High rates of misdiagnosis and delayed intervention in neonatal PWS are leading to poor prognoses. To determine the clinical and image characteristics of newborns with Prader-Willi syndrome (PWS). A total of 102 cases of newborns definitively diagnosed with PWS at the Children's Hospital of Fudan University from 02/2014 to 12/2017 were retrospectively analyzed. We analyzed the modulated voxel-based morphology (VBM) of gray matter in PWS by T2 weighted imaging. Of 102 cases, 75 (73.5%) have paternal deletion of 15q11.2-q13, whereas 27 (26.5%) have maternal uniparental disomy (UPD). Of the 75 deletion cases, 75 (100%) week crying, 71 (94.7%) hypotonia, 70 (93.3%) poor feeding, 46 (61.3%) hypopigmentation, 43 (57.3%) male cryptorchidism, 10 (13.3%) female labia minora, 48 (64%) characteristic facial features. Of 27 UPD cases, 27 (100%) week crying and hypotonia, 25 (92.6%) hypophagia, 20 (74.1%) male cryptorchidism, 1 (3.7%) female labia minora, 19 (70.4%) characteristic facial features, 12 (44.4%) hypopigmentation. The modulated VBM analysis shows that the middle frontal gyrus, orbitofrontal cortex (middle), and inferior frontal gyrus are the most variable brain regions that determine the endo-phenotype difference between the two genotypes. Hypotonia, hypophagia, and maldevelopment of sexual organs are general characteristics of newborns with PWS in Chinese population. In UPD cases, the proportions of premature newborns, elderly parturient women and congenital malformations were higher than for paternal deletion cases. The differences in the gray matter volume of these three regions between the two genotypes may explain the differences in maladaptive behaviors and emotions.