Facioscapulohumeral Muscular Dystrophy
Summary
Clinical characteristics.
Facioscapulohumeral muscular dystrophy (FSHD) typically presents with weakness of the facial muscles, the stabilizers of the scapula, or the dorsiflexors of the foot. Severity is highly variable. Weakness is slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened.
Diagnosis/testing.
The diagnosis of FSHD1 is established in a proband with characteristic clinical features by identification of a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. The diagnosis of FSHD2 is established in a proband by identification of hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. Hypomethylation of the D4Z4 repeat array can be due to a heterozygous pathogenic variant in SMCHD1 or DNMT3B.
Management.
Treatment of manifestations: Consultation with a physical therapist to establish appropriate exercise regimen; ankle/foot orthoses to improve mobility and prevent falls; occupational and speech therapy in individuals with infantile onset; surgical fixation of the scapula to the chest wall may improve range of motion of the arms over the short term; management of chronic pain by physical therapy and medication; monitoring respiratory function; lubricants to prevent drying of the sclera or taping the eyes shut during sleep to treat exposure keratitis; treatment for retinal vasculopathy as per ophthalmologist; standard treatment of sensorineural hearing loss.
Surveillance: Annual physical therapy assessment; Pain should be assessed at regular visits to the primary care physician or physical therapist; screening for hypoventilation in individuals with abnormal PFTs, severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid disease affecting ventilation; pulmonary consultation for FVC <60%, excessive daytime somnolence or nonrestorative sleep, and prior to surgical procedures requiring anesthesia; annual dilated ophthalmoscopy in individuals with early childhood-onset FSHD with large pathogenic contraction of D4Z4 and adults with visual symptoms; audiometry in infants at each visit and annually in children.
Genetic counseling.
FSHD1 is inherited in an autosomal dominant manner. Approximately 70%-90% of individuals have inherited the disease-causing deletion from a parent, and approximately 10%-30% of affected individuals have FSHD as the result of a de novo deletion. Offspring of an affected individual have a 50% chance of inheriting the deletion. Prenatal testing for pregnancies at increased risk is possible if the D4Z4 pathogenic contraction has been identified in the family. FSHD2 is inherited in a digenic manner.
Diagnosis
Evidence-based guidelines for diagnosis of FSHD are available (see Figure 1) [Tawil et al 2015].
Figure 1.
Molecular genetic testing for a heterozygous pathogenic variant in SMCHD1 or DNMT3B can be pursued in individuals with at least one permissive chromosome 4 haplotype (e.g., 4A161, 4A159, 4A168, 4A166H) and hypomethylation of D4Z4.
Suggestive Findings
Facioscapulohumeral muscular dystrophy (FSHD) should be suspected in individuals with the following:
- Weakness that predominantly involves the facial, scapular stabilizer, or foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Weakness is often asymmetric.
- Progression of weakness after pregnancy [Ciafaloni et al 2006]
- Prior diagnosis with inflammatory myopathy that was refractory to immunosuppression
- Family history of FSHD
Supportive Findings
Serum concentration of creatine kinase (CK) is normal to elevated in individuals with FSHD and usually does not exceed three to five times the upper limit of the normal range. Serum concentration of CK >1500 IU/L suggests an alternate diagnosis.
EMG can show mild myopathic changes in symptomatic muscles.
Muscle biopsy most often shows nonspecific chronic myopathic changes. Mononuclear inflammatory reaction, typically perivascular, is present in muscle biopsies in up to 40% of individuals with FSHD. Rarely, the inflammatory reaction is intense enough to suggest an inflammatory myopathy. Muscle biopsy is now performed only in individuals in whom FSHD is suspected but not confirmed by molecular genetic testing.
Establishing the Diagnosis
The diagnosis of FSHD is established in a proband who has one of the following identified on molecular genetic testing (see Table 1; Figure 1):
- FSHD1 (~95% of FSHD). A heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on the permissive chromosome 4 haplotype
- FSHD2 (~5% of FSHD). Hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on the permissive chromosome 4 haplotype due to one of the following:
- A heterozygous SMCHD1 pathogenic variant (<5% of individuals with FSHD; ~85% of individuals with FSHD2) [Lemmers et al 2015]
- A heterozygous DNMT3B pathogenic variant (3 families reported) [van den Boogaard et al 2016]
- Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (2 families) [Lemmers et al 2012a]
Allele sizes
- Normal alleles. A D4Z4 locus with ≥12 repeat units (i.e., fragments of ≥43 kb using EcoRI and the p13E-11 probe), or a D4Z4 locus with any number of repeat units on a non-permissive haplotype
- Contracted, reduced-penetrance alleles. A D4Z4 locus that has ten or 11 repeat units AND is on a permissive haplotype
- Contracted, full-penetrance alleles. A D4Z4 locus that has ≤9 repeat units AND is on a permissive haplotype
Note: Penetrance of allele sizes is dependent on multiple factors (see Penetrance) and patient-specific manifestations may vary from the categories below.
Molecular genetic testing approaches can include targeted analysis for the repeat size of D4Z4 repeat array in the subtelomeric region of chromosome 4q35 and haplotype analysis, DNA methylation studies, and single-gene testing.
Targeted Analysis and Haplotype Analysis
Targeted analysis. Testing is targeted for the abnormally contracted D4Z4 repeat array in the subtelomeric region of chromosome 4q35. Note: Contraction of an almost identical D4Z4 repeat array at 10q26 is not associated with FSHD (see Molecular Genetics).
