Noonan syndrome with multiple lentigines (LEOPARD syndrome)

Due to insufficient data, no reliable statement on prevalence can currently be made.

NSML is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Because expressivity is variable and adult manifestations may be subtle, parents of an apparently isolated proband warrant clinical and, where appropriate, molecular evaluation. Prenatal molecular testing is possible once the familial pathogenic variant has been identified.

The clinical diagnosis rests on clinical criteria, requiring either multiple lentigines plus two cardinal features, or – in the absence of lentigines – three cardinal features plus a first-degree relative with NSML. Meeting these criteria establishes the clinical diagnosis of NSML. Echocardiography is performed at diagnosis and during follow-up to assess for hypertrophic cardiomyopathy and other structural heart defects.

Main differential diagnoses include:

• : pulmonary valve stenosis predominates over hypertrophic cardiomyopathy, multiple lentigines are absent, and café au lait macules are less prominent; PTPN11, SOS1, RAF1, KRAS, LZTR1, e.g.
• : more pronounced ectodermal involvement (sparse curly hair, keratosis pilaris, ichthyosis) and typically more severe intellectual disability, with multiple lentigines absent; BRAF, KRAS, MAP2K1, MAP2K2
• : diffuse hypotonia and severe feeding difficulties in infancy, coarse facies, papillomata, loose redundant skin, joint laxity, and increased risk of solid tumours; HRAS

• Establishing the molecular diagnosis confirms the clinical suspicion and clarifies the underlying disease mechanism.
• A confirmed molecular diagnosis enables specific and individualised surveillance, including cardiovascular evaluation, audiology assessment, growth monitoring, ophthalmologic review, and developmental follow-up, as the prerequisite for targeted medical care delivered by the treating physicians.
• Identification of the familial pathogenic variant allows predictive and clarifying testing of at-risk relatives within the framework of human genetic counselling.

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