Facioscapulohumeral dystrophy (FSHD) is one of the most common types of muscular dystrophy. It has distinct regional involvement and progression. Landouzy and Dejerine first described FSHD in 1884. Tyler and Stephens described an extensive family from Utah in which 6 generations were affected. Walton and Nattrass established FSHD as a distinct muscular dystrophy with specific diagnostic criteria.
The facioscapulohumeral dystrophy (FSHD) phenotype encompasses two genetically distinct entities: FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2).
FSHD1, which accounts for 95% of all FSHD, is inherited as an autosomal dominant disease in 70–90% of patients, whereas in the remaining 10–30%, it is the result of a de novo defect. One of the FSHD genes has been localized to chromosome band 4q35, but the precise gene or genes that are affected in FSHD are still unknown. Patients with FSHD1 have a shorter Eco RI digestion fragment detected by the chromosome-4qter DNA marker p13E-11.[1]
The probe p13E-11 identifies 2 polymorphic loci at 4q35 and 10q26. The Eco R1 fragment of 4q is composed of repetitive DNA sequences that are 3.3-kilobase (kb) Kpn I tandem repeats identified as D4Z4. In control subjects, the D4Z4 repeat consists of 11–100 KpnI units, each 3.3 kb, whereas in FSHD this is shortened; the shortened Eco RI fragment in FSHD is 1–10 units. Diagnostic difficulties arise as these fragments also may come from chromosome 10, as already described. 4-type units are resistant to Bln I and 10-type units are resistant to Xap I. The combined use of EcoRI, BlnI, and XapI in pulsed-field gel electrophoresis–based DNA separation techniques allows detection of 4q fragments.
FSHD1 is caused by a contraction mutation of D4Z4 macrosatellite repeats in the subtelomeric region of the 4qA161 haplotype of chromosome 4 in 95% of patients.
Those without FSHD have approximately 11–100 D4Z4 units, whereas patients with FSHD have 1–10 D4Z4 units.[2]
At least 1 copy of D4Z4 is required to develop FSHD.
Mosaic males are mostly affected, where as mosaic females with an equal complement of affected cells are more often asymptomatic carriers.
A bi-allelic variation of chromosome 4qter is known, designated as 4qA and 4qB. FSHD alleles are exclusively of the 4qter type (4qA161).
Although the genetic lesion is well described in FSHD, the causal gene and the protein products are not known.
Additional testing may be needed in patients without D4Z4 contraction for a deletion encompassing the region.
The most extensively studied candidate genes for FSHD on 4q35 are ANT1, PDLIM3, FRG1, TUBB4q, FRG2, and DUX4
FSHD2, seen in 5% patients, has digenic inheritance and is chararterized by DNA hypomethylation in the presence of preserved D4Z4 macrosatellite repeat numbers. This may be seen as a likely result of mutation of SMCHD1 or DNMT3B genes.
Disease mechanisms
Possible disease mechanisms include the following:
Both FSHD1 and FSHD2 have inappropriate (increased) expression of the double homeobox 4 (DUX4) gene.
DUX4 is a retrogene contained within D4Z4 repeats and is normally epigenetically silenced in somatic cells. D4Z4 contraction leads to loss of DNA methylation and heterochromatin markers in the D4Z4 region, resulting in relaxation of chromatin structure and release of DUX4 repression.[4]
Position variegation effect on a proximal candidate gene or genes
Direct and indirect evidence points to epigenetic modifications in the DNA. A local deficit of a repressor complex due to the contraction of D4Z4 may cause inappropriate expression of genes. This may account for upregulation of FRG2, FRG1, and ANT1 in FSHD muscle.
The most common modification of mammalian DNA is cytosine methylation that is necessary for many regulatory processes. D4Z4 is found to be hypomethylated in both forms of FSHD.
Myoblasts from patients with FSHD also demonstrate increased susceptibility to oxidative stress.
Misexpression of FRG1 (FSHD region gene 1) may lead to the development of FSHD. Knockdown of FRG1 in Xenopus led to the decreased angiogenesis and reduced expression of DAB2 (angiogenic regulator). Of patients with FSHD, 50-75% exhibit retinal vasculopathy and increased expression of vascular or endothelial-related FRG1 transcripts in the muscle. Thus FRG1 may be at least crucial for angiogenesis.
