Noonan Syndrome (NS)
Summary
Noonan Syndrome is an Autosomal Dominant multisystem genetic disorder caused by dysregulation of the RAS-MAPK signal transduction pathway. It is characterized by a distinctive facial phenotype, short stature, congenital heart defects, and bleeding abnormalities. It is the most common single-gene cause of congenital heart disease and belongs to a family of disorders known as "RASopathies" (including Neurofibromatosis Type 1 and Costello Syndrome).
Key Facts
- Definition: A RASopathy syndrome characterized by hypertelorism, downward slanting eyes, low-set ears, short stature, and cardiac defects.
- Prevalence: 1 in 1000 to 1 in 2500 live births (Common).
- Genetics: PTPN11 (50% of cases) is the most common gene. Also SOS1, RAF1, RIT1. Inheritance is Autosomal Dominant, but 50% are de novo mutations.
- Key Phenomenology: "Turner Syndrome features but in both sexes". (Webbed neck, short stature, chest deformity).
- Key Cardiac Findings: Pulmonary Stenosis (PS) (50-60%) and Hypertrophic Cardiomyopathy (HCM) (20%).
- Key Investigation: Molecular Genetic Testing (Next Gen Sequencing panel) and Echocardiogram.
Clinical Pearls
The "Male Turner" Myth: Historically called "Male Turner Syndrome" because the appearance (webbed neck, short stature) mimics Turner Syndrome (45,X). However, the cardiac lesions differ: Turner's has Coarctation/Bicuspid Aortic Valve (Left side), while Noonan's has Pulmonary Stenosis (Right side).
The Clotting Trap: Up to 50% of Noonan patients have a bleeding diathesis (Factor XI, VIII, or XII deficiency) or platelet dysfunction. Never send a Noonan child to surgery (e.g., tonsillectomy for OSA) without a Coagulation Screen + Von Willebrand Screen first. They can bleed catastrophically.
Genotype-Phenotype Correlation: It matters which gene is broken.
- PTPN11: Classic Noonan. Pulmonary Stenosis. Normal IQ.
- RAF1: High risk (95%) of severe Hypertrophic Cardiomyopathy.
- SOS1: Normal IQ, minimal cardiac issues, prominent skin features.
Why This Matters Clinically
Noonan Syndrome is often diagnosed late. A child presenting with "clumsiness" and "short stature" at age 8 may have missed years of potential Growth Hormone therapy. More critically, the HCM risk carries a sudden death risk that requires lifelong surveillance.
Incidence & Prevalence
- General: 1:1,000 - 1:2,500. This makes it as common as Down Syndrome in some cohorts.
- Sex: Equal M:F ratio (Autosomal Dominant).
Demographics and Genetics
- Inheritance: Autosomal Dominant with variable expressivity.
- De Novo Rate: High (~50%). Unaffected parents should likely have no recurrence risk for other children, but the affected child has a 50% chance of passing it on.
- Parental Age: Associated with widespread advanced paternal age (paternal origin of mutation in sporadic cases).
Risk Factors
The RAS-MAPK Pathway: Noonan Syndrome is a disorder of "Signal Transduction". The RAS genes are usually involved in cell division (mitosis). In Noonan's, the mutations are "Gain of Function" (the switch is stuck ON). This causes cells to divide/grow dysregulatedly (hence the overgrowth of heart muscle in HCM and risk of leukemia).
