Background and ObjectivesFacioscapulohumeral dystrophy (FSHD) is an inherited muscle disorder, with childhood onset in 20% of patients. Understanding the natural history of childhood FSHD and identifying clinical and functional outcome measures are crucial for clinical care and future trials.MethodsIn a prospective nationwide FSHD cohort study (iFocus), 20 childhood-onset patients were assessed at baseline, 2 years, and 5 years. Assessments included manual muscle and functional muscle tests, FSHD clinical score (FSHD-CS), FSHD clinical severity scale (FSHD-CSS), and muscle ultrasonography (MUS).ResultsEighteen patients (aged 2-17 years at baseline) completed the 5-year follow-up. Disease progression varied, with a mean FSHD-CS increase of 1.6. Despite objective disease progression, most participants (89%) did not perceive change. The most sensitive outcome measures were FSHD-CS (standardized response mean [SRM] 1.07), FSHD-CSS score (SRM 0.92), and MUS findings (SRM 0.68). Baseline characteristics did not predict progression.DiscussionDisease progression was variable and often remained unnoticed by participants. Quality of life improved, and fatigue levels decreased over 5 years. The relatively slow progression and physiologic growth highlight the need for sensitive end points within a 1-2-year time frame. Future pediatric studies should consider larger international cohorts, assess reachable workspace, and include MUS and FSHD functional composite outcome measure (FSHD-COM).