Central Nervous System and Cardiac Abnormalities in the Setting of a De Novo Heterozygous Col4a1 Variant

Patient: Male, newborn Final Diagnosis: Absence of heterozygosity on chromosome 11 • de novo heterozygous Col4a1 variant Symptoms: Hypotension • limp • no spontaneous respiratory effort • subclinical seizure Clinical Procedure: Chromosomal microarray • CPAP treatment • electroencephalogram • fetal echocardiography • genetic analysis • MRI brain • ultrasonography • whole exome sequencing Specialty: Cardiology • Critical Care Medicine • Genetics • Nephrology • Neurology • Ophthalmology • Pediatrics and Neonatology OBJECTIVE: Rare disease • congenital defects/diseases • rare coexistance of disease or pathology BACKGROUND: The Col4a1 gene encodes a portion of type IV collagen, a major component of the tissue basement membrane. Col4a1 mutations are rare, most frequently affect neonates, and occur at a de novo mutation rate between 27% and 40%. Mutations are commonly missense and pleiotropic, presenting with cerebrovascular, renal, ophthalmological, and muscular abnormalities, collectively known as Gould Syndrome. Cerebral small vessel disease is commonly associated with Gould Syndrome and Col4a1 mutations. Children can present with infantile hemiplegia/quadriplegia, stroke, epilepsy, motor dysfunction, or white matter changes of the eye. CASE REPORT: A male infant at 38-week, 4-day gestation presented with microcephaly, scattered multifocal hemorrhagic/ischemic infarcts, ex-vacuo dilatation, polymicrogyria, ventricular septal defect, and narrowed aortic arch, seen on prenatal ultrasound and confirmed by fetal echocardiogram and fetal brain magnetic resonance imaging (MRI). Electroencephalogram showed frequent subclinical seizures that were difficult to control, requiring multiple agents. Ophthalmology evaluation demonstrated small, hypoplastic optic nerves of both eyes, concerning for septo-optic dysplasia. Postnatal brain MRI confirmed fetal findings. Postnatal genetic testing showed a de novo heterozygous variant of Col4a1 and 1 nonspecific contiguous region of copy neutral absence of heterozygosity on chromosome 11. CONCLUSIONS: This neonate was prenatally diagnosed with central nervous system (CNS) abnormalities and postnatally found to have a de novo heterozygous Col4a1 variant. CNS, cardiac, renal, and hematological findings were likely associated with the Col4a1 mutation and, possibly, a recessive genetic disorder of chromosome 11. Col4a1 mutations are rare and have no definitive treatments. Subspecialist follow-up and supportive care are essential to reduce long-term complications.