Facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder characterized by progressive weakening and wasting of certain muscles.

The prevalence of FSHD ranges from 1 in 8,333 to 1 in 15,000.

The Netherlands reports a prevalence of 1 in 8,333, and in the United States is commonly quoted as 1 in 15,000.

Race and ethnicity have not been shown to affect FSHD incidence or severity.

After genetic testing became possible, the average prevalence was found to be around 1 in 20,000: 1 in 20,000 is likely an underestimation, since many with FSHD have mild symptoms and are never diagnosed, or they are siblings of affected individuals and never seek definitive diagnosis.

It primarily affects the muscles of the face, shoulders and upper arms, but it can also involve muscles in other parts of the body.

FSHD is caused by a genetic mutation that affects the expression of a protein called DUX4 (double homeobox 4).

Normally, DUX4 is only produced during early development and then turned off.

However, in individuals with FSHD, the genetic mutation causes DUX4 to be inappropriately activated in skeletal muscle cells, leading to muscle damage and weakness.

The abnormal expression of DUX4 disrupts the normal regulation of genes involved in muscle development and function, leading to muscle degeneration.

FSHD is typically inherited in an autosomal dominant pattern.

However, not all individuals with the genetic mutation develop symptoms, and the severity of FSHD can vary widely even among affected family members.

Symptoms of FSHD usually appear in adolescence or early adulthood.

Symptoms of FSHD sometimes start in childhood.

Signs and symptoms include: weakness and atrophy of the facial muscles, difficulty closing the eyes or smiling, shoulder weakness, scapular winging and weakness in the upper arms and legs.

Less common are hearing loss, retinal abnormalities, or respiratory problems.

No cure for FSHD exists and treatment focuses on managing symptoms and improving quality of life.

Physical therapy, assistive devices, and orthopedic interventions may be recommended to maintain muscle strength and mobility.

Genetic counseling is also important for individuals with FSHD or a family history of the condition, as it can help provide information about the risk of passing the mutation to future generations.

FSHD is caused by a genetic mutation leading to deregulation of the DUX4 gene.

Normally, DUX4 is expressed in cells of the ovary and in very early human development, becoming repressed by the time an embryo is several days old.

In FSHD, DUX4 is inadequately repressed, allowing sporadic expression throughout life.

Deletion of DNA in the region surrounding DUX4 is the causative mutation in 95% of cases.

D4Z4 contraction and defines FSHD type 1 (FSHD1).

FSHD caused by other mutations is FSHD type 2 (FSHD2).

For disease to develop a 4qA allele is required, which 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 is 50%, autosomal dominant.

In 30% of cases, the mutation arises 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.

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.

Muscles of other areas usually are affected, especially those of the chest, spine, abdomen, and shin.

Almost any skeletal muscle can be affected in severe disease.

Abnormally positioned, or 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 to 30 years.

FSHD can also cause hearing loss and blood vessel abnormalities in the back of the eye.

Symptoms include: Facial weakness, scapular winging, foot drop

Complications: Chronic pain, scoliosis, Rare: respiratory insufficiency, hearing loss, retinal disease.


FSHD1, FSHD2, infantile-onset

Differential diagnosis:

Limb-girdle muscular dystrophy, Pompe disease, mitochondrial myopathy, polymyositis

While signs, symptoms, family history, and diagnostic tests can suggest FSHD, genetic testing provides definitive diagnosis.

No intervention has proven effective for slowing progression of weakness.

Screening allows for early detection and intervention.

Symptoms managed 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.

FSHD is one of three most common muscular dystrophies with myotonic dystrophy and Duchenne muscular dystrophy.

Prognosis is variable.

Many are not significantly limited in daily activity.

A wheel chair 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.

Typically, weakness develops in the face, then the shoulder girdle, then the upper arm.

Weakness appears to descend from the face to the legs.

The distribution and degree of muscle weakness is extremely variable, even between identical twins.

Musculoskeletal pain is common, most often in the neck, shoulders, lower back, and the back of the knee.

Fatigue is also common.

Muscle weakness usually IS MORE noticeable on one side of the body before the other, and is a hallmark of the disease.

The right shoulder and arm muscles are more often affected than the left upper extremity muscles, independent of handedness.

Symptoms usually appear in those 15 – 30 years of age, although infantile onset, adult onset, and absence of symptoms despite having the causal genetics also occur.

FSHD1 with a very large D4Z4 deletion is more strongly associated with infantile onset and severe weakness.

FSHD2 presents 10 year later than FSHD1.

