Clinical characteristics for early diagnosis of PACS1 neurodevelopmental disorder: Two case reports

PACS1 neurodevelopmental disorder ( PACS1 -NDD), also known as Schuurs-Hoeijmakers syndrome, is a rare autosomal dominant disorder predominantly caused by the recurrent de novo pathogenic PACS1 variant c.607C>T (p.Arg203Trp). The characteristic features include varying degrees of global developmental delay, autism spectrum disorder (ASD), behavioral problems, and distinct facial features. Although the number of reported cases has increased, PACS1 -NDD remains underrecognized, suggesting that many cases remain undiagnosed. We report two Japanese pediatric patients diagnosed with PACS1 -NDD using whole-exome sequencing (WES) and filtering analysis to identify the recurrent pathogenic variant [NM_018026.4:c.607C>T,p.(Arg203Trp)]. Patient 1, a 4-year-old boy, demonstrated severe global developmental delay, ASD, behavioral problems, sleep disturbances, epilepsy, cryptorchidism, and chronic constipation. Patient 2, a 3-year-old girl, demonstrated profound global developmental delay, ASD, behavioral problems, sleep disturbances, mild cerebral atrophy, congenital heart defects, and chronic constipation. Both patients shared consistent facial features, including hypertelorism, downslanted palpebral fissures, a short nose with anteverted nares, a thin upper lip, and downturned mouth corners. This study provides critical diagnostic clues for PACS1 -NDD to facilitate early recognition based on a combination of characteristic facial features, global developmental delays, ASD, and sleep disturbances. In addition, other systemic complications such as cryptorchidism, congenital heart defects, and chronic constipation have been frequently reported in PACS1 -NDD. Recognizing these clinical features can strengthen the clinical indication for comprehensive genetic testing, such as WES. Early diagnosis enables tailored clinical management and genetic counseling for patients and their families.