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Noonan Syndrome

Genetic MONDO:0018997 RASopathy Congenital Heart Disease

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.

0
Mappings
0
Definitions
1
Inheritance
8
Pathophysiology
0
Histopathology
16
Phenotypes
6
Genes
6
Treatments
2
Subtypes
0
Differentials
0
Datasets
0
Trials
👪

Inheritance

1
Autosomal Dominant
Most cases follow autosomal dominant inheritance with variable expressivity. Approximately 30-75% of cases are de novo mutations.
◆

Subtypes

2
Noonan Syndrome 1 (PTPN11-related) Not Yet Curated MONDO:0008104
Most common form caused by PTPN11 mutations, accounting for approximately 50% of cases.
Noonan Syndrome with Multiple Lentigines Not Yet Curated MONDO:0007893
Formerly known as LEOPARD syndrome, characterized by lentigines and hypertrophic cardiomyopathy.
⚙

Pathophysiology

8
SHP2 Gain-of-Function Activation
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.
protein tyrosine phosphatase activity link
Show evidence (1 reference)
PMID:11992261 SUPPORT Human Clinical
"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"
PTPN11 mutations cluster at the N-SH2/PTP interface, disrupting autoinhibition.
SOS1-Mediated RAS-GTP Loading
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.
Ras guanyl-nucleotide exchange factor activity link
Show evidence (1 reference)
PMID:17143285 SUPPORT Human Clinical
"Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation."
SOS1 mutations are gain-of-function, enhancing RAS-GTP loading.
RAF1 Kinase Hyperactivation
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.
protein serine/threonine kinase activity link
Show evidence (1 reference)
PMID:17603483 SUPPORT Human Clinical
"Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding."
RAF1 mutations disrupt autoinhibitory 14-3-3 binding.
RIT1-Mediated RAF Recruitment
RIT1 gain-of-function mutations cause aberrant membrane localization and RAF recruitment, bypassing normal RAS regulation and driving excessive MAPK pathway activation.
Ras protein signal transduction link
Show evidence (1 reference)
PMID:23791108 SUPPORT Human Clinical
"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."
RIT1 gain-of-function mutations drive aberrant MAPK signaling.
LZTR1-Mediated RAS Proteostasis Defect
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.
protein ubiquitination link regulation of proteolysis link
ERK Cascade Hyperactivation
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.
MAPK cascade link regulation of ERK1 and ERK2 cascade link
Cardiac Valve Morphogenesis Defects
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.
endocardial cell link
endocardial cushion to mesenchymal transition link heart valve morphogenesis link
pulmonary valve link heart link
Show evidence (1 reference)
PMID:11992261 SUPPORT Human Clinical
"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)"
Demonstrates that pulmonary valve stenosis is highly associated with PTPN11 mutations in Noonan syndrome.
Cardiomyocyte Hypertrophy
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.
cardiomyocyte link
cardiac muscle hypertrophy link
heart link
Show evidence (2 references)
PMID:17603483 SUPPORT Human Clinical
"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."
Demonstrates strong association between RAF1 mutations and HCM, implicating the kinase pathway in cardiac hypertrophy.
PMID:23791108 SUPPORT Human Clinical
"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."
RIT1 mutations are strongly associated with hypertrophic cardiomyopathy.
⬡

Causal Graph

graph LR
    RIT1_Mediated_RAF_Recruitment["RIT1-Mediated RAF Recruitment"]
    ERK_Cascade_Hyperactivation["ERK Cascade Hyperactivation"]
    LZTR1_Mediated_RAS_Proteostasis_Defect["LZTR1-Mediated RAS Proteostasis Defect"]
    Cardiomyocyte_Hypertrophy["Cardiomyocyte Hypertrophy"]
    SHP2_Gain_of_Function_Activation["SHP2 Gain-of-Function Activation"]
    SOS1_Mediated_RAS_GTP_Loading["SOS1-Mediated RAS-GTP Loading"]
    Cardiac_Valve_Morphogenesis_Defects["Cardiac Valve Morphogenesis Defects"]
    RAF1_Kinase_Hyperactivation["RAF1 Kinase Hyperactivation"]

