09 May 2023: Articles
Rare disease, Congenital defects / diseases, Rare coexistence of disease or pathologyHeerali Patel1ABDEF, Mohammed Elkhwad1ABCDE*, Gregory C. Martin1BCDE
Am J Case Rep 2023; 24:e938651
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.
Keywords: brain infarction, Porencephaly, Rare Diseases, Chromosome Aberrations, Basement Membrane, Genetic Pleiotropy, Prenatal Diagnosis, Magnetic Resonance Imaging, Loss of Heterozygosity
Diagnoses associated with the
A male infant born at 38 weeks and 4 days gestation presented to the Neonatal Intensive Care Unit with microcephaly, central nervous system (CNS) anomalies, and a hypoplastic aortic arch. The mother was a 24-year-old, gravida 2 para 1, who received prenatal care. Prenatal ultrasound showed multiple fetal anomalies, including microcephaly, scattered multifocal hemorrhagic/ischemic infarcts, ex-vacuo dilatation, polymicrogyria, moderate ventricular septal defect (VSD), and a narrowed aortic arch. The mother subsequently underwent a fetal MRI of the brain, which confirmed suspected ultrasound findings. Fetal echocardiogram showed a dilated right cardiac chamber and mild hypoplasia of the left cardiac chambers, along with a moderate muscular VSD and narrow aortic arch. She was then seen by the Cardiology, Palliative Medicine, and Neonatology Departments for prenatal care.
The infant was born via cephalic vaginal delivery, with meconium-stained amniotic fluid. The birth weight was 2.45 kg. The APGAR scores at 1 and 5 min were 4 and 8, respectively. On physical examination, the infant had a dusky appearance of the bilateral feet and cool extremities. No other physical abnormalities were seen. The baby was limp at birth with no spontaneous respiratory effort, required positive pressure ventilation at birth, and was then transitioned to continuous positive airway pressure. Postnatal echocardiography showed a fenestrated atrial septum and moderate mid-muscular VSD, mild to moderate hypoplastic left ventricle, moderately hypo-plastic left aortic arch, small to moderate patent ductus arteriosus, and suprasystemic right ventricular systolic pressure. The infant was started on intravenous (i.v.) prostaglandin E1 owing to suspected coarctation of the aorta. He was then given i.v. epinephrine and dopamine drips because of hypotension. Respiratory support was escalated from nasal continuous positive airway pressure to noninvasive positive pressure ventilation as a result of apnea, presumably secondary to prostaglandin administration. An echocardiogram obtained after initiation of prostaglandin E demonstrated a widely patent aortic arch with a VSD. A subsequent echocardiogram showed no evidence of coarctation, and prostaglandin E was discontinued.
Electroencephalogram showed frequent subclinical seizures. Seizures were difficult to control, requiring multiple agents, including i.v. levetiracetam 75 to 150 mg, i.v. lacosamide 6 mg every 12 h, and i.v. phenobarbital 13 to 50 mg. A subsequent electroencephalogram after treatment showed no additional seizures. An ophthalmology evaluation showed small, hypo-plastic optic nerves of both eyes, concerning for septo-optic dysplasia. The left eye showed a posterior polar cataract with microspherophakia. Postnatal MRI of the brain (Figures 1, 2) confirmed findings of multifocal infarcts of unknown etiology, diffuse mild polymicrogyria, dysgenesis of the corpus callosum, optic nerve hypoplasia, a defect within the intraventricular septum, and inferior vermian hypoplasia.
Genetic analysis with rapid whole exome sequencing and chromosomal microarray were obtained owing to concern for parental consanguinity. XomeDxXpress Clinical Exome Sequence Analysis showed a de novo heterozygous variant at c. 2771 G>A of the
Postnatal renal ultrasound showed mild calyceal dilatation of the left kidney. Cytomegalovirus workup was negative.
The infant was weaned to room air and continued to improve on oral feeds. By the time of discharge, the infant was taking most of the feeds orally. The infant was discharged on room air and oral hydrochlorothiazide-spironolactone 3 mg, given the VSD with the pulmonary over-circulation. Oral phenobarbital 20 mg/5 mL, oral levetiracetam 100 mg/mL, and oral lacosamide 10 mg/mL were continued for seizure management with the Neurology Department.
No specific treatment is available for the sequelae of
Genetic counseling is needed to identify the mechanism of inheritance and potential downstream effects on family members and descendants. Prenatal testing is a consideration when the familial pathogenic variant is known .
Lastly, previous cases of
This case presents a neonatal patient who was prenatally diagnosed with CNS and cardiac abnormalities and postnatally found to have a de novo heterozygous variant of the
FiguresFigure 1.. Postnatal magnetic resonance imaging of brain without contrast: sagittal view demonstrating intracranial abnormalities within the periventricular parenchyma, including diffusion restriction hemorrhage and possible calcification (white arrow), in the setting of multifocal infarcts of unknown etiology. Dysgenesis of the corpus callosum and inferior vermian hypoplasia are also apparent (red arrow). Figure 2.. Postnatal magnetic resonance imaging of brain without contrast: axial view demonstrating diffuse mild polymicrogyria, dysgenesis of the corpus callosum, and defect within the intraventricular septum (arrow).
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