Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm. These areas can be spared. Muscles of other areas usually are affected, especially those of the chest, abdomen, spine, and shin. Most skeletal muscle can be affected in advanced disease. Abnormally positioned, termed 'winged', scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15–30 years. FSHD can also cause hearing loss and blood vessel abnormalities at the back of the eye.
FSHD is caused by a genetic mutation leading to deregulation of the DUX4 gene. Normally, DUX4 is expressed (i.e., turned on) only in select human tissues, most notably in the very young embryo. In the remaining tissues, it is repressed (i.e., turned off). In FSHD, this repression fails in muscle tissue, allowing sporadic expression of DUX4 throughout life. Deletion of DNA in the region surrounding DUX4 is the causative mutation in 95% of cases, termed "D4Z4 contraction" and defining FSHD type 1 (FSHD1). FSHD caused by other mutations is FSHD type 2 (FSHD2). To develop the disease, a 4qA allele is also required, and is a common variation in the DNA next to DUX4. The chances of a D4Z4 contraction with a 4qA allele being passed on to a child are 50% (autosomal dominant); in 30% of cases, the mutation arose spontaneously. Mutations of FSHD cause inadequate DUX4 repression by unpacking the DNA around DUX4, making it accessible to be copied into messenger RNA (mRNA). The 4qA allele stabilizes this DUX4 mRNA, allowing it to be used for production of DUX4 protein. DUX4 protein is a modulator of hundreds of other genes, many of which are involved in muscle function. How this genetic modulation causes muscle damage remains unclear.
Signs, symptoms, and diagnostic tests can suggest FSHD; genetic testing usually provides a definitive diagnosis. FSHD can be presumptively diagnosed in an individual with signs/symptoms and an established family history. No intervention has proven effective in slowing the progression of weakness. Screening allows for early detection and intervention for various disease complications. Symptoms can be addressed with physical therapy, bracing, and reconstructive surgery such as surgical fixation of the scapula to the thorax. FSHD affects up to 1 in 8,333 people, putting it in the three most common muscular dystrophies with myotonic dystrophy and Duchenne muscular dystrophy. Prognosis is variable. Many are not significantly limited in daily activity, whereas a wheelchair or scooter is required in 20% of cases. Life expectancy is not affected, although death can rarely be attributed to respiratory insufficiency due to FSHD.
FSHD was first distinguished as a disease in the 1870s and 1880s when French physicians Louis Théophile Joseph Landouzy and Joseph Jules Dejerine followed a family affected by it, thus the initial name Landouzy–Dejerine muscular dystrophy. Descriptions of probable individual FSHD cases predate their work. The significance of D4Z4 contraction on chromosome 4 was established in the 1990s. The DUX4 gene was discovered in 1999, found to be expressed and toxic in 2007, and in 2010, the genetic mechanism causing its expression was elucidated. In 2012, the gene most frequently mutated in FSHD2 was identified. In 2019, the first drug designed to counteract DUX4 expression entered clinical trials.
Signs and symptoms Classically, weakness develops in the face, then the shoulder girdle, then the upper arm. These muscles can be spared, and other muscles usually are affected. The order of muscle involvement can cause the appearance of weakness, "descending" from the face to the legs. The distribution and degree of muscle weakness are extremely variable, even between identical twins. Musculoskeletal pain is very common, most often described in the neck, shoulders, lower back, and the back of the knee. Fatigue is also common. Muscle weakness usually becomes noticeable on one side of the body before the other, a disease hallmark. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, independent of handedness. Otherwise, neither side of the body is at more risk. Classically, symptoms appear in those 15–30 years old, although adult-onset can also occur. Infantile-onset (also called early-onset), defined as onset before age 10, occurs in 10% of affected individuals. FSHD1 with a substantial D4Z4 deletion (EcoRI 10-11 kb) is more strongly associated with infantile-onset and severe weakness. Absence or near absence of symptoms is not uncommon, approaching up to 30% of mutation-carrying individuals in select FSHD1 families. On average, FSHD2 presents 10 years later than FSHD1. Otherwise, FSHD1 and FSHD2 are indistinguishable on the basis of weakness. Disease progression is slow, and long static phases, in which no progression is apparent, are not uncommon. Less commonly, individual muscles rapidly deteriorate over several months. The symptom burden of FSHD is typically more severe than it is perceived to be by those without the disease.The FDA held an externally-led Patient-Focused Drug Development meeting with about 400 FSHD patients on June 29, 2020, resulting in a seminal document called the "Voice of the Patient Report." The report captures the impact of FSHD on the daily lives of affected people as conveyed by the patients. While FSHD is often perceived as "mild," the report shows that over 80% of patients report being "moderately" or "severely" limited in daily activities.
