facioscapulohumeral muscular dystrophy facioscapulohumeral muscular dystrophy 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, and 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 – 30 years. fshd can also cause hearing loss and blood vessel abnormalities in the back of the eye. facioscapulohumeral muscular dystrophyother nameslandouzy–dejerine muscular dystrophy, fshmd, fsha diagram showing the muscles commonly affected by fshdpronunciation/ˌfeɪʃiːoʊˌskæpjəloʊˈhjuːmərəl/ fay-shee-oh-skap-yə-low-hew-mər-əl alt. /feɪs-, fɑːʃ-, fɑːs-/specialtyneurology, neuromuscular medicinesymptomsfacial weakness, scapular winging, foot dropcomplicationschronic pain, scoliosisrare: respiratory insufficiency, hearing loss, retinal diseaseusual onsetages 15 – 30 yearsdurationlifelongtypesfshd1, fshd2, infantile-onsetcausesgenetic (inherited or new mutation)risk factorsmale sex, extent of genetic mutationdiagnostic methodgenetic testingdifferential diagnosislimb-girdle muscular dystrophy (especially calpainopathy), pompe disease, mitochondrial myopathy, polymyositismanagementphysical therapy, bracing, reconstructive surgerymedicationclinical trials ongoingprognosisprogressive, unaffected life expectancyfrequencyup to 1/8,333 fshd is caused by a genetic mutation leading to deregulation of the dux4 gene. normally, dux4 is expressed (i.e., turned on) in cells of the ovary and in very early human development, becoming repressed (i.e., turned off) 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, termed "d4z4 contraction" and defining fshd type 1 (fshd1). fshd caused by other mutations is fshd type 2 (fshd2). for disease to develop, also required is a 4qa allele, 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 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, family history, and diagnostic tests can suggest fshd; genetic testing can provide definitive diagnosis. no intervention has proven effective for slowing 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 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. 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. their work is predated by descriptions of probable individual fshd cases. 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. distribution and degree of muscle weakness is 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 hallmark of the disease. the right shoulder and arm muscles are more often affected than the left upper extremity muscles, independent of handedness.: 139 otherwise, neither side of the body has been found to be at more risk. classically, symptoms 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 (ecori 10-11 kb) is more strongly associated with infantile onset and severe weakness. on average, fshd2 presents 10 year 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, is not uncommon. less commonly, individual muscles rapidly deteriorate over several months. 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 inability to purse the lips, causing inability to pucker, whistle, or blow up a balloon. the implicated muscle is the orbicularis oris muscle. a third common deficit is inability raise the corners of the mouth, causing a "horizontal smile," which looks more like a grin. responsible is the zygomaticus major muscle. weakness of various facial muscles contributes to difficulty pronouncing the letters m, b, and p. 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 can occur in advanced cases. fshd is generally progressive, but it is not established whether facial weakness is progressive or stable throughout life. shoulder, chest, and arm bilateral scapular winging, right moreso than left. left image showing wall push test, right image showing attempted shoulder flexion. after the facial weakness, weakness usually develops in the muscles of the chest and those that span from scapula to 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 weaknesss 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 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 between 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, although 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 to be the last group affected. pelvic muscle weakness can manifest as pelvic tilt, causing the hips to be held in slight flexion. pelvic weakness can also cause a trendelenburg's sign. weakness of the back of the thigh (hamstrings) is more common than weakness of the front of the thigh (quadriceps). 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 funduscopy of the retinal: (a) normal blood vessels (b) tortuous blood vessels, as often seen with fshd 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 weakness of abdominal, hip extensor, and spinal muscles. 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, general consensus is that the heart is not affected. genetics structure of dux4 protein full-length (fl), with short (s) version indicated. the genetics of fshd is complex. fshd and the myotonic dystrophies have unique genetic mechanisms that differ substantially from the rest of genetic myopathies. the dux4 gene is the focal point of fshd genetics. normally, dux4 is expressed during embryogenesis and later repressed in all tissues except the testes. in fshd, there is failure of dux4 repression and continued production of dux4 protein, which is toxic to muscles. the mechanism of failed dux4 repression is hypomethylation of dux4 and its surrounding dna on the tip of chromosome 4 (4q35), allowing transcription of dux4 into messenger rna (mrna). several mutations can result in disease, upon which fshd is sub-classified into fshd type 1 (fshd1) and fshd type 2 (fshd2). disease can only result when a mutation is present in combination with select, commonly found variations of 4q35, termed haplotype polymorphisms. there are at least 17 4q35 haplotype polymorphisms, roughly dividable into the groups 4qa and 4qb. a 4qa haplotype polymorphism, often referred to as a 4qa allele, is necessary for disease, as it contains a polyadenylation sequence that allows dux4 mrna to resist degradation long enough to be translated into dux4 protein. dux4 and the d4z4 repeat array d4z4 array with three d4z4 repeats and the 4qa allele. cencentromeric endteltelomeric end nde boxnon-deleted elementpaspolyadenylation site triangled4z4 repeattrapezoidpartial d4z4 repeat white boxplamgray