Cardiofaciocutaneous Syndrome Type 4 (MAP2K2)

Cardiofaciocutaneous Syndrome Type 4 (MAP2K2) is a RASopathy characterized by distinctive craniofacial features, congenital heart disease, feeding and growth impairment, ectodermal abnormalities, hypotonia and variable neurodevelopmental disability, epilepsy and structural brain abnormalities.
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Genetics

Usually caused by a de novo heterozygous activating variant in MAP2K2, which encodes MEK2. The disorder is autosomal dominant, although affected individuals rarely reproduce.

Molecular Mechanism

Pathogenic MAP2K2 variants increase or dysregulate MEK2-dependent ERK signaling. Abnormal signal amplitude and timing during embryogenesis alter cardiac, craniofacial, cutaneous and neural development.

Therapy

Management is multidisciplinary and organ-specific. MEK inhibitors have preclinical rationale and limited off-label experience for severe RASopathy manifestations, but no MEK inhibitor is approved specifically for CFC syndrome and developmental toxicity is a major constraint.

CCP Activity

Generation of a MAP2K2 p.Glu270Lys knock-in model is ongoing. Once established, the model will be used for comprehensive developmental, cardiac, neurologic and growth phenotyping.

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