Abstract
Pathogenic variants in pleckstrin homology domain interacting protein (PHIP) are associated with Chung-Jansen syndrome characterized by developmental delay, intellectual disability, behavioral challenges, hypotonia, obesity, and dysmorphic features. We report phenotypes and genotypes of 47 individuals with likely pathogenic/pathogenic PHIP variants. Variants were de novo in 61.7%, unknown inheritance in 29.8%, and inherited in 8.5%. The median age of the individuals was 10.9 years, approximately equally divided by sex. Individuals in this cohort frequently had a history of developmental delay (85.1%), attention-deficit/hyperactivity disorder (51.1%), anxiety (46.8%), depression (27.7%), and sleep difficulties (42.6%). Depression was significantly higher in the older age group (>12 years old). Most individuals had moderately low adaptive functioning based on the Vineland-3 (mean = 76.8, standard deviation = 12.0). Overall, 55.8% of individuals were obese/overweight. The percentage of obese individuals was greater in the older age group (>12 years old) and evolves over time. Other common symptoms were hypotonia (78.7%), constipation (48.9%), visual problems (66%), and cryptorchidism (39.1% of males). Our findings provide additional natural history data for Chung-Jansen syndrome and provide opportunities for early intervention of healthy eating habits and awareness of developing mood and behavioral challenges over the life course.