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

We report a female infant with cardiofaciocutaneous syndrome type 4 (CFC4), an ultra-rare RASopathy caused by a heterozygous MAP2K2 (c.619G>A, p.Glu207Lys) variant. From birth, she presented with neonatal hypotonia, respiratory distress, and feeding dysfunction characterized by absent sucking reflex, orofacial hypotonia, and sensory disturbances. Distinct dysmorphic features, including characteristic craniofacial anomalies and macroglossia, were noted. Cardiac evaluation revealed a patent foramen ovale and two small atrial septal defects. Neurologic manifestations included cyanotic apnea, dystonic stiffening, and tremor. Electroencephalography demonstrated bilateral temporoparietal epileptiform discharges, and brain MRI revealed reduced cerebral white matter volume. Although epilepsy has not been definitively diagnosed, the patient remains under ongoing neurological surveillance. Cutaneous involvement included xerotic, papular skin with multiple pigmented nevi and segmental hemangiomas. Ophthalmologic evaluation demonstrated hyperopia with astigmatism. Metabolic assessment suggested mild energetic dysfunction, with elevated triglycerides and citric acid cycle intermediates, without evidence of a defined inborn error of metabolism. Over time, the patient developed persistent feeding difficulties with choking due to oropharyngeal dysfunction, sleep disturbances, delays in gross and fine motor development, and behavioral dysregulation, including aggressive and self-injurious behaviors. Despite the preserved social interest and frequent social approach toward unfamiliar individuals, pronounced anxiety and distress were observed during caregiver absence or reduced attention. This case expands the clinical spectrum of CFC4 associated with MAP2K2 variants, highlighting early feeding dysfunction, paroxysmal neurologic events, and prominent sleep and behavioral disturbances as key diagnostic features.