Microcephaly, Hypotonia, and Intracranial Calcification: Is It Always Intrauterine Infection?

Aicardi–Goutières syndrome (AGS) is a rare inherited disease predominantly affecting the brain, immune system, and skin. AGS is caused by a mutation in one or more of a small group of specific genes leading to the accumulation of calcium in the brain, which is thought to trigger the immune response that causes symptoms of AGS. A male neonate weighing 2760 g was delivered at 38 weeks of gestation by lower segment cesarean section to a 30-year-old mother in her third pregnancy. The antenatal period was uneventful except for the anomaly scan revealing enlarged cisterna magna. On examination, microcephaly was noted with sutural overriding. The neonate exhibited multiple dysmorphic features, including low-set ears, hypertelorism, a thin upper lip, a long philtrum, and microcephaly. Other findings include paucity of limb movements, lethargy, hepatosplenomegaly noted on the first day of life, generalized hypotonia, and a characteristic central pattern of breathing manifesting occasionally as labored breathing. The neonate was then transferred to the neonatal intensive care unit for further evaluation, where the neonate continues to be encephalopathic. The detailed neurological examination revealed generalized hypotonia with diminished level of consciousness and poor suck. The family history is significant for a similar clinical presentation in an older male sibling, who had exhibited intracranial calcifications, generalized hypotonia, and global developmental delay. However, the cause was not evaluated. This sibling had died at 1 year of age following recurrent lower respiratory tract infections and prolonged hospitalization. The cranial ultrasound revealed bilateral periventricular calcification, corpus callosal dysgenesis. The magnetic resonance imaging brain was done later which showed periventricular, subcortical white matter, and basal ganglia calcifications, thinning of corpus callosum with colpocephaly, mild flattening of pontine belly with enlargement of retrocerebellar space. TORCH evaluation was negative. Hence, whole exam sequencing was done which demonstrated the mutation of RNASEH2C gene revealing the diagnosis of AGS type 3. AGS can mimic congenital infections, making diagnosis challenging. A neonate presenting with microcephaly and hypotonia should be thoroughly evaluated once intrauterine infections are ruled out. Genetic testing can confirm the diagnosis.