Deletion of D4Z4 macrosatellites results in aberrant gene expression. DUX4 transcript from the last D4Z4 (most telomeric) unit generates small si/miRNA-sized fragments; uncapped, polyadenylated 3-prime fragments encoding C-terminal portion of DUX4; capped and polyadenylated mRNAs containing the double-homeobox domain of DUX4, but splice-out the C-terminal polypeptide. C-terminal polypeptide produced by transfection studies inhibits myogenesis.[3]
Facioscapulohumeral dystrophy (FSHD) is considered one of the more common hereditary muscular disorders, with it being recognized as the third most common muscular dystrophy. Estimated prevalence of FSHD in the United States is 1 case per 20,000 persons.[5] Estimated worldwide prevalence is between 4 and 10 cases per 100,000 people.[6, 7]
Mortality/morbidity
Most patients with FSHD have a normal life expectancy.
Gender differences
Frequency of FSHD is higher in males; however, asymptomatic cases are more common in females.
Age
The usual presentation is between the first and third decades of life. Ninety-five percent of patients show clinical features before age 20 years. As many as one third of patients are asymptomatic.
Size of deletion affects disease severity and thus prognosis. Ricci studied 122 Italian families affected by FSHD and 230 healthy control subjects. An Eco RI fragment shorter than 30 kb that was resistant to Bln I restriction was found in 114 of 122 families (93%) with FSHD. Fifteen percent of the control group showed Eco RI fragments smaller than 30 kb that were Bln I sensitive, suggesting that these were 10 qter alleles. Prognosis varied with the length of the fragment size and the remaining Kpn I units.[17] The probabilities of developing the severe form of the disease were as follows:
100% with very short segment length of 10-13 kb (1-2 Knp I repeats left)
54% in patients with fragment length of 16-20 kb (3-4 Knp I repeats left)
19% in patients with fragment length greater than 21 kb (more than 4 Knp I repeats left)
Age of onset is variable. The disease tends to progress from the face downwards. Asymmetry and selective muscle group involvement distinguish FSHD from other muscular dystrophies. Many authors describe stepwise deterioration with prolonged periods of apparent arrest. Extraocular muscles, bulbar muscles, deltoids, and respiratory muscles usually are spared. Ventilatory impairment is seen in fewer than 10% of patients.
Approximately 20% of patients may require wheelchair assistance.
Facioscapulohumeral dystrophy (FSHD) can present from infancy to late adulthood, with early onset often indicating severe disease. It typically starts with weakness of the facial, shoulder girdle, and upper arm muscles, involved to a varying degree. Difficulty in raising the arms above shoulder level and scapular winging is often the first reported symptom, and this can impact the shoulders in an asymmetric fashion. Other symptoms may include inability to fully close the eyes, move the lips, or smile fully. With disease progression, distal leg muscle weakness with preferential involvement of the anterolateral compartment leading to foot drop may occur. Later in the disease course, proximal lower extremity, pelvic girdle muscles, as well as abdominal and paraspinal muscle weakness can be seen.
More than 90% of patients report fatigue, which impacts quality of life significantly. Chronic pain is also often described, likely a result of muscle weakness causing joint misalignment.
Progression of FSHD occurs with slow, gradual decline in the overall strength of the affected muscles. Patients with infantile presentation may become wheelchair bound in the second decade, whereas a smaller percentage (20%) of later-onset patients may require wheelchair assistance to a varying degree after the age of 50 years.
Initial weakness is seen in facial muscles, starting in the orbicularis oculi, orbicularis oris, and zygomaticus.
Patients may have difficulty with labial sounds, whistling, or drinking through a straw.
Weakness may be asymmetric.
Extraocular and pharyngeal muscles are spared.
Shoulder weakness is the presenting symptom in more than 82% of patients with symptoms.
Scapular fixation is weak from the onset. Winging of the scapula is the most characteristic sign. The scapula is placed more laterally than normal. It moves upwards in shoulder abduction.
The deltoid muscle usually is spared, and shoulder abduction weakness is predominantly due to weak scapula fixation.
If the scapula is stabilized manually against the chest wall, the patient may experience improved movement. Upward slope of the anterior axillary fold results from weakness of the pectoralis major.
Truncal weakness is early. Lower abdominal muscles are weaker than upper abdominal muscles, resulting in the Beevor sign, a physical finding very specific for facioscapulohumeral dystrophy (FSHD). The Beevor sign is the upward movement of the umbilicus toward the head when flexing the neck.
Weakness of foot dorsiflexion follows shoulder weakness.
Tibialis anterior muscle weakness is highly characteristic, whereas posterior muscles of the leg are spared.
