To illustrate the broad phenotypic range of COL4A1-related disorders through a short series of pediatric cases with distinct modes of inheritance.

Pathogenic variants in COL4A1 disrupt vascular basement membrane integrity, leading to a spectrum of disease ranging from severe perinatal intracerebral hemorrhage to milder adult-onset nephropathy. While recognized as a cause of cerebral small vessel disease, clinical variability in the perinatal period remains incompletely characterized, presenting significant diagnostic and genetic counseling challenges.

We retrospectively reviewed the clinical, radiological, and genetic findings of three pediatric patients with molecularly confirmed pathogenic COL4A1 variants.

Case 1: Female infant with intrauterine growth restriction and oligohydramnios presented with microcephaly, atypical retinal hemorrhages, and neonatal seizures. Brain MRI revealed extensive multifocal cystic encephalomalacia and diffuse cerebellar atrophy, suggestive of a significant in utero vascular insult. Genetic testing identified a de novo pathogenic variant in COL4A1.

Case 2: Male infant presented with prenatally identified left-hemisphere porencephaly, agenesis of the corpus callosum, microhemorrhages, and congenital heart disease. His course was complicated by global developmental delay and refractory infantile spasms. Genetic testing revealed a paternally inherited pathogenic COL4A1 variant (c.2528 G>A p.(G843E)). The father was found to be 31% mosaic with a milder phenotype of early-life cataracts.

Case 3: 9-year-old male was evaluated for mild esotropia and muscle cramps, prompting targeted genetic testing due to a strong family history of COL4A1-related disorder (Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC) syndrome). Testing confirmed paternal inheritance of the COL4A1 variant (c.3733G>A, p.Gly1245Ser). In contrast to his affected first-degree relatives, his clinical phenotype was mild, and neuroimaging was unremarkable.

This case series underscores the clinical, radiological, and genetic heterogeneity of COL4A1-related disorder. Genetic counseling for this disorder is challenging and must address the broad clinical spectrum of COL4A1-related disorder and the variable recurrence risk based on mode of inheritance.