Classic “PCH” genes are a rare cause of radiologic pontocerebellar hypoplasia

Abstract

Background: The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types, many other disorders can result in a similar imaging appearance. Objective: To review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging. Methods: We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH. Results: Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identified in 65% and included chromosomal (21%), monogenic (34%) and acquired (10%) causes. Only one patient had pathogenic variants in a “classic” PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. Conclusion: Radiologic PCH has heterogenous etiologies and the “classic” PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic findings, and not to imply neurogenerative disorders.

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“…Patients usually present developmental delay, feeding problems and motor abnormalities, with the most severe cases showing regression and early death due to respiratory problems (van Dijk et al , 2018). Current classification comprises 17 types of PCH which are distinguished by the genetic diagnosis, brain imaging and clinical features (Zakaria et al , 2023). Functional annotation of PCH associated genes suggest impaired protein synthesis, RNA or energy metabolism as the underlaying pathogenic mechanism (van Dijk et al ., 2018).…”