Phelan-McDermid syndrome (PMS) is a genetic condition associated with profound neurodevelopmental disabilities. This study described patterns of onset and loss of developmental milestones and associated skills using questionnaire data from the PMS International Registry (N = 374) and clinician-led assessment data from the Developmental Synaptopathies Consortium natural history study (N = 207). Across studies, an overwhelming proportion of people with PMS were reported to have delays in acquiring basic skills, and regression or loss of skills was commonly reported across multiple developmental domains, including some after the age of 10. The current descriptive study synthesizes two complementary data sources showing loss occurring in the context of significant delays and frequent lack of milestone attainment in people with PMS. Further work to elucidate mechanisms is needed.