Facioscapulohumeral muscular dystrophy

INTRODUCTION — The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in several genes required for normal muscle function. Some of the genes responsible for these conditions have been identified. Muscle weakness is the primary symptom.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common type of muscular dystrophy. It is a complex genetic disorder characterized in most cases by slowly progressive muscle weakness involving the facial, scapular, upper arm, lower leg, and hip girdle muscles, usually with asymmetric involvement.

The clinical aspects of facioscapulohumeral muscular dystrophies are discussed here. Other muscular dystrophies are presented separately. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Emery-Dreifuss muscular dystrophy" and "Limb-girdle muscular dystrophy" and "Myotonic dystrophy: Etiology, clinical features, and diagnosis" and "Oculopharyngeal, distal, and congenital muscular dystrophies".)

ETIOLOGY

Genetics — The cause of FSHD is inappropriate expression of the double homeobox protein 4 gene (DUX4) [1,2]. The DUX4 gene lies within each unit of a macrosatellite array known as D4Z4, located in the 4q35 region. The DUX4 gene is normally expressed in germ line tissue but is epigenetically repressed in somatic cells [3]. Release of DUX4 repression (derepression) only occurs in the context of a permissive genetic background.

There are two genetically distinct forms of FSHD, FSHD1, and FSHD2, which are caused by the inappropriate expression of DUX4 [4]. Different pathways, including the D4Z4 repeat number in FSHD1 and heterozygous pathogenic SMCHD1 variants in FSHD2, result in D4Z4 chromatin relaxation and abnormal expression of DUX4.

Both FSHD1 and FSHD2 require the polyadenylation signal provided by a permissive 4qA haplotype [5]. The polyadenylated DUX4 transcripts remain stable and lead to the development of FSHD by a toxic gain-of-function mechanism (figure 1). In the absence of polyadenylation, DUX4 transcripts are unstable, and FSHD does not develop.

FSHD1 — In approximately 95 percent of patients with FSHD, the disorder is causally related to a short repeat array that remains after deletion of an integral number of tandemly arrayed 3.3 kb repeat units (called D4Z4) in the 4q35 region (figure 2) [6-8]. The number of D4Z4 repeat units in the general population varies from 11 to 100. In patients with FSHD1, one D4Z4 allele is contracted (1 to 10 repeat units), and the other D4Z4 allele has the normal number (11 to 100 repeat units). Contracted D4Z4 repeat arrays are associated with DNA hypomethylation, favoring a more relaxed chromatin structure, which facilitates stable expression of the myotoxic DUX4 with a 4qA permissive haplotype [2,9,10]. In a retrospective cohort study of over 800 patients with FSHD1, the degree of 4q35 distal D4Z4 hypomethylation was correlated with disease severity and progression [11].

There is a rough and inverse relationship between the onset and clinical severity of FSHD, and the size of the pathogenic (contracted) D4Z4 repeat array. Individuals with one to three repeat D4Z4 units are typically at the severe end of the disease spectrum and usually present as “infantile” cases with severe weakness and a higher incidence of extramuscular manifestations (see 'Infantile form' below). In patients with one to six repeats, the repeat number correlates inversely with disease severity. With 7 to 10 repeat units, the clinical variation ranges from asymptomatic to severely affected and nonpenetrance (no signs of FSHD on examination) is more common [1,2]. Only approximately one-half of the contractions of the D4Z4 repeat array to a size of 1 to 10 units are pathogenic, as the array needs to reside on an FSHD-permissive genetic background of chromosome 4 that contains a polymorphic polyadenylation signal for DUX4 [12].

FSHD2 — Approximately 5 percent of patients with FSHD have no contracted D4Z4 repeat array but show DNA hypomethylation on both normal D4Z4 alleles [9], a condition termed FSHD2. Patients with FSHD2 typically have a lower number of D4Z4 repeats, ranging from 11 to 20, compared with 11 to 100 repeats in the general population [13]. Heterozygous pathogenic variants in SMCHD1, a chromatin modifier gene, are the cause of most cases of FSHD2 via D4Z4 chromatin relaxation [14]. The SMCHD1 protein is an epigenetic modifier that directly binds to the D4Z4 repeat to maintain a repressed chromatin state in somatic cells via methylation, and its reduced activity in FSHD2 patients leads to hypomethylation of the D4Z4 repeat array and thus the derepression of DUX4 transcription [15,16]. Other causes of FSHD2 include rare pathogenic variants of DNMT3B and LRIF1 genes that lead to chromatin relaxation [17,18].

