Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

Figure 1. The genetic pathomechanisms of FSHD types 1 and 2. Normal individuals have 11 to more than 100 repeats (50–300 kb) of D4Z4 repeats on the sub-telomeric region of chromosome 4q35, whereas individuals with FSHD1 have a deletion of the array to 10 or fewer D4Z4 units (<39 kb). Contraction of D4Z4 repeats with the presence of a permissive 4qA haplotype or allele containing a polyadenylation signal (PAS, green box) then disrupts CpG methylation (hypomethylation), leading to chromatin relaxation at the array and allowing for the expression of a toxic transcription factor, DUX4 (double homeobox 4). Additionally, the DUX4 retrogene within the D4Z4 unit lacks a stabilizing PAS but can use an additional exon immediately distal to the repeat that contains a polyadenylation signal (DUX4-PAS). In FSHD2, mutation of methylase-related genes, SMCHD1 or DNMT3B, also causes hypomethylation of D4Z4 chromatin structure, resulting in DUX4 expression. There are several potential mechanisms of DUX4 involving in FSHD pathogenies. DUX4 has been implicated as being involved in apoptosis, myogenesis, epigenetic regulation, and regulatory signaling pathways in skeletal muscle and extramuscular tissues,…

Figure 2. Characteristic muscular and extramuscular signs of FSHD. Generally, most patients with FSHD have multiple distinctive features (as listed in Table 1). Illustrated FSHD-related signs and symptoms marked with red text indicate atypical and relatively rare features that are usually presented in infantile FSHD or at the advanced stage of disease course. Figure modified from Mul et al. 2016 [11].

Figure 3. Muscle computed tomography (CT) of upper thighs in infantile FSHD patients. (A) A male with 13 kb EcoRI showing early degeneration of left hamstring muscles and rectus femoris (white arrows) at 12 years old, compared to a relatively normal appearance of right thigh muscles; (B) Follow-up at 15 years old showing a rapid progression of muscle degeneration depicting a “wrench-head” appearance caused by extensive muscle wasting at the bilateral hamstring muscles with selectively affected rectus femoris of quadriceps (red arrows). Another two CT findings of (C) right leg of a 16-year-old female (11 kb EcoRI), and (D) both legs of a 28-year-old male (10 kb EcoRI), showing a similar muscle pattern, respectively. Informed consents were obtained from above reported patients.

Figure 4. The paradigm of multidisciplinary care of infantile FSHD, incorporating disease-modifying therapies with the standard of care (SOC). Novel disease-modifying agents and evolving multidisciplinary supportive management need to occur concomitantly to achieve the best possible outcome for patients with infantile FSHD. Implementation of comprehensive SOC also plays a critical role in drug development because it may eliminate the variability of treatment outcomes due to variable care received.