PURPOSE OF REVIEW: In recent years, we have seen remarkable progress in our 
understanding of the disease mechanism underlying facioscapulohumeral muscular 
dystrophy (FSHD). The purpose of this review is to provide a comprehensive 
overview of our current understanding of the disease mechanism and to discuss 
the observations supporting the possibility of a developmental defect in this 
disorder.
RECENT FINDINGS: In the majority of cases, FSHD is caused by contraction of the 
D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable 
expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic 
DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin 
relaxation and stable DUX4 expression occur in the absence of D4Z4 array 
contraction. DUX4 is a germline transcription factor and its expression in 
skeletal muscle leads to activation of early stem cell and germline programs and 
transcriptional activation of retroelements.
SUMMARY: Recent studies have provided a plausible disease mechanism for FSHD in 
which FSHD results from inappropriate expression of the germline transcription 
factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle 
damage, and provide potential biomarkers and therapeutic targets that should be 
investigated in future studies.