Last updated 2mo ago
A child with short stature has a webbed neck, pectus excavatum, and low-set posteriorly rotated ears. Echocardiogram reveals pulmonary valve stenosis. He has mild learning difficulties.
AD; RAS-MAPK pathway genes
- PTPN11 (~50%), SOS1, RAF1, KRAS, RIT1, others
- Facial: Hypertelorism, ptosis, low-set posteriorly rotated ears, deep philtrum
- Cardiac: Pulmonary valve stenosis (most common), HCM
- Growth: Short stature, feeding difficulties
- Other: Webbed neck, pectus deformity, cryptorchidism, bleeding diathesis, learning difficulties (variable)
Overlap: Shares features with Turner syndrome (but normal karyotype)
- Clinical features supported by molecular confirmation on a multigene RASopathy panel (PTPN11, SOS1, RAF1, KRAS, RIT1, others); a negative panel does not exclude the diagnosis
- Baseline echo and ECG for pulmonary valve stenosis, hypertrophic cardiomyopathy, and conduction abnormalities
- Coagulation studies for the bleeding diathesis, renal ultrasound, and growth and developmental assessment
- Cardiology follow-up with intervention as needed (balloon valvuloplasty for pulmonary stenosis, standard hypertrophic cardiomyopathy care)
- Growth hormone may be used for short stature, with cardiac monitoring
- Developmental and educational support; periodic hearing and vision screening
- Bleeding precautions before surgical or dental procedures
- Cascade testing of relatives once the familial variant is identified
A clinically distinct RASopathy allelic to Noonan; previously called LEOPARD syndrome (now formally Noonan syndrome with multiple lentigines, NSML).
- AD; PTPN11 (different missense variants than typical Noonan, usually p.Tyr279Cys, p.Thr468Met), less commonly RAF1 or BRAF
- Mechanism: in NSML the PTPN11 variants are catalytically inactive (loss-of-function for SHP2 phosphatase activity), opposite to gain-of-function variants in classic Noonan
LEOPARD mnemonic:
- Lentigines (multiple, develop by mid-childhood, spare mucosae)
- ECG conduction abnormalities
- Ocular hypertelorism
- Pulmonary stenosis (and frequently hypertrophic cardiomyopathy, more prominent in NSML than in classic Noonan)
- Abnormal genitalia
- Retardation of growth
- Deafness (sensorineural)
Gene, "Please order TPN by 11": "Please order TPN one hour before Noon (i.e. 11 am)" = PTPN11, which causes ~50% of Noonan syndrome. Noon = chromosome 12 (12 o'clock), and 12 - 1 = 11 (PTPN11)
Cardiac, "HAPpy": The heart lesions in Noonan are Hypertrophic Cardiomyopathy, ASD, and Pulmonic stenosis. "Pool-monic stenosis at noon": spell POOL backwards (LOOP), adding letters in between (LMNOOP) to get NOOnan
Noonan vs Turner: Same features as Turner syndrome, but with right-sided heart lesions (vs left-sided lesions in Turner) and a normal karyotype