    SHP2_Gain_of_Function_Activation --> ERK_Cascade_Hyperactivation
    SOS1_Mediated_RAS_GTP_Loading --> ERK_Cascade_Hyperactivation
    RAF1_Kinase_Hyperactivation --> ERK_Cascade_Hyperactivation
    RAF1_Kinase_Hyperactivation --> Cardiomyocyte_Hypertrophy
    RIT1_Mediated_RAF_Recruitment --> ERK_Cascade_Hyperactivation
    RIT1_Mediated_RAF_Recruitment --> Cardiomyocyte_Hypertrophy
    LZTR1_Mediated_RAS_Proteostasis_Defect --> ERK_Cascade_Hyperactivation
    ERK_Cascade_Hyperactivation --> Cardiac_Valve_Morphogenesis_Defects
    ERK_Cascade_Hyperactivation --> Cardiomyocyte_Hypertrophy

    style RIT1_Mediated_RAF_Recruitment fill:#dbeafe
    style ERK_Cascade_Hyperactivation fill:#dbeafe
    style LZTR1_Mediated_RAS_Proteostasis_Defect fill:#dbeafe
    style Cardiomyocyte_Hypertrophy fill:#dbeafe
    style SHP2_Gain_of_Function_Activation fill:#dbeafe
    style SOS1_Mediated_RAS_GTP_Loading fill:#dbeafe
    style Cardiac_Valve_Morphogenesis_Defects fill:#dbeafe
    style RAF1_Kinase_Hyperactivation fill:#dbeafe
●

Phenotypes

16
Blood(1) Cardiovascular(3) Digestive(1) Ear(1) Eye(2) Genitourinary(1) Head and Neck(2) Metabolism(1) Musculoskeletal(1) Nervous System(2) Growth(1)
Blood 1
Bruising Susceptibility FREQUENT Bruising susceptibility (HP:0000978)
Cardiovascular 3
Pulmonary Valve Stenosis FREQUENT Pulmonic stenosis (HP:0001642)
Show evidence (1 reference)
PMID:11992261 SUPPORT Human Clinical
"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)"
Confirms high prevalence of pulmonary stenosis in Noonan syndrome, especially with PTPN11 mutations.
Hypertrophic Cardiomyopathy FREQUENT Hypertrophic cardiomyopathy (HP:0001639)
Show evidence (3 references)
PMID:17603483 SUPPORT Human Clinical
"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."
RAF1 mutations are strongly associated with HCM.
PMID:23791108 SUPPORT Human Clinical
"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."
RIT1 mutations confer high risk of hypertrophic cardiomyopathy.
PMID:11992261 SUPPORT Human Clinical
"hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005)"
PTPN11 mutations are associated with lower HCM risk compared to other NS genes.
Atrial Septal Defect OCCASIONAL Atrial septal defect (HP:0001631)
Digestive 1
Feeding Difficulties in Infancy FREQUENT Feeding difficulties in infancy (HP:0008872)
Ear 1
Low-set Ears VERY_FREQUENT Low-set ears (HP:0000369)
Eye 2
Hypertelorism VERY_FREQUENT Hypertelorism (HP:0000316)
Ptosis FREQUENT Ptosis (HP:0000508)
Genitourinary 1
Cryptorchidism FREQUENT Cryptorchidism (HP:0000028)
Show evidence (1 reference)
PMID:11992261 SUPPORT Human Clinical
"The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."
Cryptorchidism is recognized as a common feature across Noonan syndrome genotypes.
Head and Neck 2
Downslanted Palpebral Fissures VERY_FREQUENT Downslanted palpebral fissures (HP:0000494)
Webbed Neck FREQUENT Webbed neck (HP:0000465)
Metabolism 1
Lymphedema OCCASIONAL Lymphedema (HP:0001004)
Musculoskeletal 1
Pectus Deformity FREQUENT Pectus excavatum (HP:0000767)
Show evidence (1 reference)
PMID:11992261 SUPPORT Human Clinical
"The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."
Pectus deformity is recognized as a common feature across genotypes.
Nervous System 2
Global Developmental Delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (1 reference)
PMID:11992261 SUPPORT Human Clinical
"The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups."
Developmental delay is a recognized feature across Noonan syndrome genotypes.
Mild Intellectual Disability OCCASIONAL Mild intellectual disability (HP:0001256)
Growth 1
Short Stature VERY_FREQUENT Short stature (HP:0004322)
🧬