The phenotype of FSHD2 appears to be clinically indistinguishable from FSHD1 [19]. Patients with both 8 to 10 D4Z4 repeats (FSHD1) and a pathogenic variant in the SMCHD1 gene (FSHD2) are more severely affected compared with affected family members who have only one of the two pathogenic variants [15,16,20].

Inheritance pattern — The inheritance pattern of FSHD1 is autosomal dominant [6]. However, sporadic occurrences are frequent, as de novo pathogenic contraction variants of the D4Z4 locus account for 10 to 30 percent of FSHD1 cases [21,22].

The inheritance of FSHD2 is digenic, requiring a pathogenic variant in a chromatin modifier gene and a borderline-sized D4Z4 repeat array on a permissive 4qA haplotype [2,14]. Although data are limited, approximately 60 percent of FSHD2 cases appear to be sporadic [19].

EPIDEMIOLOGY — The estimated prevalence of FSHD is 4 to 12 per 100,000 population [23-26]; a study from the Netherlands found an incidence of 0.3 per 100,000 person-years [26]. FSHD is the third most common type of muscular dystrophy, behind only the dystrophinopathies (Duchenne and Becker muscular dystrophies) and myotonic dystrophy [7,23]. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

CLINICAL FEATURES

Disease onset — The age of symptom onset varies from infancy to middle age but is usually in the second decade. By age 20 years, findings are seen in approximately 90 percent of affected patients [6], although some or all of the signs may be subclinical [27]. Progression is usually slow with a normal or near-normal life span. However, disease severity is also highly variable. (See 'Prognosis' below.)

Muscle weakness — The typical or classic form of FSHD is characterized by muscle weakness involving the facial, scapular, upper arm, lower leg, and abdominal muscles, usually with asymmetric involvement (figure 3) [6,27,28].

●Facial involvement – The facial muscles are involved initially, in some cases with inability to close the eyes tightly, smile, or whistle, with a pouting appearance of the lips, an expressionless face, and mild dimpling in the areas lateral to the angles of the mouth (picture 1). However, the facial weakness can be mild early in the course and may remain mild for many years.

Dysphagia is rare in patients with FSHD but can develop due to weakness of the jaw and lingual muscles [29].

●Shoulders and upper arms – Weakness of the shoulder and upper arm muscles is characteristic [6,27]. Scapular winging is a common early feature. A distinctive appearance of the shoulders can develop (picture 2) with protrusion of the trapezii muscles, riding of the scapulae upwards and over the lateral parts of the thorax, and forward jutting of the medial ends of the clavicles when the arms are abducted. The deltoid muscles are relatively spared in the early stages and are relatively less affected compared with other shoulder girdle muscles as the disease progresses. By contrast, the pectoral muscles are severely affected with weakness and atrophy [30]. There is also marked weakness and atrophy of the biceps and triceps, while forearm muscles are usually spared.

●Lower body – Weakness of the lower abdominal muscles is often present, leading to a protuberant abdomen, an exaggerated lumbar lordosis, and a positive Beevor sign, characterized by upward deflection of the umbilicus with neck flexion in supine position (movie 1) [6,27]. The lower leg (peroneal) muscles are variably affected in FSHD, resulting in foot drop. In addition, there can be associated hip girdle weakness.

●Respiratory function – Respiratory function is usually but not always preserved. A Dutch population-based study reported that respiratory insufficiency requiring nocturnal ventilatory support affected approximately 1 percent of patients with FSHD [31], while a cross-sectional observational study of 69 patients with FSHD found that restrictive lung disease by pulmonary function testing was present in approximately 10 percent [32]. One case-control study of 14 adults with FSHD and 14 matched controls found that both the diaphragm and expiratory abdominal muscles were weak in the FSHD group compared with the control group [33]. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation".)