Genotype-Phenotype Correlations (Detailed)
Predicting the clinical course based on the gene.
| Gene | Prevalence | Cardiac Risk | Intellectual | Skin/Hair |
|---|---|---|---|---|
| PTPN11 | 50% | PS (60%), HCM (6%) | Normal / Mild | Classic features. Easy bruising. |
| SOS1 | 10% | PS (60%) | Normal IQ | Keratosis Pilaris (Rough skin). Curly hair. |
| RAF1 | 10% | HCM (75%) | Mild delay | Multiple nevi (moles). |
| RIT1 | 5% | HCM (70%) | Moderate | Lymphatic issues (Hydrops, Chylothorax). |
| KRAS | 2% | Variable | Moderate/Severe | Craniosynostosis (skull shape). |
| SHOC2 | <1% | PS / Septal defects | Moderate | Loose Anagen Hair (Hair pulls out easily). |
Mechanism of Defects
- Cardiac: Valvular dysplasia (PS) results from overgrowth of valve cushions. Myocardial hypertrophy (HCM) results from over-signaling of growth pathways in myocytes.
- Growth: Post-receptor signal resistance to Growth Hormone (GH). They make GH but respond poorly to it (IGF-1 is low).
- Heme: Platelet function defects + Factor deficiencies are distinctive but mechanism unclear.
The RASopathy Spectrum: Differential Diagnosis
Noonan Syndrome is the "Prototypic" RASopathy, but others exist on the same pathway.
| Condition | Gene(s) | Key Distinguishing Features | Cancer Risk |
|---|---|---|---|
| Noonan Syndrome | PTPN11, SOS1, RAF1 | PS, Short Stature, Normal-ish IQ. | Low (JMML). |
| Neurofibromatosis Type 1 | NF1 | Café-au-lait spots, Neurofibromas, Lisch Nodules. | Moderate (Glioma). |
| Costello Syndrome | HRAS | Coarse face, deep palmar creases, papillomas (warts). | High (Rhabdomyosarcoma, Bladder Ca). |
| CFC Syndrome | BRAF, MEK1/2 | Severe Intellectual Disability. Ectodermal (Skin/Hair) defects. Ichthyosis. | Low. |
| Noonan with Multiple Lentigines | PTPN11 | Formerly "LEOPARD" Syndrome. Thousands of black freckles (Lentigines). Deafness. | Low. |
Clinical Pearl: If a child looks like Noonan's but has severe skin issues (eczema/ichthyosis) and severe developmental delay, think CFC.
Facial Features (The Gestalt)
Changes with age.
Newborn/Infant:
Child/Adolescent:
Systemic Features
Red Flags
[!CAUTION] Red Flag: "The Quiet Heart"
- Unlike Pulmonary Stenosis which has a loud ejection murmur, Hypertrophic Cardiomyopathy (HCM) can be silent until arrest.
- Action: Every Noonan child needs an ECG and Echo at diagnosis and every 3-5 years, even if asymptomatic.
Structured Approach
General:
- Height/Weight: Plot on specific Noonan Syndrome Growth Charts.
- Neck: Look for webbing or low posterior hairline.
Face:
- Eyes: Check for Ptosis and spacing.
- Ears: Check position.
Chest:
- Deformity: Shield chest? Pectus?
- Murmurs:
- Ejection Systolic: Upper Left Sternal Edge -> Pulmonary Stenosis.
- Pansystolic: Lower Left Sternal Edge -> VSD.
- Quiet: Check for HCM (Apical heave?).
Abdomen:
- Hepatosplenomegaly: Can occur in infants (Myeloproliferative disorder risk).
- Males: Check testes.
Management Algorithm
(See Section 2 for ASCII)
Cardiac Management (Deep Dive)
1. Pulmonary Stenosis (PS)
- Pathology: Dysplastic valve. Thick, fleshy leaflets (unlike the thin fused leaflets of non-syndromic PS).
- Treatment Gradient:
- Mild (<40mmHg): Watch and wait.
- Moderate (40-60mmHg): Consider intervention if symptomatic.
- Severe (>60mmHg): Intervene.
- Intervention:
- Balloon Valvuloplasty: First line, but less successful in dysplastic valves (recoil).
- Surgical Valvotomy: Often required.
2. Hypertrophic Cardiomyopathy (HCM)
- Pathology: Asymmetric septal hypertrophy causing LVOT (Left Ventricular Outflow Tract) obstruction.
