Cobblestone‐like brain malformation with a new bi‐allelic ADGRG1 (GPR‐56) mutation: Fetal imaging‐pathology correlation

Background and Purpose Autosomal recessive cobblestone‐like cortical malformation of the brain, with no eye or muscle involvement, has been reported in patients with biallelic mutations in ADGRG1 (formerly GPR56) and in other brain surface defects (eg, variants in COL3A1). We reported the intra‐uterine brain MRI (iu‐MRI), post‐mortem MRI (pm‐MRI), and neuropathology findings of a new ADGRG1 mutation in a fetus at early gestation. Imaging findings were compared with those of the sibling harboring the same mutation, to provide insights about the evolving morphology of such malformation. Methods A 21‐week fetus underwent iu‐MRI for a suspected cortical anomaly on ultrasound. After the MRI results, the termination of the pregnancy was carried out. A pm‐MRI scan and autopsy were performed. A neuropathology‐imaging correlation was achieved. The 5‐year old sibling affected by developmental impairment also underwent a brain MRI. Both subjects underwent a genetic investigation. Results Two patterns of abnormality of the cerebral surface were identified on both fetal MRI: one at the vertex resembling a cobblestone‐cortex due to neuronal overmigration into the subarchnoid space and the other in the occipital areas resembling polymicrogyria. These details closely matched the neuropathology findings. MRI findings of the sibling consisted of typical ADGRG1/GPR56‐related brain findings showing a polymicrogyric‐like cortex, also reported as bilateral frontal‐parietal polymicrogyria. A flattened pons and small cerebellar vermis were present in both cases. Genetic testing demonstrated a novel homozygous variant c.1484T>C in the c gene in both cases. Conclusion Our findings provide further evidence of the overlap of ADGRG1/GPR56‐related brain dysgenesis with cobblestone‐like cortical malformation of the brain.