Patients are at risk for sleep-related breathing disorders. In a study of adults with FSHD admitted to a sleep laboratory complaining of morning headaches, excessive daytime sleepiness, or other sleep-related symptoms, nocturnal hypoventilation and obstructive sleep apnea were common findings [34].

Other manifestations — Other manifestations of FSHD may include pain, retinal vasculopathy, hearing loss, cardiac arrhythmia, cognitive impairment, and epilepsy [6,27].

●Pain – Chronic pain affects 55 to 80 percent of patients with FSHD, with severe pain in up to 23 percent [35-38]. The most common locations for pain include the shoulder, neck, lower back, and lower legs. The pathophysiology of pain in FSHD is likely multifactorial, including contributions from myalgias and from biomechanical stress related to muscle weakness and postural problems such as kyphosis and lordosis [39].

●Retinal vasculopathy – Vision is typically normal in FSHD despite the presence of retinal vascular disease, which occurs in 50 to 75 percent of patients [40,41]. The retinal vasculopathy is characterized by bilateral retinal telangiectasias and microaneurysms as demonstrated by fluorescein angiography. Rare patients with FSHD demonstrate retinal telangiectasia and exudation that can progress to retinal detachment and visual loss, a condition known as Coats disease when unilateral and idiopathic [42,43]. Coats syndrome associated with FSHD can be bilateral [44]. Visual acuity loss affects approximately 1 percent of patients with FSHD.

●Hearing loss – Progressive hearing loss may occur with an increased prevalence in FSHD compared with the general population and is described in both typical and particularly in severe infantile cases [40,45,46]. Hearing loss in children with FSHD appears to correlate with larger D4Z4 repeat contraction size (ie, smaller EcoRI/BlnI fragment size) [46]. However, other studies have failed to corroborate an increased rate of hearing loss in FSHD [47,48].

●Cardiac function – Cardiac arrhythmias, generally asymptomatic, probably have a higher prevalence in FSHD compared with the general population as reported by several studies [49-52] but not all [53].

●Cognition – Cognitive impairment, sometimes with epilepsy, has been reported in patients with severe early-onset FSHD [54-57]. (See 'Infantile form' below.)

Atypical forms — Genetically confirmed variants (with contraction of the D4Z4 macrosatellite repeat in the subtelomeric region of chromosome 4q35) of FSHD include the following types:

●Infantile (early onset) form (see 'Infantile form' below)

●Scapulohumeral dystrophy phenotype with facial sparing [58-61]

●Limb-girdle muscular dystrophy phenotype [62]

●Distal myopathy [58,62,63]

●Focal monomelic lower limb or upper limb atrophy [64,65]

●Axial myopathy with camptocormia [66-68]

The phenotypic spectrum of FSHD may continue to expand with the ability to confirm the diagnosis by molecular genetic testing.

Infantile form — The infantile variety of FSHD, which is often sporadic in inheritance, is observed in approximately 4 percent of patients with FSHD [69,70]. The onset is within the first few years of life and the course is rapidly progressive in most cases, with wheelchair confinement by the age of 12 years or earlier. Children with this form of FSHD develop early facial weakness, with an inability to close the eyes in sleep, and inability to smile or show facial expression. The weakness soon involves the shoulder and hip girdles resulting in severe lumbar lordosis, pronounced forward pelvic tilt, and hyperextension of the knees and the head upon walking. Marked weakness of the wrist extensors may result in a wrist drop.

While infantile FSHD is usually associated with severe limb weakness and marked disability, rare cases manifest with milder limb weakness – despite severe facial diplegia – and retained ability to ambulate [70-73].

Young children with early onset FSHD and a very small number of chromosome 4q35 repeats often have epilepsy, intellectual disability, and severe sensorineural hearing loss [54,74].

Laboratory abnormalities — Serum creatine kinase is often but not always elevated in patients with symptomatic FSHD, usually to no more than five times the upper limit of normal [6]. Creatine kinase is rarely elevated in asymptomatic patients.

The EMG typically displays myopathic features with low amplitude, short duration, polyphasic potentials. (See "Overview of electromyography", section on 'Myopathies'.)