- Gene Link: Strong association with RAF1 and RIT1.
- Management:
- Beta Blockers (Propranolol/Atenolol): Reduce heart rate, increase filling time, decrease obstruction.
- Disopyramide: Anti-arrhythmic with negative inotropic effect.
- Myectomy: Surgical removal of muscle septum (Morrow procedure) for severe drug-resistant obstruction.
- Cardiac Transplant: End stage.
Endocrine Management (Growth)
Short stature is the most common reason for referral.
Growth Hormone (rhGH) Therapy
- Rationale: Noonan patients have partial GH insensitivity (Neurosecretory dysfunction). They produce GH, but their IGF-1 response is blunted.
- Indication: Height < -2.25 SD (SDS).
- Start Age: Typically 4-5 years old.
- Dosing: Higher doses required (up to 0.066 mg/kg/day) compared to GHD.
- Monitoring:
- IGF-1 Levels: Titrate to upper normal limits.
- Echo: Monitor for HCM hypertrophy (Theoretical risk).
- Scoliosis: Rapid growth can worsen curve.
- Outcome: Gain of 1.5 - 1.8 SD in height (approx 9-13cm).
Puberty: Usually delayed by 2 years. Males may need Testosterone for microphallus/delayed puberty.
Hematology Management
- Bleeding History: Ask about bruising, nosebleeds.
- Screening: PT, aPTT, Factor XI, VIII, XII, vWF.
- Treatment:
- Tranexamic Acid (for minor procedures).
- DDAVP (Desmopressin) or FFP (Fresh Frozen Plasma) for major surgery.
- Alert: Avoid Aspirin/NSAIDs if platelet defect suspected.
Anaesthetic & Surgical Considerations
Noonan patients are "High Risk" candidates for anaesthesia.
- Airway Management:
- Difficult Intubation: Micrognathia (small jaw) + Short Webbed Neck + Limited neck extension.
- Action: Have videolaryngoscopy available.
- Cardiac Risk:
- Pulmonary Stenosis: Avoid hypotension (Right heart depends on preload).
- HCM: Critical Risk. Avoid inotropes (worsens obstruction). Maintain preload. Avoid tachycardia.
- Action: Cardiology clearance mandatory pre-op.
- Bleeding Risk:
- Factor XI deficiency is unpredictable. PT/APTT may be normal but child still bleeds.
- Action: Hematology plan (Transexamic acid / DDAVP) in place.
- Lymphatic Risk:
- High risk of postoperative chylothorax / lymphedema after thoracic surgery.
Longitudinal Care Checklist
| Age Group | Focus Area | Action Items |
|---|---|---|
| Infancy (0-1y) | Heart & Feeding | Echo at diagnosis. Manage failure to thrive (Calorie supplements). check renal US. |
| Toddler (1-3y) | Development | Speech Therapy referral. Physio for hypotonia. Orchiopexy if testes undescended. |
| Preschool (3-5y) | Growth & Behavior | Endocrine referral for Growth Hormone? Pre-school visuospatial assessment. Coagulation screen pre-tonsillectomy. |
| School (5-12y) | Learning | Educational Psychology assessment. Annual Vision/Hearing check. Echo every 3-5 years if mild/normal. |
| Adolescence (12-18y) | Puberty & Transition | Monitor puberty delay. Transition to Adult Congenital Heart Disease (ACHD) services. Genetic counselling. |
Learning and Development
- Motor Delay: Clumsiness/hypotonia is common (Physiotherapy).
- Cognition:
- Mean IQ is usually normal (85-100), but skewed lower than siblings.
- Specific deficit in Visual-Spatial processing.
- 20-30% require Special Education support.
- PTPN11 mutations usually have better cognitive outcomes than KRAS.
Malignancy Risk
Because RAS is a pro-oncogene pathway.
- JMML (Juvenile Myelomonocytic Leukemia): Rare leukemia in infancy.
