Noonan syndrome

The estimated incidence is 1:1,000 to 1:2,500 live births.

Noonan syndrome is inherited in an autosomal dominant manner. Approximately 30-75% of individuals have an affected parent; the remaining 25-70% represent de novo occurrences. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Prenatal molecular testing is possible once the familial pathogenic variant has been identified.

Diagnosis rests primarily on molecular genetic testing. Testing is pursued when the characteristic combination of facial, cardiac, growth, and developmental features raises clinical suspicion, and identification of a pathogenic germline variant in one of the genes encoding components of the Ras/MAPK signalling pathway confirms the diagnosis.

Main differential diagnoses include:

• : lentigines and café au lait macules distinguishing from classic NS facies; PTPN11, RAF1, BRAF, MAP2K1
• : pronounced ectodermal involvement and more severe intellectual disability; BRAF, KRAS, MAP2K1, MAP2K2
• : coarse facial features, loose skin, joint laxity, and predisposition to malignancy; HRAS

• Establishing the molecular diagnosis confirms the clinical impression and provides the basis for genetic counselling.
• Identification of the underlying pathogenic variant enables condition-specific and individualised surveillance and clinical management; this is a prerequisite for targeted medical care, with decisions made by the treating physicians in consultation with the affected individual.
• A confirmed familial pathogenic variant enables targeted predictive testing of at-risk relatives, with implications for their own surveillance and reproductive planning.

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• Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381(9863):333-342. PMID: .
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• Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126(4):746-759. PMID: .