The muscle biopsy shows mainly nonspecific myopathic changes, with variability in fiber size including large hypertrophic fibers and a few angulated atrophic fibers. In addition, inflammatory cell infiltrates are present in up to 40 percent of patients with FSHD [6,27]. The inflammation is usually mild but may be intense. Histological differentiation from polymyositis is based upon the fact that hypertrophy of the muscle fibers is not observed in the myositis. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

DIAGNOSIS — The diagnosis of typical (classic) FSHD is suspected in patients who present with weakness of the face, shoulder girdle, and upper arm with relative sparing of the deltoid muscles [75]. Genetic testing is the principle method for confirming the diagnosis (algorithm 1) [6,27,76,77]. However, genetic testing is not necessary for each affected person with a typical clinical presentation if the family history is consistent with autosomal dominant inheritance and the diagnosis has been genetically confirmed in a first-degree relative [77].

In general, patients with suspected muscular dystrophy should be referred to a specialist with expertise in neuromuscular disorders (where available) for evaluation and diagnosis.

Clinical diagnosis — The clinical diagnosis of typical FSHD is suspected in patients who present with relatively selective weakness of the face and shoulder girdle muscles, typically including weakness of the scapular fixators with scapular winging [75]. In occasional FSHD cases where symptomatic lower leg or hip girdle weakness leads to presentation, there is nearly always some degree of face and shoulder girdle involvement on clinical examination. (See 'Muscle weakness' above.)

The clinical diagnostic criteria for FSHD, proposed in the 1990s, have been largely supplanted by molecular genetic testing [27]. The relevance of these criteria is challenged by the finding that some patients with a confirmed genetic diagnosis of FSHD do not fulfill the clinical criteria [63].

Electromyography (EMG) and muscle biopsy are not necessary when the diagnosis of FSHD is confirmed by genetic testing. However, EMG and muscle biopsy (see 'Laboratory abnormalities' above) are suggested for patients with a clinical suspicion of FSHD who have negative standard genetic testing for FSHD1 and FSHD2 [76].

Limited data suggest that a positive Beevor sign has a high sensitivity and specificity for FSHD. In one prospective case-control study, a Beevor sign was present in 27 of 30 patients (90 percent) with FSHD, and was absent in 40 control patients with other neuromuscular disorders [78]. A later unblinded case-control study found a positive Beevor sign in 19 of 20 patients (95 percent) with FSHD, 2 of 28 patients (7 percent) with other neuromuscular disorders, and 0 of 20 control patients without muscle disease [79].

Inspection of the extensor digitorum brevis (EDB) muscle is helpful in the diagnosis of FSHD, because it is usually hypertrophic. By comparison, atrophy of the EDB muscle is common in peripheral motor neuropathies.

Genetic confirmation — A commercial genetic test for FSHD uses a p13E-11 DNA probe to detect a specific deletion of a tandem array of 3.3 kb repeated DNA elements (D4Z4) that is located within the subtelomere region of chromosome 4q (4q35). This diagnostic test is positive in approximately 95 percent of typical FSHD1 cases [80-82].

When the clinical suspicion for FSHD is high, a positive genetic test is sufficient to confirm the diagnosis of FSHD1 and further testing to exclude a false positive result is generally not necessary [76]. However, if the genetic test for the D4Z4 repeat array contraction is negative, genetic testing of the SMCHD1 gene for FSHD2 should be pursued along with haplotype and methylation analysis [83]. In these patients, if SMCHD1 gene testing is negative, pathogenic variants in DNMT3B and LRIF1 should be considered as a rare cause of the disease [18].

A number of issues can complicate the genetic diagnosis of FSHD and lead to a false negative or false positive result [6,76]. Some of the more important issues include the following:

●A false negative result can occur when there is proximal deletion of DNA sequences encompassing the diagnostic probe region p13E-11 that prevents the detection of a mutation in a patient with FSHD [84]. In cases with a typical FSHD phenotype that have negative standard DNA testing with the p13E-11 probe, a more detailed genetic evaluation is needed to look for a contracted 4q35 D4Z4 repeat array [85-87]. Proximally extended deletions that carry a p13E-11 deletion can be detected by using additional probes.