FSHD1 and FSHD2 are indistinguishable on the basis of weakness.[

Disease progression is usually slow, with long static phases, in which no progression is apparent.

Less commonly, individual muscles rapidly deteriorate over several months.

Muscles weakening of the face is the most distinguishing sign of FSHD.

It is typically the earliest sign, and at least mild facial weakness can be found in 90% or more with FSHD.

Deficits is the ability to close the eyelids, can result in sleeping with the eyelids open and dry eyes: the orbicularis oculi muscle.

A common deficit is inability to purse the lips, causing inability to pucker, whistle, or blow up a balloon: orbicularis oris muscle.

A third common deficit is inability raise the corners of the mouth, causing a horizontal smile: 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.

Bilateral scapular winging occurs, right moreso than left.

After the facial weakness, weakness usually develops in the muscles of the chest and those that span from scapula to thorax.

80% of patients initially have symptoms involving the shoulder, such as difficulty working with the arms overhead, with the serratus anterior and middle and lower trapezii muscles being affected, while the upper trapezius is often spared.

Trapezius weakness causes winged scapulas, horizontal clavicles, and sloping shoulders, and arm abduction is impaired.

Serratus anterior weaknesss impairs arm flexion.

Severe muscle wasting can make bones and spared shoulder muscles very visible.

Shoulder weakness and pain lead to shoulder instability, with recurrent dislocation, subluxation, or downward translation of the humeral head.

In the chest, particularly the parts of the pectoralis major muscle that connect to the sternum and ribs can be affected, contributing to a prominent horizontal anterior axillary fold.

After upper torso weakness, weakness can move to the upper arms, biceps muscle and, particularly, the triceps muscle.

After the upper body, weakness can appear in either the pelvis, or it involves the tibialis anterior, causing foot drop.

The pelvic and thigh muscles tend to be the last group affected.

Weakness can occur in the abdominal muscles and paraspinal muscles, manifesting as a protuberant abdomen and lumbar hyperlordosis.

The most common non-musculoskeletal manifestation of FSHD is abnormalities occur in the arterioles in the retina.

Tortuosity of the retina arterioles is seen in approximately 50% of those with FSHD, and less common arteriole abnormalities include telangiectasias and microaneurysms.

The retinal abnormalities of arterioles usually do not affect vision or health.

A severe form of retinal arteriole changes occur in 1% of FSHD cases and are associated with large 4q35 deletions.

High-frequency sensorineural hearing loss can occur with large 4q35 deletions, but otherwise is no more common than in the general population.

Scoliosis can occur, due to rweakness of abdominal, hip extensor, and spinal muscles.

Breathing can be impaired and is associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-using patients.

Ventilator support is required in only 1% of cases.

In FSHD, there is failure of DUX4 repression and continued production of DUX4 protein, which is toxic to muscles.

FSHD involving deletion of D4Z4 repeats on 4q is classified as FSHD1, which accounts for 95% of FSHD cases.

The number of repeats is roughly inversely related to disease severity, with 8 – 10 repeats tend to have the mildest presentations, sometimes with no symptoms; those with 4 – 7 repeats have moderate disease that is highly variable; and those with 1 – 3 repeats are more likely to have severe, atypical, and early-onset disease.

De novo mutations are implicated in 10 – 30% of cases, up to 40% of which exhibit somatic mosaicism.

The severity of disease is correlated to the proportion of their cells carrying the mutation.

FSHD without D4Z4 contraction is classified as FSHD2, which constitutes 5% of FSHD cases.

DUX4 protein is a transcription factor that regulates many other genes.

Some of these genes are involved in apoptosis, such as p53, p21, MYC, and β-catenin, and and makes muscle cells more prone to apoptosis.

DUX4 expression lowers muscle cell tolerance of oxidative stress.

The variation in the ability of individual muscles to handle oxidative stress partially explains the muscle involvement patterns of FSHD.

DUX4 protein downregulates many genes involved in muscle development.

DUX4 expression has shown to reduce muscle cell proliferation, differentiation, and fusion.

DUX4 protein regulates a few genes that are involved in RNA quality control, and causes accumulation of RNA with subsequent apoptosis.

Estrogen may play a role in modifying DUX4 protein effects on muscle differentiation, possibly explain why females are lesser affected than males.

The hypoxia-inducible factors (HIFs) are upregulated by DUX4 protein, possibly causing pathologic signaling leading to cell death.

DUX4 expression in muscle cells lead to the recruitment and alteration of fibrous/fat progenitor cells, which explains why muscles become replaced by fat and fibrous tissue.