Face Weakness of the muscles of the face is the most distinguishing sign of FSHD. It is typically the earliest sign, although it is rarely the initial complaint. At least mild facial weakness can be found in 90% or more with FSHD. One of the most common deficits is inability to close the eyelids, which can result in sleeping with the eyelids open and dry eyes. The implicated muscle is the orbicularis oculi muscle. Another common deficit is an inability to purse the lips, causing an inability to pucker, whistle, or blow up a balloon. The implicated muscle is the orbicularis oris muscle. A third common deficit is the inability to raise the corners of the mouth, causing a "horizontal smile," which looks more like a grin. Responsible is the zygomaticus major muscle.
Weakness of facial muscles contributes to difficulty pronouncing words. Facial expressions can appear diminished, arrogant, grumpy, or fatigued. Muscles used for chewing and moving the eyes are not affected. Difficulty swallowing is not typical, although it can occur in advanced cases, which is at least in part due to facial muscle weakness. FSHD is generally progressive, but it is not established whether facial weakness is progressive or stable throughout life.
Shoulder, chest, and arm
After the facial weakness, weakness usually develops in the muscles of the chest and those that span from the scapula to the thorax. Symptoms involving the shoulder, such as difficulty working with the arms overhead, are the initial complaint in 80% of cases. Predominantly, the serratus anterior and middle and lower trapezii muscles are affected; the upper trapezius is often spared. Trapezius weakness causes the scapulas to become downwardly rotated and protracted, resulting in winged scapulas, horizontal clavicles, and sloping shoulders; arm abduction is impaired. Serratus anterior weakness impairs arm flexion, and worsening of winging can be demonstrated when pushing against a wall. Muscles spanning from the scapula to the arm are generally spared, which include the deltoid and the rotator cuff muscles. The deltoid can be affected later on, especially the upper portion.
Severe muscle wasting can make bones and spared shoulder muscles very visible, a characteristic example being the "poly-hill" sign elicited by arm elevation. The first "hill" or bump is the upper corner of scapula appearing to "herniate" up and over the rib cage. The second hill is the AC joint, seen between a wasted upper trapezius and wasted upper deltoid. The third hill is the lower deltoid, distinguishable from the wasted upper deltoid and wasted humeral muscles. Shoulder weakness and pain can, in turn, lead to shoulder instability, such as recurrent dislocation, subluxation, or downward translation of the humeral head.
Also affected is the chest, particularly the parts of the pectoralis major muscle that connect to the sternum and ribs. The part that connects to the clavicle is less often affected. This muscle-wasting pattern can contribute to a prominent horizontal anterior axillary fold. Beyond this point, the disease does not progress further in 30% of familial cases. After upper torso weakness, weakness can "descend" to the upper arms (biceps muscle and, particularly, the triceps muscle). The forearms are usually spared, resulting in an appearance some compare to the fictional character Popeye. When the forearms are affected in advanced disease, the wrist extensors are more often affected.
Lower body and trunk After the upper body, weakness can next appear in either the pelvis or it "skips" the pelvis and involves the tibialis anterior (shin muscle), causing foot drop. One author considers the pelvic and thigh muscles the last group affected. Pelvic weakness can manifest as a Trendelenburg's sign. Weakness of the back of the thigh (hamstrings) is more common than weakness of the front of the thigh (quadriceps). In more severe cases, especially infantile FSHD, there can be anterior pelvic tilt, with associated hyperextension of the knees.
Weakness can also occur in the abdominal muscles and paraspinal muscles, which can manifest as a protuberant abdomen and lumbar hyperlordosis. Abdominal weakness can cause inability to do a sit-up or the inability to turn from one side to the other while lying on one's back. Of the rectus abdominis muscle, the lower portion is preferentially affected, manifesting as a positive Beevor's sign. In advanced cases, neck extensor weakness can cause the head to lean towards the chest, termed head drop.
Non-muscular
The most common non-musculoskeletal manifestation of FSHD is abnormalities in the small arteries (arterioles) in the retina. Tortuosity of the arterioles is seen in approximately 50% of those with FSHD. Less common arteriole abnormalities include telangiectasias and microaneurysms. These abnormalities of arterioles usually do not affect vision or health, although a severe form of it mimics Coat's disease, a condition found in about 1% of FSHD cases and more frequently associated with large 4q35 deletions. High-frequency sensorineural hearing loss can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population. Large 4q35 deletion can lead to various other rare manifestations.
Scoliosis can occur, thought to result from muscular weakness in the abdomen, hip extensors, and spine. Conversely, scoliosis can be viewed as a compensatory mechanism to weakness. Breathing can be affected, associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-using patients. However, ventilator support (nocturnal or diurnal) is needed in only 1% of cases. Although there are reports of increased risk of cardiac arrhythmias, the consensus is that the heart is unaffected.
Genetics