●A false negative result can occur with an epigenetic variant called FSHD2, which is not associated with D4Z4 repeat contractions but does require at least one permissive 4qA allele and profound DNA hypomethylation on both normal D4Z4 alleles (see 'Etiology' above). FSHD2 accounts for approximately 3 percent of all cases of FSHD. The discovery that pathogenic SMCHD1, DNMT3B and LRIF1 variants cause FSHD2 has led to commercial availability of molecular genetic testing for FSHD2.

●In the absence of haplotype analysis, a false positive result can occur if the contracted D4Z4 array is located on the non-permissive 4qB haplotype. Thus, it is important to know if the genetic testing includes haplotype analysis with the ability to distinguish whether the contracted D4Z4 is located on 4qA or 4qB [6].

●Although most patients with FSHD have one contracted D4Z4 allele with 1 to 10 repeat units, there is no definitive cut-off for the number of repeats that unequivocally establish the diagnosis [6]. A D4Z4 locus with 10 or 11 repeats should be considered borderline and interpreted in the context of clinical suspicion for the diagnosis.

●The sensitivity of genetic testing for atypical FSHD cases (see 'Atypical forms' above) remains uncertain [82].

Novel techniques that may facilitate the genetic diagnosis of FSHD are under development [76].

Differential diagnosis — Neuromuscular conditions that can be confused with FSHD include the following [6,75]:

●Scapuloperoneal syndromes, particularly myotonic dystrophy type 1 and type 2 (see "Myotonic dystrophy: Etiology, clinical features, and diagnosis")

●Limb girdle muscular dystrophy (see "Limb-girdle muscular dystrophy")

●Polymyositis (see "Clinical manifestations of dermatomyositis and polymyositis in adults")

●Inclusion body myositis and autosomal recessive inclusion body myopathy (see "Clinical manifestations and diagnosis of inclusion body myositis")

●Mitochondrial myopathies (see "Mitochondrial myopathies: Clinical features and diagnosis")

●Congenital myopathies (see "Congenital myopathies")

●Juvenile and adult forms of acid maltase deficiency (see "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)")

The clinical pattern of muscle weakness and histopathologic findings for the scapuloperoneal syndromes, myotonic dystrophy, and limb-girdle muscular dystrophies may not be easily distinguished from FSHD. In such cases, the definitive diagnosis requires molecular genetic testing [6].

The remaining conditions (polymyositis, inclusion body myositis and autosomal recessive inclusion body myopathy, mitochondrial myopathies, congenital myopathies and acid maltase deficiency) can usually be distinguished from FSHD based on their distinct muscle histopathology [6].

MANAGEMENT — The management of FSHD is primarily supportive, as no disease-modifying therapy is available. Recommendations regarding management are based more on consensus and clinical experience than on evidence from randomized trials. The main focus of management involves physical therapy and rehabilitation, exercise, pain control, and orthopedic interventions [75,77]. Other issues requiring surveillance include potential pulmonary, ophthalmologic, and auditory problems related to FSHD. Cardiac evaluation is needed for those who develop overt symptoms or signs of cardiac disease but routine screening is not otherwise necessary [77].

Physical therapy and rehabilitation — Patients with FSHD and functional limitations may benefit from a physical therapy and rehabilitation consultation with assessment of posture, gait, and the need for exercise, stretching, assistive devices, and orthopedic interventions [75]. Patients with mild disease may need only yearly follow-up. Those with severe disease and disability, particularly those with severe early-onset forms of FSHD, may benefit from ongoing physical, occupational, and speech therapy.

Exercise — Although data are limited, the available evidence suggests that exercise is not harmful for patients with FSHD [88,89], and that aerobic exercise is beneficial in terms of improved cardiovascular fitness and strength [90,91]. These findings led an expert panel to recommend that patients with FSHD engage in aerobic training at least three times a week for 30 minutes per session at an intensity to reach the age-adjusted target heart rate for aerobic fitness [75]. For patients who cannot participate in aerobic exercise, the expert panel recommended a moderate intensity resistance training program. Similarly, 2015 guidelines from the American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) state that clinicians might encourage low-intensity aerobic exercise for patients with FSHD [77].

