
    hypertrophic cardiomyopathy in Noonan syndrome.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: MAXO:0010203
      label: echocardiography
  evidence:
  - reference: PMID:41517739
    reference_title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Echocardiography demonstrated obstructive hypertrophic cardiomyopathy
      with vegetation located in the left ventricular outflow tract.
    explanation: >-
      Supports echocardiography as an essential modality for defining Noonan
      syndrome cardiac phenotype and complications.
differential_diagnoses:
- name: Cardiofaciocutaneous syndrome
  disease_term:
    preferred_term: cardiofaciocutaneous syndrome
    term:
      id: MONDO:0015280
      label: cardiofaciocutaneous syndrome
  description: >-
    Cardiofaciocutaneous syndrome is a RASopathy with substantial overlap in
    growth, dysmorphology, neurodevelopmental, and cardiac findings.
  distinguishing_features:
  - More often associated with BRAF-pathway variants than classic PTPN11-predominant Noonan syndrome.
  - Ectodermal/skin and hair abnormalities are often more prominent in CFC.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RASopathies are a heterogeneous group...presenting with overlapping
      features... Final diagnoses included...two with
      cardiofaciocutaneous syndrome (BRAF)...
    explanation: >-
      Demonstrates overlap requiring differential diagnosis, with BRAF genotype
      pattern helping separate CFC from classic Noonan syndrome.
- name: Costello syndrome
  disease_term:
    preferred_term: Costello syndrome
    term:
      id: MONDO:0009026
      label: Costello syndrome
  description: >-
    Costello syndrome is an overlapping RASopathy that can resemble Noonan
    syndrome in early referral contexts.
  distinguishing_features:
  - HRAS pathogenic variants support Costello syndrome rather than classic Noonan syndrome.
  - Relative burden of coarse facies, deep palmar/plantar creases, and tumor predisposition favors Costello syndrome.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included...one each with...Costello syndrome (HRAS)...
    explanation: >-
      Supports Costello syndrome as a practical molecular differential in
      suspected Noonan-spectrum patients.
- name: Neurofibromatosis type 1
  disease_term:
    preferred_term: neurofibromatosis type 1
    term:
      id: MONDO:0018975
      label: neurofibromatosis type 1
  description: >-
    NF1-related phenotypes can overlap with Noonan syndrome (including
    Neurofibromatosis-Noonan presentations) and require molecular distinction.
  distinguishing_features:
  - NF1 pathogenic variants and neurofibromatosis features (e.g., neurofibromas, cafe-au-lait patterning) support NF1-spectrum diagnosis.
  - Shared RAS-MAPK dysregulation can create overlapping craniofacial and growth findings.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Final diagnoses included...two with Neurofibromatosis-Noonan (NF1)...
    explanation: >-
      Confirms clinically relevant NS vs NF1-overlap differential diagnosis in
      molecularly evaluated RASopathy cohorts.
- name: Noonan syndrome with multiple lentigines
  disease_term:
    preferred_term: Noonan syndrome with multiple lentigines
    term:
      id: MONDO:0007893
      label: Noonan syndrome with multiple lentigines
  description: >-
    Noonan syndrome with multiple lentigines shares core Noonan features but is
    separated by pigmentation pattern and genotype-phenotype context.
  distinguishing_features:
  - Diffuse lentigines and characteristic pigmentary findings support NSML over classic Noonan syndrome.
  - PTPN11 variant context and clinical trajectory help separate NSML from other Noonan subtypes.
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two with Noonan syndrome with multiple lentigines (both with variants in PTPN11)
    explanation: >-
      Supports NSML as a frequent practical differential diagnosis in
      Noonan-spectrum genomic evaluation.
treatments:
- name: Growth Hormone Therapy
  description: >-
    Recombinant human growth hormone (rhGH) is FDA-approved for treatment of short
    stature
    in Noonan syndrome. Can improve final adult height by approximately 1 standard
    deviation.
  treatment_term:
    preferred_term: human growth hormone replacement therapy
    term:
      id: MAXO:0000780
      label: human growth hormone replacement therapy
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41577878
    reference_title: "Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Large multicenter cohort evidence supports growth hormone therapy for
      short stature in Noonan syndrome spectrum disorders.
- name: Cardiac Surgical Intervention
  description: >-
    Balloon valvuloplasty or surgical valvotomy for pulmonary valve stenosis;
    septal myectomy or alcohol ablation for severe hypertrophic cardiomyopathy.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_phenotypes:
  - preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:41718520
    reference_title: "Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was treated with trametinib to improve cardiac hypertrophy and
      then underwent successful surgical closure of the atrial septal defect.
    explanation: >-
      Demonstrates feasibility of staged surgical management for structural
      heart disease in severe Noonan-associated cardiomyopathy.
