Noonan syndrome (NS)

Description

RASopathy - autosomal dominant, Ras/MAPK pathway dysregulation
Characteristic facies + short stature + congenital heart disease ("male Turner-like" phenotype but normal karyotype)
Part of a family of related RASopathies (Costello, cardiofaciocutaneous syndrome)

Gain-of-function mutations in Ras/MAPK pathway genes
PTPN11 - commonest (~50%)
Others: SOS1, RAF1, KRAS, RIT1 and more
Overactive Ras/MAPK signalling during development -> cardiac, growth, craniofacial, haematological effects

Clinical: characteristic facies (hypertelorism, downslanting palpebral fissures, ptosis, low-set posteriorly rotated ears), short webbed neck, chest deformity (pectus), short stature
Genetic testing (multi-gene RASopathy panel) - confirms, guides specific surveillance (e.g. RAF1/RIT1 -> higher hypertrophic cardiomyopathy risk)
Echocardiogram at diagnosis - pulmonary stenosis and hypertrophic cardiomyopathy characteristic

Surveillance (MDT)

Cardiac - echo at diagnosis and periodically; pulmonary valve stenosis (often dysplastic) and HCM are the two classic lesions
Growth - growth hormone therapy improves final height in a proportion (evidence weaker than Turner)
Bleeding - coagulation screen (factor XI deficiency, platelet dysfunction common) before any surgery
Renal - baseline ultrasound (mild anomalies)
Developmental - learning difficulties in a substantial minority - early intervention
Lymphatic - lymphoedema surveillance

Pulmonary valve stenosis (dysplastic), hypertrophic cardiomyopathy, ASD/VSD
Bleeding diathesis (factor XI deficiency, other coagulation factor and platelet defects) - screen before surgery
Cryptorchidism, delayed puberty
Lymphoedema (congenital, hands/feet, like Turner)
Mildly inc risk of juvenile myelomonocytic leukaemia (esp. PTPN11-related, overlaps with Ras pathway leukaemogenesis)
Learning difficulties (variable, usually mild)

Life expectancy near-normal for most; cardiomyopathy determines outcome in the minority affected
Short stature persists without GH treatment
Fertility usually normal (unlike Turner) once cryptorchidism managed
Cardiac lesions may progress - lifelong cardiology follow-up

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