Orthopedic interventions — Because the deltoid muscles are usually preserved, patients with significant weakness may show some improvement in abduction and flexion of the upper arm with surgical fixation of the scapulae to the posterior part of the thorax [92-95]. Scapulothoracic fusion can also relieve shoulder pain and fatigue, and improve the appearance of the neck and shoulder in patients with FSHD who have symptomatic scapular winging. Since loss of scapular fixation may recur after surgery, we suggest surgery on one side and, if successful, consideration of fixation on the opposite side. Wrist and ankle supports may also be useful. The 2015 AAN/AANEM guidelines note that surgical scapular fixation "might be cautiously offered to selected patients" with FSHD after accounting for individual characteristics, including the potential gain in range of motion by manual fixation of the scapula, the rate of disease progression, and the potential adverse effects of surgery and postsurgical bracing [77].

Pain — Pain is a common problem in FSHD (see 'Other manifestations' above) and is generally managed with physical therapy, exercise, and a wide variety of analgesic medications [36,39]. The 2015 AAN/AANEM guidelines recommend that practitioners routinely inquire about musculoskeletal pain in FSHD, and note that a trial of nonsteroidal anti-inflammatory medications is appropriate for acute pain, while antidepressants or antiepileptics are appropriate for chronic pain [77]. However, pain control in FSHD is poorly studied.

Respiratory surveillance — Respiratory insufficiency is rare, but approximately 1 percent of patients with FSHD may require nocturnal ventilatory support, usually decades after disease onset [31].

In accord with the 2015 AAN/AANEM guidelines [77], we recommend baseline pulmonary function tests with supine and sitting forced vital capacity (FVC) measurements for all patients diagnosed with FSHD. We also suggest routine pulmonary monitoring (eg, yearly pulmonary function tests) for patients with any of the following conditions [75,77]:

●Abnormal baseline pulmonary function test results

●Severe proximal weakness

●Kyphoscoliosis

●Lumbar hyperlordosis

●Chest wall deformities such as pectus excavatum

●Wheelchair dependence

●Chronic obstructive pulmonary disease

●Cardiac disease

Patients with FSHD who do not fulfill these conditions should nevertheless have pulmonary function testing prior to any procedure requiring general anesthesia or conscious sedation [75,77].

Respiratory insufficiency initially may manifest during sleep [77]. Thus, the 2015 AAN/AANEM guidelines recommend pulmonary or sleep medicine evaluation and consideration of nocturnal sleep monitoring or nocturnal noninvasive ventilation for patients with FSHD who have either of the following [77]:

●Abnormal pulmonary function studies (eg, forced vital capacity <60 percent)

●Symptoms of excessive daytime somnolence or nonrestorative sleep (eg, frequent nocturnal arousals, morning headaches)

The evaluation and management of respiratory muscle weakness due to neuromuscular disease is discussed in detail separately. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation" and "Respiratory muscle weakness due to neuromuscular disease: Management".)

Eye care — A dilated retinal examination by ophthalmoscopy is recommended at the time of diagnosis for all patients with FSHD to look for evidence of retinal vascular disease and Coats syndrome (see 'Other manifestations' above), which is usually treatable with photocoagulation of the abnormal vessels [75]. Photocoagulation, if done early, is thought to be effective in preventing retinal damage and detachment of the retina.

The frequency of subsequent monitoring can be determined by the presence and severity of retinal vascular disease at the initial screening [77]. No further follow-up is needed for adults if vascular disease is absent unless visual symptoms arise. Annual follow-up is recommended for children with early onset of FSHD, at least until the child is mature enough to report visual symptoms. Closer surveillance is suggested for patients with D4Z4 repeat array fragments ≤15 kb in size [43].

In some patients with FSHD, facial weakness can lead to exposure keratitis if the eyes remain partially open during sleep [6]. To prevent drying of the sclera, ophthalmic ointments and eye patches can be used at night. However, tape should not be placed directly on the eyelid since the patch could slip and abrade the cornea.