- name: MEK Inhibitor Therapy
  description: >-
    Trametinib (MEK1/2 inhibitor) has shown promising results in case reports
    for treatment-refractory hypertrophic cardiomyopathy and lymphatic complications.
    MEK inhibition can reverse cardiomyocyte hypertrophy in animal models.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  - preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  notes: >-
    Emerging therapy based on case reports; controlled trials are needed.
    Typical pediatric dosing 0.01-0.025 mg/kg/day.
  evidence:
  - reference: PMID:41718520
    reference_title: "Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trametinib, an MEK inhibitor that attenuates abnormal signaling in the
      RAS/MAPK pathway, has been shown to improve NS-HCM outcomes.
    explanation: >-
      Supports MEK inhibition as a targeted strategy for severe
      Noonan-associated hypertrophic cardiomyopathy in early clinical use.
- name: Early Intervention Services
  description: >-
    Developmental support including speech therapy, physical therapy, occupational
    therapy, and special education services for developmental delays and learning
    disabilities.
  treatment_term:
    preferred_term: early intervention services
    term:
      id: MAXO:0009101
      label: early intervention services
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301303
    reference_title: "Noonan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental disabilities are addressed by early intervention programs
      and individualized education strategies.
    explanation: >-
      GeneReviews supports early intervention services as standard management
      for developmental disability in Noonan syndrome.
- name: Speech Therapy
  description: >-
    Speech and language therapy for articulation difficulties and language delays.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physiotherapy and/or speech therapy should be offered if indicated.
    explanation: >-
      Supports speech therapy as recommended supportive care in Noonan syndrome
      management.
- name: Physical Therapy
  description: >-
    Physical therapy to address motor delays and hypotonia common in Noonan syndrome.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:17222357
    reference_title: "Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physiotherapy and/or speech therapy should be offered if indicated.
    explanation: >-
      Supports physiotherapy (physical therapy) for motor/developmental support
      in Noonan syndrome.
definitions:
- name: Noonan syndrome molecular-clinical case definition
  definition_type: CASE_DEFINITION
  description: >-
    Noonan syndrome is defined as a RASopathy with compatible craniofacial,
    growth, developmental, and cardiovascular phenotype supported by molecular
    evidence in a causative RAS-MAPK pathway gene.
  scope: Clinical genetics and pediatric cardiology evaluation for suspected RASopathy
  evidence:
  - reference: PMID:41675685
    reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Cohort evidence supports a combined phenotype-plus-genotype approach for
      Noonan syndrome case definition in modern practice.
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
    evidence:
    - reference: PMID:41675685
      reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        Supports Noonan syndrome as an inherited RAS-MAPK pathway disorder
        within hereditary disease classification.
  - classification_value: cardiovascular disorder
    evidence:
    - reference: PMID:41675685
      reference_title: "Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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%).
      explanation: >-
        Supports cardiovascular disorder classification based on substantial
        burden of congenital and structural heart disease in Noonan-spectrum
        patients.
experimental_models:
- name: Noonan syndrome cortical organoid model
  description: >-
    Human Noonan syndrome induced pluripotent stem cell-derived cortical organoids
    with matched corrected controls used to study cortical layer specification and
    neuronal connectivity phenotypes.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  conditions:
  - Noonan syndrome
  - isogenic corrected control
  cell_source: Noonan syndrome induced pluripotent stem cells differentiated into cortical organoids
  culture_system: Three-dimensional cortical organoid time-course culture
  publication: PMID:36430334
  findings:
  - statement: Noonan cortical organoids show abnormal excitatory-neuron composition, cortical-layer identity, and reduced synaptic connectivity
    evidence:
    - reference: PMID:36430334
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."
      explanation: Establishes that NS-derived cortical organoids capture disease-relevant neurodevelopmental abnormalities.
    - reference: PMID:36430334
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS."
      explanation: Supports mechanistic alignment of the organoid model with neurological manifestations in Noonan syndrome.
  evidence:
  - reference: PMID:36430334
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs)."
    explanation: Supports a first-class cortical organoid model for Noonan syndrome.
  notes: >-
    Replaces the prior implicit reliance on GEO-only cross-reference with a
    direct disease-model anchor publication.
