Caregiver-reported developmental regression in Coffin-Lowry syndrome

Coffin-Lowry syndrome (CLS) is a rare X-linked neurodevelopmental disorder traditionally considered non-progressive. Emerging reports suggest that a subset of individuals may experience developmental regression, although this phenomenon remains poorly characterized in CLS. We conducted a cross-sectional, caregiver-reported survey of individuals with CLS to assess the frequency, clinical features, diagnostic findings, and caregiver-reported treatment responses associated with developmental regression. Descriptive statistics and univariate logistic regression analyses were used to evaluate associations with reported regression. Among caregivers of 93 individuals with CLS, 45.2% of respondents reported experiencing developmental regression. Median age of regression onset was 15 years (interquartile range: 9–22). Regression was characterized by a multi-domain neuropsychiatric syndrome, including language/communication (100%), cognitive (76.2%), psychiatric (66.7%), and motor dysfunction symptoms (54.8%). Regression frequently followed identifiable triggers, including infection and hormonal changes. Exploratory analyses revealed that patients with regression were older at diagnosis and more likely to have neurological, musculoskeletal, gastrointestinal, metabolic, allergic, and cardiac comorbidities. Diagnostic evaluations were heterogeneous and caregiver-reported abnormalities were variable across modalities. A small number of caregivers reported perceived improvement following immunomodulatory therapies; these retrospective, non-standardized observations should not be interpreted as evidence of treatment efficacy. Caregiver-reported regression was frequent in this selected survey cohort, but its clinical nature and population prevalence remain uncertain. Developmental regression is a clinically significant complication of CLS, with features overlapping other neurodevelopmental regression syndromes. These findings raise the hypothesis that immune-mediated, or neuroinflammatory mechanisms may contribute to CLS regression in a subset of individuals, highlighting the need for prospective, biomarker-driven studies. Not applicable.