Genetic Associations

6
PTPN11 (Pathogenic Variants)
Show evidence (1 reference)
PMID:11992261 SUPPORT Human Clinical
"Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS."
Confirms PTPN11 mutations account for approximately half of Noonan syndrome cases.
SOS1 (Pathogenic Variants)
Show evidence (1 reference)
PMID:17143285 SUPPORT Human Clinical
"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."
SOS1 mutations are a significant cause of PTPN11-negative Noonan syndrome.
RAF1 (Pathogenic Variants)
Show evidence (1 reference)
PMID:17603483 SUPPORT Human Clinical
"18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals)...have missense mutations in RAF1"
RAF1 mutations account for approximately 3% of Noonan syndrome.
RIT1 (Pathogenic Variants)
Show evidence (1 reference)
PMID:23791108 SUPPORT Human Clinical
"we identified a total of nine missense, nonsynonymous mutations in RIT1...in 17 of 180 individuals (9%) with Noonan syndrome"
RIT1 mutations account for approximately 9% of cases without mutations in other known genes.
KRAS (Pathogenic Variants)
Show evidence (1 reference)
PMID:17143285 SUPPORT Human Clinical
"KRAS mutations account for <5% of cases of Noonan syndrome"
KRAS mutations are a rare cause of Noonan syndrome.
LZTR1 (Pathogenic Variants)
💊

Treatments

6
Growth Hormone Therapy MAXO:0000780
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.
Target Phenotypes: Short stature ↗
Cardiac Surgical Intervention MAXO:0000004
Balloon valvuloplasty or surgical valvotomy for pulmonary valve stenosis; septal myectomy or alcohol ablation for severe hypertrophic cardiomyopathy.
Target Phenotypes: Pulmonic stenosis ↗ Hypertrophic cardiomyopathy ↗
MEK Inhibitor Therapy MAXO:0000058
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.
Target Phenotypes: Hypertrophic cardiomyopathy ↗ Lymphedema ↗
Early Intervention Services MAXO:0009101
Developmental support including speech therapy, physical therapy, occupational therapy, and special education services for developmental delays and learning disabilities.
Target Phenotypes: Global developmental delay ↗
Speech Therapy MAXO:0000930
Speech and language therapy for articulation difficulties and language delays.
Target Phenotypes: Global developmental delay ↗
Physical Therapy MAXO:0000011
Physical therapy to address motor delays and hypotonia common in Noonan syndrome.
Target Phenotypes: Global developmental delay ↗
{ }

Source YAML

click to show 
name: Noonan Syndrome
creation_date: '2026-02-04T01:40:11Z'
updated_date: '2026-02-17T21:53:14Z'
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.
- 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.
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.
  biological_processes:
  - 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:11992261
    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.
  biological_processes:
  - preferred_term: Ras guanyl-nucleotide exchange factor activity
    term:
      id: GO:0005088
      label: Ras 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
    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.
  biological_processes:
  - 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.
  - target: Cardiomyocyte Hypertrophy
    description: RAF1 kinase hyperactivation is strongly associated with
      hypertrophic cardiomyopathy development.
  evidence:
  - reference: PMID:17603483
    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.
  - target: Cardiomyocyte Hypertrophy
    description: RIT1 mutations are strongly associated with hypertrophic
      cardiomyopathy.
  evidence:
  - reference: PMID:23791108
    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.

- 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.
  - target: Cardiomyocyte Hypertrophy
    description: Sustained ERK signaling promotes hypertrophic growth and fetal
      gene reprogramming.

- 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: endocardial cushion to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition involved in endocardial
        cushion formation
  - 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
    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.
- 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
    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
    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.
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
- 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
- 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
- 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
- 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
- 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
    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
    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
    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
    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
- 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
- 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
    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
    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
- 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
- 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
    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
- 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
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
    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
    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
    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
    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
    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.
inheritance:
- name: Autosomal Dominant
  description: Most cases follow autosomal dominant inheritance with variable
    expressivity. Approximately 30-75% of cases are de novo mutations.
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
- 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
- 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.
- 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
- 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
- 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
datasets:
references:
- 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: []