- name: Noonan syndrome iPSC-cardiomyocyte model
  description: >-
    Patient-derived Noonan syndrome induced pluripotent stem cell cardiomyocytes
    modeling childhood-onset cardiomyopathy and RAF1/PTPN11-driven transcriptional
    dysregulation with matched corrected or comparator controls.
  experimental_model_type: IPSC_DERIVED_MODEL
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  conditions:
  - Noonan syndrome-associated cardiomyopathy
  - RAF1 S257L/+ Noonan syndrome
  - PTPN11N308S/+ Noonan syndrome
  cell_source: Patient-derived induced pluripotent stem cell-derived cardiomyocytes with isogenic or non-diseased controls
  culture_system: Two-dimensional iPSC-cardiomyocyte differentiation with transcriptomic and pathway-perturbation readouts
  publication: PMID:34988410
  findings:
  - statement: Noonan iPSC-cardiomyocytes capture cardiomyopathy-linked cell-cycle and signaling defects in a genotype-resolved human cardiac model
    evidence:
    - reference: PMID:34988410
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, through analysis of sarcomeric myosin conformational states,
        histopathology, and gene expression in left ventricular myocardial tissue
        from NS-CM, HCM, and normal hearts complemented with disease modeling in
        cardiomyocytes differentiated from patient-derived PTPN11 N308S/+
        induced pluripotent stem cells, we demonstrate distinct disease
        phenotypes between NS-CM and HCM and uncover cell cycle defects as a
        potential driver of NS-CM.
      explanation: Supports patient-derived iPSC-cardiomyocytes as a disease-relevant Noonan cardiomyopathy model.
    - reference: PMID:31163979
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        METHODS: We used patient-derived RAF1S257L/+ and CRISPR-Cas9-generated
        isogenic control inducible pluripotent stem cell (iPSC)-derived
        cardiomyocytes to model NS RAF1-associated HCM and to further delineate
        the molecular mechanisms underlying the disease.
      explanation: Supports mutation-specific mechanistic modeling in Noonan iPSC-cardiomyocytes.
  evidence:
  - reference: PMID:34988410
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, through analysis of sarcomeric myosin conformational states,
      histopathology, and gene expression in left ventricular myocardial tissue
      from NS-CM, HCM, and normal hearts complemented with disease modeling in
      cardiomyocytes differentiated from patient-derived PTPN11 N308S/+
      induced pluripotent stem cells, we demonstrate distinct disease
      phenotypes between NS-CM and HCM and uncover cell cycle defects as a
      potential driver of NS-CM.
    explanation: Supports this as a first-class Noonan iPSC-cardiomyocyte model entry.
  notes: >-
    Groups the two strongest existing dismech cardiac experimental-model resources under a single
    disease-level experimental-model concept.
datasets:
- accession: geo:GSE213798
  title: Aberrant cortical layer development of brain organoids developed from Noonan syndrome-iPSCs
  description: >-
    Human induced pluripotent stem cell-derived cortical organoid transcriptomic
    resource profiling neurodevelopmental abnormalities in Noonan syndrome and
    matched isogenic corrected controls across developmental time points.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 9
  conditions:
  - Noonan syndrome iPSC-derived cortical organoids
  - isogenic corrected control cortical organoids
  platform: GPL24676
  publication: GEO:GSE213798
  evidence:
  - reference: GEO:GSE213798
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      single-cell transcriptomic analysis represented increment of EN population
      and overexpression of cortical layer markers in NS-COs.
    explanation: >-
      Provides disease-relevant human neurodevelopmental transcriptomic evidence
      for cortical-layer and neuronal-connectivity abnormalities in Noonan syndrome.
- accession: geo:GSE188238
  title: Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome
  description: >-
    Bulk transcriptomic dataset integrating left ventricular myocardial tissue
    and patient-derived PTPN11N308S/+ iPSC-cardiomyocyte modeling to define
    mechanisms of Noonan syndrome-associated childhood cardiomyopathy.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 11
  conditions:
  - Noonan syndrome-associated cardiomyopathy
  - sarcomeric hypertrophic cardiomyopathy comparator
  - non-diseased cardiac control
  platform: GPL20301
  publication: PMID:34988410
  evidence:
  - reference: GEO:GSE188238
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gene expression in left ventricular myocardial tissue from NS-CM, HCM and
      normal hearts
    explanation: >-
      Supports human myocardial tissue evidence for transcriptomic distinctions
      between Noonan cardiomyopathy and sarcomeric HCM.
  - reference: GEO:GSE188238
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      complemented with disease modeling in cardiomyocytes differentiated from
      patient-derived PTPN11N308S/+ induced pluripotent stem cells
    explanation: >-
      Supports complementary in vitro iPSC-cardiomyocyte modeling of Noonan
      cardiomyopathy mechanisms.