Microscopic cross-sectional views of FSHD-affected muscle fibers show inflammation and fibrosis, as well as muscle fiber shape change, death, and regeneration.

Endomysial blood vessels can be surrounded by inflammation, which is relatively unique to FSHD.

FSHD inflammation contains CD4+ T-cells, and is succeeded by deposition of fatty infiltration, then fibrosis.

It is unexplained why individual muscles can weaken while adjacent muscles remain strong.

The right shoulder and arm muscles are more often affected than the left upper extremity muscles.

The deltoid is often spared in FSHD which is not seen in any other condition that affects the muscles around the scapula.

Medical imaging (CT and MRI) have shown muscle involvement not readily apparent otherwise.

The semimembranosus muscle, part of the hamstrings, is commonly affected: it is the most frequently and severely affected muscle.

Of the quadriceps muscles, the rectus femoris is commonly affected.’

The iliopsoas, a hip flexor muscle, is very often spared.

Tortuosity of the retinal arterioles, and less often microaneurysms and telangiectasia, are common in FSHD.


FSHD can be presumptively diagnosed in many cases based on signs, symptoms, and/or non-genetic medical tests, especially if a first-degree relative has genetically confirmed FSHD.

Genetic testing can provide a definitive diagnosis.

Genetic testing is the gold standard for FSHD diagnosis.

MRI show asymmetrical involvement of various muscles in FSHD And can support the diagnosis of FSHD, although they are all less sensitive and less specific than genetic testing.

In FSHD, Creatinine kinase level is normal to mildly elevated, never exceeding five times the upper limit of normal.

Electromyogram (EMG) measures the electrical activity in the muscle. EMG can show nonspecific signs of muscle damage or irritability.

Muscle biopsy is rarely indicated: Findings in FSHD are nonspecific, such as presence of white blood cells or variation in muscle fiber size.

Muscle MRI is sensitive for detecting muscle damage, and can help differentiate FSHD from other muscle diseases, directing genetic testing.

Differential diagnosis of FSHD: limb-girdle muscular dystrophy, scapuloperoneal myopathy, Pompe disease, and polymyositis.

Features that are suggestive of FSHD are facial weakness, asymmetric weakness, and lack of benefit from immunosuppression medications.

Findings suggestive of an alternative diagnosis are contractures, respiratory insufficiency, weakness of muscles controlling eye movement, and weakness of the tongue or throat.

No drug treatment has proven to significant slow the progression of weakness or meaningfully improve strength.

Screening and monitoring of complications: dilated eye exam to look for retinal abnormalities, hearing tests, and pulmonary function testing,

Aerobic exercise reduces chronic fatigue and decelerate fatty infiltration of muscle in FSHD.

Physical activity may slow disease progression in the legs.

Occupational therapy, cognitive behavioral therapy (CBT) has been shown to reduce chronic fatigue in FSHD, and it also decelerates fatty infiltration of muscle by increasing daily activity.

Braces are often used to address muscle weakness.

Scapular winging is benefitted by operative scapular fixation: involves inducing bony fusion, called arthrodesis, between the scapula and ribs.

Another form of operative scapular fixation is scapulopexy: scapula is secured to the ribs with only wire, tendon grafts, or other material.

Another form of scapular fixation, involves surgically rearranging the attachments of muscles to bone.

Other procedures: eyelid implants,drooping lower lip plastic surgery, foot drop can surgical correction with tendon transfer, and scoliosis correction with spinal fusion.

A cloth brace to hold the scapulas in retraction reduces shoulder symptoms, such as collarbone pain.

Genetics partially predicts prognosis: large D4Z4 repeat deletions are more likely to have severe and early disease, as well as non-muscular symptoms.

Patients with genetic mutations of both FSHD1 and FSHD2 are more likely to have severe disease.

D4Z4 shortening is less and disease manifestation is milder when a prominent family history is present, as opposed to a new mutation.

Women tend to develop symptoms later in life and have less severe disease courses in facioscapulohumeral muscular dystrophy

Pregnancy outcomes are overall good in mothers with FSHD, although increased weakness may occur.

The disease manifests less often in women, and even when it manifests in women, they on average are less severely affected than affected males.

Estrogen has been suspected to be a protective factor that accounts for this discrepancy.

However, disease progression was not different through periods of hormonal changes, such as menarche, pregnancy, and menopause.

Gene therapy is the administration of nucleotides to treat disease, are in the preclinical stage of development for the treatment of FSHD.

disease progression was not different through periods of hormonal changes, such as menarche, pregnancy, and menopause.Disease progression was not different through periods of hormonal changes, such as menarche, pregnancy, and menopause.


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