ABSTRACT Chung‐Jansen Syndrome (CJS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous mutations in the PHIP gene (6q14.1). It is characterized by developmental delay, intellectual disability, behavioral disturbances including autism spectrum disorder and attention deficit hyperactivity disorder, obesity, and distinct facial dysmorphism such as synophrys and an upturned nose. Although clinical presentations vary, behavioral problems and delayed motor and speech milestones are common. We report a 7‐year‐old male with delayed motor and speech development, synophrys, and an upturned nose—features that are rarely documented in CJS. The patient exhibited significant resistance to multiple psychotropic treatments and presented with severe psychological and neurological symptoms. Whole Exome Sequencing revealed pathogenic mutations in both the PHIP and CLCN4 genes. The PHIP mutation was associated with core neuropsychiatric symptoms, including anxiety and depression, whereas the CLCN4 mutation contributed to severe brain atrophy observed in neuroimaging, further exacerbating cognitive and behavioral deficits. Additional copy number variations (CNVs) were detected, indicating a complex genetic background. The interplay between PHIP and CLCN4 mutations appeared to disrupt neuronal growth and synaptic function, thereby intensifying the clinical phenotype. The constellation of symptoms, including resistance to standard therapies, highlights how genetic overlap can aggravate neurodevelopmental and psychiatric manifestations in CJS. This case underscores the necessity of comprehensive genetic testing, including whole exome sequencing and CNV analysis, in patients with atypical or severe presentations of CJS. The findings emphasize that genetic interactions can amplify clinical severity and advocate for further research into the molecular mechanisms underlying such complex syndromes to improve diagnostic precision and inform targeted therapeutic strategies.
Khalili et al. (Mon,) studied this question.