In a few patients, a foot-drop gait is the presenting complaint. In more than 50% of patients, the pelvic girdle muscles are never involved.
Atypical phenotypes in patients with FSHD include:
Scapulohumeral dystrophy (SHD) or facial-sparing SHD with or without myalgia
FSHD with chronic progressive external ophthalmoplegia (CPEO)
Limb-girdle muscular dystrophy syndrome
Distal myopathy
Asymmetric brachial weakness
Extramuscular manifestations are as follows:
High-frequency hearing loss in almost 75%
Retinal telangiectasias in about 60%
Atrial arrhythmias in 5%
Restrictive respiratory disease in 1%
Intellectual disability
Seizures
Sleep-disordered breathing (SDB) is very common in FSHD. Obstructive sleep apnea, REM-related oxygen desaturation, or mixed pattern were observed in 39% of FSHD patients. SDB is not related to severity of the disease.[8]
Coats syndrome: This syndrome, a retinal vasculopathy with telangiectasia, exudation, and retinal detachment, is seen in 49-75% of affected individuals. If detected early, retinal photocoagulation may prevent serious consequences.
Hearing loss: Sensorineural deafness is observed in 64% of patients; it may be unilateral.
Mental impairment and epilepsy: These are seen in the early onset group. Intellectual disability is observed in about 40% of patients with early onset 4q35-FSHD. Epilepsy also is observed often in this subset of patients.
Labile hypertension
Cardiac complications: Atrial arrest, bundle branch block, and dilated cardiomyopathy have been reported.[16]
Serum creatine kinase levels may be elevated, though usually do not exceed 3–5 times the upper limit of normal. Consider an alternate diagnosis if CPK is higher than 1500 IU/L.
Imaging studies in facioscapulohumeral dystrophy (FSHD) show a selective destructive process involving the anterior compartment muscles of the leg. Hypertrophy of the psoas muscles is also observed occasionally.[9, 10]
Other tests for facioscapulohumeral dystrophy (FSHD) include FSHD gene testing and electrodiagnostic studies, which may reveal myopathic potentials. Focal neuropathies and occasionally a brachial plexopathy may be seen as a result of stretch injury.
If results of genetic testing for facioscapulohumeral dystrophy (FSHD) are negative, a muscle biopsy is strongly recommended to rule out other conditions that mimic FSHD.
Targeted testing for contracted the D4Z4 macrosatellite is done by Southern blotting. Presence of a permissive allele (4qA) should be determined concurrently with haplotype analysis. Pathogenic D4Z4 contraction (repeats < 10) in the setting of permissive allele is diagnostic of FSHD1.
In case of normal D4Z4 repeat size with permissive 4qA haplotype, DNA methylation analysis for the D4Z4 segment should be done. Presence of hypomethylation of D4Z4 suggests occurence of one of the abovementioned mutations seen in FSHD2.
No definitive therapy is available for facioscapulohumeral dystrophy (FSHD).
Custom-made ankle-foot orthosis (AFO) may help patients with prominent foot drop. Sometimes AFO may worsen the gait in the presence of knee extensor weakness and these patients may benefit from floor reaction AFO (FRAFO) or newer knee-ankle-foot-orthosis (KAFO).[11]
Corticosteroids failed to improve muscle strength or muscle mass.
A pilot trial of sustained-release albuterol taken PO (16 mg/d) for 3 months increased lean body mass. A modest 12% increase in muscle strength was noted.
A double-blind placebo-controlled trail randomizing the patients to placebo, 8 mg albuterol twice daily, or 16 mg albuterol twice daily showed no improvement in global strength. However, albuterol improved grip strength and muscle mass. Basing on the information available, albuterol cannot be recommended.
In a randomized, double-blinded, cross-over trial in a mixed population of dystrophies (12 with FSHD), a creatine monohydrate value of 10 g/d demonstrated a slight improvement in overall strength.
Payan et al studied the effect of salbutamol on muscle strength in patients with genetically confirmed FSHD. Ambulatory patients received either salbutamol (n=56) or placebo (n=56) for 6 months. No significant change in muscle strength was shown with salbutamol compared with placebo. Results from this study do not support the routine use of salbutamol for FSHD.[12]
Creatine monohydrate, folic acid and methionine supplementation and myostatin inhibition (MYO-29) have been tried with no benefit.
Aerobic training may improve exercise performance.[13] Twelve weeks of low-intensity aerobic exercises (on a cycle ergometer at a heart rate corresponding to a work intensity of 65% of VO2 max for 35-min weekly sessions and increased to 5-times weekly in 4 wk) improved maximal oxygen uptake and work load with no signs of muscle damage.
