Cardiofaciocutaneous Syndrome Type 4 due to a MAP2K2 Variant: Expanding the Phenotypic Spectrum With Feeding...

Area of Science:

• Genetics and Molecular Biology
• Pediatric Neurology
• Rare Diseases

Background:

• Cardiofaciocutaneous syndrome type 4 (CFC4) is an ultra-rare RASopathy.
• It is caused by heterozygous variants in the MAP2K2 gene.
• This report details a novel case in a female infant.

Purpose of the Study:

• To describe the clinical presentation and diagnostic features of CFC4 in an infant with a MAP2K2 variant.
• To expand the known clinical spectrum of CFC4.
• To highlight key early diagnostic indicators.

Main Methods:

• Clinical case report of a female infant.
• Genetic analysis identifying a heterozygous MAP2K2 (c.619G>A, p.Glu207Lys) variant.
• Comprehensive multi-system evaluation including neurological, cardiac, ophthalmologic, and metabolic assessments.

Main Results:

• The infant presented with neonatal hypotonia, respiratory distress, feeding dysfunction, and distinct dysmorphic features.
• Neurologic manifestations included apnea, dystonic stiffening, tremor, and epileptiform discharges on EEG.
• Cutaneous findings included xerotic skin, nevi, and hemangiomas; metabolic assessment suggested mild energetic dysfunction.
• Developmental delays, sleep disturbances, and behavioral dysregulation (aggression, self-injury) were observed.

Conclusions:

• This case expands the clinical spectrum of CFC4 associated with MAP2K2 variants.
• Early feeding dysfunction, paroxysmal neurologic events, and prominent sleep and behavioral disturbances are key diagnostic features.
• Ongoing neurological surveillance is crucial for managing potential epilepsy.