- Risk: 8-fold increased risk of childhood cancer.
- Screening: check spleen size and FBC if unwell.
Lymphatic Issues
- Pathology: Dysplasia of the lymphatic vessels (lymphangiectasia).
- Presentation:
- Peripheral: Lymphedema of feet (dorsal pedal edema) - often the first sign in neonates.
- Pulmonary: Chylothorax (fluid in lung). Can be spontaneous or post-op.
- Gut: Protein Losing Enteropathy (Low albumin, edema).
- Management:
- Diet: MCT (Medium Chain Triglyceride) Diet. MCTs bypass the lymphatic system and are absorbed directly into the portal vein.
- Medical: Octreotide (Somatostatin analogue) to reduce lymph flow.
- Surgical: Thoracic Duct Ligation (Difficult and often fails).
Genituourinary
- Cryptorchidism -> Infertility risk. Orchiopexy recommended by age 1-2 years.
| Condition | Distinguishing Features |
|---|---|
| Turner Syndrome | Females only (45,X). Left-sided heart defects (Coarctation). Normal PTPN11. |
| Cardio-Facio-Cutaneous (CFC) | More severe learning disability. Severe skin issues (Ichthyosis). Sparse hair. |
| Costello Syndrome | Deep palmar creases. Papillomas (warts) around nose. High cancer risk (Rhabdomyosarcoma). |
| Williams Syndrome | "Elfin" facies. Supravalvular Aortic Stenosis. "Cocktail party" personality. |
| Fetal Alcohol Syndrome | Smooth philtrum. Thin upper lip. Maternal history. |
Life Expectancy
- Generally Normal, provided cardiac defects are managed.
- HCM is the main driver of early mortality.
Quality of Life
- Most adults lead independent lives.
- Social cognition/anxiety can be a lifelong struggle.
Q: Is it like Down Syndrome? A: No. Children with Noonan Syndrome usually have normal intelligence or very mild learning differences. They are often indistinguishable from their peers socially, although they may be shorter.
Q: Will they need heart surgery? A: About 50% of children need some heart intervention. For most, this is a "balloon" procedure for the pulmonary valve, which is safe and effective. Only a small minority need open-heart surgery.
Q: Why do they bruise so easily? A: Many have slightly "lazy" platelets or lower clotting factors. It is usually not dangerous for day-to-day cuts, but we need to be very careful before any dentist work or surgery.
Q: Can they have children? A: Yes, fertility is usually normal (though boys may need surgery for undescended testes). There is a 50% chance they will pass the condition to their children.
Key Guidelines
- Dykens et al. Management of Noonan Syndrome: A Clinical Guideline. Pediatrics. 2010.
- Romano AA et al. Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines. Pediatrics. 2010.
Landmark Trials
National Cooperative Growth Study (NCGS)
- Funding: Registry data on GH use.
- Finding: GH effectively restores height velocity in Noonan Syndrome towards mid-parental height.
PTPN11 Discovery (Tartaglia et al, 2001)
- Impact: Identified the first gene, proving Noonan is a RASopathy. Opened door for targeted MEK-inhibitor therapies currently in trials for HCM.
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Growth Hormone | 1b | Long-term registry studies (NCGS/KIGS). |
| Balloon Valvuloplasty | 2a | Standard of care for Dysplastic Pulmonary Valve. |
| MEK Inhibitors | 3 | Emerging (Trametinib) for severe HCM. |
Primary Sources
- Roberts AE et al. Noonan syndrome. Lancet. 2013;381(9863):333-342. PMID: 23312968
- Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and pathogenesis. Am J Hum Genet. 2002.
Image Sources
- Figure 1: Facial Features. Source: Wikimedia (CC-BY).
- Figure 2: Pulmonary Stenosis. Source: Radiopaedia.
Further Resources
- Noonan Syndrome Association (UK): noonansyndrome.org.uk
- RASopathies Network: rasopathiesnet.org
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.