Abstract Details

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant form of muscular dystrophy characterized by progressive asymmetric muscle weakness involving the face, shoulder girdle, abdomen, and legs. FSHD arises in the context of toxic DUX4 protein expression, which typically occurs when the D4Z4 tandem repeats, each carrying a copy of the DUX4 gene, becomes permissively contracted (1-10 repeats; FSHD1). In approximately 5% of patients, DUX4 expression results from hypomethylation of the D4Z4 repeats (FSHD2). Here, we present a pediatric patient with an early onset, severe phenotype of FSHD with genetically confirmed FSHD1 and FSHD2. 

The patient is a 12-year-old girl who came to medical attention at 2 years of age due to lumbar lordosis. She was conceived via in vitro fertilization using a donor egg with pregnancy complicated by pre-eclampsia. Neonatal course was unremarkable. She met normal developmental milestones and walked at 15 months, but was slower than peers, requiring frequent breaks. She had difficulty climbing stairs and rising from the ground. Exam at age 12 was notable for pectus excavatum, significant lumbar lordosis, straight clavicles, scapular winging, and hip flexion contractures. Neurologic exam demonstrated bifacial weakness, significant neck flexion weakness, proximal greater than distal weakness with shoulder and pelvic girdle muscles rated 2/5, and positive Beevor sign. She ambulated short distances with a walker. Initially, genetic testing revealed D4Z4 hypomethylation (10%) and one FSHD-permissive 4qA allele without repeat contraction or SMCHD1 mutation. Repeat genetic testing revealed a D4Z4 duplication on the 4qA allele with one copy having 54 repeat units and the second having 2 repeat units. A pathogenic mutation in SMCHD1 was uncovered. These results confirmed a diagnosis of both FSHD1 and FSHD2. 

Concomitant FSHD1 and FSHD2 is an extremely rare occurrence with individuals presenting with a severe phenotype suggesting a synergistically deleterious effect of these genetic changes.