Hearing loss — The infantile form of FSHD may be associated with an increased risk of hearing loss (see 'Other manifestations' above), leading to the recommendation to test hearing in infants and preschool-aged children with FSHD at baseline and yearly thereafter [75,77]. Routine school-based hearing assessments are sufficient for school-aged children with FSHD and normal language development. Adults with FSHD do not need hearing evaluations unless they have symptoms.

PROGNOSIS — Progression of FSHD is typically slow and most studies suggest that the life span is not significantly affected [6,27]. In some cases, patients remain asymptomatic or have minimal symptoms throughout their life. In other cases, rapid or stuttering deterioration leads to significant disability. A number of studies have found that individuals with large D4Z4 contractions resulting in a small repeat (one to three residual repeats) tend to have earlier onset disease and faster progression than those with smaller D4Z4 contractions [69,74,81,96-98].

Eventual wheelchair dependence occurs in approximately 20 percent of patients. In one study that prospectively followed 81 patients with FSHD for over three years, there was a slow but detectable decrease in muscle strength over time that was not associated with age, sex, age at symptom onset, or disease duration [99]. However, patients with early onset and a longer duration tend to have more clinical symptoms [98]. Some reports suggest that men with FSHD are more severely affected than women [100,101].

Pregnancy outcomes — There are few data regarding pregnancy outcomes in women with FSHD. In a survey of 38 women with FSHD that included 105 gestations and 78 live births, pregnancy outcomes were generally favorable [102]. However, both the rate of low birth weight and the combined rate for all operative vaginal deliveries were significantly higher than expected in the general population. Further, worsening of FSHD symptoms was observed in 24 percent of the pregnancies, usually without return to baseline after delivery.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Muscular dystrophy (The Basics)")

●Beyond the Basics topics (see "Patient education: Overview of muscular dystrophies (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Facioscapulohumeral muscular dystrophy (FSHD) is a complex genetic disorder characterized in most cases by slowly progressive muscle weakness involving the facial, scapular, upper arm, lower leg, and hip girdle muscles. (See 'Introduction' above.)

●Etiology – The probable cause of FSHD is inappropriate expression of the DUX4 gene. Different pathways (D4Z4 repeat contractions in FSHD1 (figure 2) and heterozygous pathogenic SMCHD1 variants in FSHD2) lead to D4Z4 chromatin relaxation ("unwinding" of the DNA) and abnormal expression of DUX4. (See 'Etiology' above.)

●Epidemiology – FSHD is the third most common type of muscular dystrophy. (See 'Epidemiology' above.)

●Clinical features – The typical or classic form of FSHD is characterized by muscle weakness involving the facial, scapular, upper arm, lower leg, and abdominal muscles, usually with asymmetric involvement. The age of symptom onset is usually in the second decade. By age 20 years, findings are seen in approximately 90 percent of affected patients, although some or all the signs may be subclinical. Progression is ordinarily slow. However, progression and disease severity are highly variable. Other manifestations of FSHD may include pain, retinal vasculopathy, hearing loss, cardiac arrhythmia, cognitive impairment, and epilepsy. FSHD1 and FSHD2 are clinically indistinguishable. (See 'Clinical features' above and 'Prognosis' above.)

●Atypical and infantile forms – Several atypical variants of FSHD are recognized, including infantile or early onset FSHD. (See 'Atypical forms' above and 'Infantile form' above.)

●Evaluation and diagnosis – The diagnosis of typical FSHD is suspected in patients who present with weakness of the face, shoulder girdle, and upper arm with relative sparing of the deltoid muscles. Genetic testing is the principle method for confirming the diagnosis (algorithm 1). Electromyography (EMG) and/or muscle biopsy are used infrequently in cases with atypical phenotypes and negative genetic testing for FSHD1 and FSHD2. In general, patients with suspected muscular dystrophy should be referred to a specialist with expertise in neuromuscular disorders for evaluation and diagnosis. (See 'Diagnosis' above.)

●Management – The management of FSHD is primarily supportive, as no disease-modifying therapy is available. The main focus of management involves physical therapy and rehabilitation, exercise, pain control, and orthopedic interventions. Other issues requiring surveillance include potential pulmonary, ophthalmologic, and auditory problems related to FSHD. (See 'Management' above.)