Scapulothoracic arthrodesis may be attempted in select facioscapulohumeral dystrophy (FSHD) patients with preserved deltoid function. An improved functional range of abduction can be achieved if the scapula is fixed in 15-20° of rotation. In a series by Bunch and Siegel, 11 of 12 patients improved with this procedure.[14]
Demirhan, using multifilament cable for scapulothoracic arthrodesis, provided satisfactory function (Level IV evidence) in 13 patients.[15]
Long-term monitoring for facioscapulohumeral dystrophy (FSHD) should include baseline pulmonary function testing in all patients. In patients with abnormal testing or with wheelchair dependence or kyphoscoliosis, pulmonary function should be monitored periodically.
Hearing assessment should be done at baseline and yearly thereafter.
What is facioscapulohumeral dystrophy (FSHD)?What is the pathophysiology of facioscapulohumeral dystrophy (FSHD)?What causes facioscapulohumeral dystrophy (FSHD)?What is the prevalence of facioscapulohumeral dystrophy (FSHD) in the US?What is the mortality associated with facioscapulohumeral dystrophy (FSHD)?What are the sexual predilections of facioscapulohumeral dystrophy (FSHD)?At what age does facioscapulohumeral dystrophy (FSHD) typically present?What is the prevalence of facioscapulohumeral dystrophy (FSHD)?What are the signs and symptoms of facioscapulohumeral dystrophy (FSHD)?What are the differential diagnoses for Facioscapulohumeral Dystrophy?What is the role of lab tests in the workup of facioscapulohumeral dystrophy (FSHD)?What is the role of imaging studies in the workup of facioscapulohumeral dystrophy (FSHD)?What is the role of EMG in the workup of facioscapulohumeral dystrophy (FSHD)?What is the role of biopsy in the workup of facioscapulohumeral dystrophy (FSHD)?Which histologic findings are characteristic of facioscapulohumeral dystrophy (FSHD)?How is facioscapulohumeral dystrophy (FSHD) treated?What is the role of surgery in the treatment of facioscapulohumeral dystrophy (FSHD)?What is the role of medications in the treatment of facioscapulohumeral dystrophy (FSHD)?
Kavita M Grover, MD, FAAN, Associate Professor, Wayne State University School of Medicine; Senior Staff Neurologist, Vice Chair of Clinical Operations, Department of Neurology, Henry Ford Hospital; Neurology Service Chief, Henry Ford West Bloomfield Hospital
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Janssen; UCB pharma<br/>Received income in an amount equal to or greater than $250 from: Janssen; UCB pharma.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA, Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
James J Riviello, Jr, MD, George Peterkin Endowed Chair in Pediatrics, Professor of Pediatrics, Section of Neurology and Developmental Neuroscience, Professor of Neurology, Peter Kellaway Section of Neurophysiology, Baylor College of Medicine; Chief of Neurophysiology, Director of the Epilepsy and Neurophysiology Program, Texas Children's Hospital
Disclosure: Partner received royalty from Up To Date for section editor.
Naganand Sripathi, MD, Director, Neuromuscular Clinic, Department of Neurology, Henry Ford Hospital
Snider L, Asawachaicharn A, Tyler AE, et al. RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for pathophysiology of facioscapulohumeral dystrophy. Hum Mol Genet. 2009. 18:2414-2430.
Dr Arnab K Rana, Dr Yuranga Weerakkody◉ et al. Facioscapulohumeral Muscular Dystrophy. www.radiopaedia.org. Available at https://radiopaedia.org/articles/facioscapulohumeral-muscular-dystrophy?lang=us
Clara Hageman, Kathryn R. Wagner, Kennedy Krieger. Facioscapulohumeral Muscular Dystrophy. www.rarediseases.org. Available at https://rarediseases.org/rare-diseases/facioscapulohumeral-muscular-dystrophy/
Demirhan M, Uysal O, Atalar AC, et al. Scapulothoracic arthrodesis in facioscapulohumeral dystrophy with multifilament cable. Clin Orthop Relat Res. in press. 2009:
Wuebbles RD, Hanel ML, Jones PL. FSHD region gene 1 (FRG1) is crucuial for angiogenesis linkinh FRG! to facioscapulohumeral muscular dystrophy-associated vasculopathy. Dis Model Mech. May-Jun 2009. 2(5-6):267-274.
