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Cardiofaciocutaneous Syndrome Type 4 due to a MAP2K2 Variant: Expanding the Phenotypic Spectrum With Feeding Dysfunction and Neurodevelopmental Involvement

Year: 2026

Type: article

Abstract: (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.

Source: Clinical Case Reports

DOI: 10.1002/ccr3.72024

Authors: Aleksandra Świeca, Małgorzata Rydzanicz, Rafal Ploski, Krzysztof Szczałuba

Institution: Medical University of Warsaw

Language: English

Topic: Genomics and Rare Diseases

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,820