- accession: geo:GSE131069
  title: Differential gene expression in human RAF1 S257L/+ and isogenic corrected iPSC-derived cardiomyocytes
  description: >-
    Bulk RNA-seq dataset from human RAF1 S257L/+ Noonan syndrome iPSC-derived
    cardiomyocytes and isogenic corrected controls, including pathway-perturbation
    conditions targeting MEK/ERK signaling.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 12
  conditions:
  - RAF1 S257L/+ Noonan syndrome iPSC-derived cardiomyocytes
  - isogenic corrected control cardiomyocytes
  - MEK/ERK pathway inhibition perturbation
  platform: GPL23934
  publication: PMID:31163979
  evidence:
  - reference: GEO:GSE131069
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hence, to gain insights into the transcriptional alterations induced by
      the NS-associated RAF1S257L/+ mutation in human iPSC-derived
      cardiomyocytes, we performed quantitative transcriptome profiling by
      RNA-sequencing.
    explanation: >-
      Supports a mutation-specific human cardiomyocyte transcriptomic resource
      linking RAF1-driven signaling dysregulation to Noonan cardiac phenotypes.
references:
- reference: DOI:10.1159/000545410
  title: Genotype-Phenotype Analysis and New Clinical Findings in a Series of
    24 Patients Presenting with Noonan Syndrome and Related Disorders
  findings: []
- reference: DOI:10.1007/s00431-026-06764-2
  title: Noonan syndrome spectrum disorders in real life patient characteristics
    and response to growth hormone therapy in a genetically defined single-country
    multicenter cohort
  findings: []
- reference: DOI:10.1002/ajmga.70060
  title: 'Neuropathic Pain and Enlarged Nerves in Adult Noonan Syndrome and
    Noonan Syndrome With Multiple Lentigines: Health-Related Quality of Life
    and Neurologic Symptoms'
  findings: []
- reference: DOI:10.1097/MD.0000000000046340
  title: 'Novel characterization of MRAS mutation-associated Noonan syndrome:
    Mild adult-onset hypertrophic cardiomyopathy combined with infective
    endocarditis: A case report'
  findings: []
- reference: DOI:10.1016/j.jaccas.2026.107006
  title: Atrial Septal Defect Surgical Closure Following Trametinib Utilization
    in Noonan Syndrome-Associated Hypertrophic Cardiomyopathy
  findings: []
- reference: DOI:10.1007/s00431-023-05263-y
  title: Novel therapeutic perspectives in Noonan syndrome and RASopathies
  findings: []
- reference: DOI:10.1007/s10557-022-07324-0
  title: An Assessment of the Therapeutic Landscape for the Treatment of Heart
    Disease in the RASopathies
  findings: []
- reference: DOI:10.1016/j.jacc.2019.01.066
  title: Hypertrophic Cardiomyopathy in Noonan Syndrome
    Treated by MEK-Inhibition
  findings: []
- reference: DOI:10.1126/sciadv.adf4766
  title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a
    therapeutic target in Noonan syndrome–associated cardiac hypertrophy
  findings: []
- reference: DOI:10.1158/1078-0432.ccr-24-1611
  title: Update on Pediatric Cancer Surveillance Recommendations for Patients
    with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello
    Syndrome, and Related RASopathies
  findings: []
- reference: DOI:10.1172/jci.insight.182382
  title: Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation
    induces Noonan syndrome–like phenotypes in mice
  findings: []
- reference: DOI:10.1172/jci172839
  title: 'Central conducting lymphatic anomaly: from bench to bedside'
  findings: []
- reference: DOI:10.3389/fped.2025.1475143
  title: Trametinib as a targeted treatment in cardiac and lymphatic
    presentations of Noonan syndrome
  findings: []
- reference: DOI:10.3390/children11111342
  title: 'Refractory Chylothorax and Ventricular Hypertrophy Treated with Trametinib
    in a Patient with Noonan Syndrome: 18-Month Follow-Up'
  findings: []
- reference: DOI:10.3390/genes15081015
  title: Cardiac Phenotype and Gene Mutations in RASopathies
  findings: []
- reference: DOI:10.3390/ijms26083515
  title: 'Update on the Clinical and Molecular Characterization of Noonan Syndrome
    and Other RASopathies: A Retrospective Study and Systematic Review'
  findings: []
- reference: DOI:10.3390/life14060731
  title: 'Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies:
    A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib
    and Selumetinib'
  findings: []