RASopathies

RASopathies are a phenotypically overlapping spectrum of syndromic disorders sharing dysregulation of RAS/MAPK signalling. Across the spectrum, all forms are syndromic; nonsyndromic presentations are not recognised within this clinical group. Affected individuals characteristically display a distinctive craniofacial appearance, postnatal short stature, congenital heart disease (most often pulmonary valve stenosis and hypertrophic cardiomyopathy), variable ectodermal and musculoskeletal anomalies, and a spectrum of neurodevelopmental involvement ranging from learning difficulties to intellectual disability. Specific entities show characteristic features: (formerly LEOPARD syndrome) develops progressive lentigines and sensorineural hearing loss in later childhood, while (Mazzanti syndrome) presents with easily pluckable sparse hair. Most features are recognisable from the perinatal period through early childhood, with progressive findings emerging thereafter. Cardiovascular manifestations represent one of the principal sources of clinical morbidity across the spectrum.

The estimated incidence of Noonan syndrome, the most common RASopathy, is 1/1,000 to 1/2,500 live births. Other RASopathies contribute additional cases; cardiofaciocutaneous, Costello and Noonan syndrome with multiple lentigines are individually rare.

The genetic conditions associated with RASopathies predominantly follow autosomal dominant inheritance, as documented in the current overview literature. De novo variants are common, particularly in severe forms such as Costello syndrome and cardiofaciocutaneous syndrome. Less common alternative inheritance patterns are described for individual entities, including biallelic LZTR1 variants causing an autosomal recessive form of Noonan syndrome.

• Where a RASopathy is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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