Schizophrenia (SCZ) is a neuropsychiatric disorder with strong genetic heritability and predicted genetic heterogeneity, but limited knowledge regarding the underlying genetic risk variants. Classification into phenotype-driven subgroups or endophenotypes is expected to facilitate genetic analysis. Here, we report a teen boy with chronic psychosis and cerebellar hypoplasia (CBLH) and analyze data on 16 reported individuals with SCZ or chronic psychosis not otherwise specified associated with cerebellar hypoplasia to look for shared features.

We evaluated an 18-year-old boy with neurodevelopmental deficits from early childhood and onset of hallucinations and other features of SCZ at 10 years who had mild vermis-predominant CBLH on brain imaging. This prompted us to review prior reports of chronic psychosis or SCZ with cerebellar malformations using paired search terms including (1) cerebellar hypoplasia, Dandy-Walker malformation, Dandy-Walker variant, or mega-cisterna magna with (2) psychosis or SCZ. We found reports of 16 affected individuals from 13 reports. We reviewed clinical features focusing on demographic information, prenatal-perinatal history and neuropsychiatric and neurodevelopmental phenotypes, and independently reviewed brain imaging features.

All 17 individuals had classic psychiatric features of SCZ or chronic psychosis as well as shared neurodevelopmental features not previously highlighted including a downward shift in IQ of about 20 points, memory impairment, speech-language deficits, attention deficits and sleep disturbances. The brain imaging findings among these individuals consistently showed posterior vermis predominant CBLH with variable cerebellar hemisphere hypoplasia and enlarged posterior fossa (a.k.a. mega-cisterna magna). None had features of classic DWM.

In 17 individuals with chronic psychosis or SCZ and cerebellar malformation, we found a high frequency of neurodevelopmental disorders, a consistent brain malformation consisting of posterior vermis-predominant (and usually symmetric) CBLH, and no evidence of prenatal risk factors. The consistent phenotype and lack of prenatal risk factors for CBLH leads us to hypothesize that psychosis or schizophrenia associated with vermis predominant CBLH comprises a homogeneous subgroup of individuals with chronic psychosis/schizophrenia that is likely to have an underlying genetic basis. No comprehensive targeted gene panel for CBLH has yet been defined, leading us to recommend trio-based exome sequencing for individuals who present with this combination of features.