Clinical spectrum and ascertainment pathways in pediatric female dystrophinopathy

Pediatric female dystrophinopathy may be asymptomatic at evaluation or may show skeletal muscle and cardiac manifestations, but childhood presentations are often subtle. We aimed to characterize the clinical spectrum, ascertainment pathways, subclinical muscle involvement, and inheritance patterns in this population.

This single-center retrospective case series was conducted between January 2024 and December 2025 and included 35 girls with genetically confirmed DMD gene variants identified from existing clinical records. Primary ascertainment route was recorded separately from cross-sectional clinical status at evaluation and classified as symptom-driven presentation, incidental or unexplained hyperCKemia, family-based cascade screening, or incidental genomic discovery. Clinical status at evaluation was assigned after systematic clinical review with reference to published female dystrophinopathy classifications. Statistical analyses were exploratory.

The median age was 5 years (range, 1-10). Primary ascertainment routes were symptom-driven presentation in 8/35 (22.9%), incidental or unexplained hyperCKemia in 18/35 (51.4%), family-based cascade screening in 8/35 (22.9%), and incidental genomic discovery in 1/35 (2.9%). After systematic clinical review, clinical status at evaluation was classified as asymptomatic in 29 participants, BMD-like in 1, DMD-like in 3, and cardiac-symptom/CMR observations in 2. All 18 girls initially identified through incidental or unexplained hyperCKemia were classified as asymptomatic because no muscle weakness was documented on neurological examination, although some had exercise intolerance, easy fatigue, myalgia, or cramps. EMG abnormalities were identified in 14/34 participants, including definite myopathic findings in 5 and subtle short-duration motor-unit-potential changes in 9. Variants were apparently de novo in 15 cases, maternally inherited in 18, and paternally inherited in 2, including one case inherited from a father with low-level mosaicism in peripheral blood.

Pediatric female dystrophinopathy shows a broad childhood spectrum and may be recognized before objective muscle weakness is documented. Separating ascertainment route from clinical status highlights recurrent or persistent hyperCKemia and mild exercise-related complaints as practical entry points for targeted neuromuscular assessment and longitudinal follow-up. Earlier recognition in childhood may support timely neuromuscular and cardiac surveillance, parental evaluation when appropriate, family-based genetic counseling, and future reproductive planning.