Note: Targeted testing is typically done by Southern blotting (Table 1); molecular combing techniques have also been described. Molecular combing has a higher resolution than Southern blotting: in individuals with a normal D4Z4 repeat array by Southern blot testing, molecular combing has been used to identify a short D4Z4 repeat array (5-6 repeat units), which may not be recognized by Southern blot [Lemmers et al 2018]. However, molecular combing may not be clinically available.
Haplotype analysis. Haplotype analysis is recommended concurrently with testing for a D4Z4 contraction to determine if an abnormal allele is present on a permissive or non-permissive haplotype distal to the last D4Z4 repeat (see Molecular Genetics). In individuals with a contracted D4Z4 repeat array (see Allele sizes), a permissive haplotype is required to confirm FSHD1.
Examples of chromosome 4q35 permissive (known as 4A or A) and non-permissive (known as 4B or B) haplotypes:
- Permissive: 4A161, 4A159, 4A168, 4A166H
- Non-permissive: 4A166, 4B
Note: The presence of a typical FSHD clinical profile without a contracted repeat but with at least one allele with a permissive haplotype, raises the possibility of FSHD2.
DNA Methylation Studies
In individuals who do not have a contracted D4Z4 repeat array identified and have at least one repeat array with a permissive chromosome 4 haplotype, D4Z4 methylation analysis should be done next. D4Z4 hypomethylation suggests the presence of a heterozygous SMCHD1 or DNMT3B pathogenic variant.
Single-Gene Testing
Sequence analysis of SMCHD1 and DNMT3B should be done in individuals with D4Z4 hypomethylation to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
Table 1.
Molecular Genetic Testing Used in Facioscapulohumeral Muscular Dystrophy
| Locus/ Gene 1 | Method | Pathogenic Variants/Alterations 2 Detected | Proportion of FSHD-Related Alterations Detected 3 |
|---|---|---|---|
| D4Z4 | Targeted analysis for pathogenic variants 4 | Pathogenic contraction of number of D4Z4 repeats 5, 6, 7 | ~95% |
| Haplotype analysis | Analysis to confirm that the D4Z4 pathogenic contraction occurred on a permissive haplotype 8 | Not applicable | |
| Methylation analysis | D4Z4 hypomethylation (<25% methylation) 9 | ~5% | |
| SMCHD1 | Sequence analysis 10 | SMCHD1 sequence variants | ~4% 11 |
| Gene-targeted deletion/duplication analysis 12 | SMCHD1 deletion/duplication | See footnote 13. | |
| DNMT3B | Sequence analysis 10 | DNMT3B sequence variants | 3 families 14 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
The ability of the test method used to detect a variant that is present in the indicated gene/locus
- 4.
Molecular genetic testing to determine the length or number of repeat units of the D4Z4 locus has typically relied on Southern blot analysis, typically with a probe (e.g., p13E-11) immediately proximal to D4Z4. Standard DNA diagnostic testing (defined here as linear gel electrophoresis and Southern blot analysis) uses the restriction enzyme EcoRI, which recognizes the D4Z4 locus on chromosomes 4 and 10. Pulsed-field gel electrophoresis and Southern blot analysis requires EcoRI/HindIII double digestion for a better resolution of DNA fragments between 20 and 50 kb. An EcoRI/BlnI double digestion further fragments the chromosome 10 array, allowing one to distinguish D4Z4 arrays located on chromosome 4 from the similar benign arrays on chromosome 10. Molecular combing, which has a higher resolution than Southern blotting [Nguyen et al 2017, Lemmers et al 2018, Nguyen et al 2019] has also been described, but may not be clinically available.
- 5.
Detection of the pathogenic contraction of the D4Z4 locus by Southern blot analysis requires high-quality DNA; a false negative test result can be caused by poor-quality DNA that was sheared into small fragments.
- 6.
In approximately 3% of the European families with FSHD1 the D4Z4 contraction on chromosome 4q35 is not visible using the standard genetic test because a deletion encompasses the region of the molecular diagnostic probe p13E-11. These individuals require additional testing to visualize the contracted D4Z4 repeat and resolve the size of the repeat [Lemmers et al 2003, Ehrlich et al 2007].
- 7.
A combination of Southern blotting and molecular combing detected complex rearrangements of 4q35 with duplication of D4Z4 array [Nguyen et al 2017, Lemmers et al 2018] and a 4q deletion proximal to D4Z4 [Nguyen et al 2019].
- 8.
4A161 is most common permissive haplotype, but others are reported (4A159, 4A168, 4A166H) [Lemmers et al 2010a]. All individuals with FSHD carry a permissive haplotype. Because 66% of controls also carry a permissive haplotype, this analysis (without sizing of the repeat array) is often not informative. Lemmers et al developed a clinically available diagnostic test to discriminate both haplotype variants using HindIII-digested DNA and specific probes for 4A and 4B [Lemmers et al 2002, Lemmers et al 2007].
- 9.
D4Z4 methylation values below the threshold of 25% are indicative of FSHD. However, the CpG methylation at the D4Z4 repeat array is also determined by the size of the D4Z4 arrays on chromosomes 4q and 10q. Contracted D4Z4 arrays on chromosomes 4q and 10 have a significantly lower level of methylation than normal-sized arrays. D4Z4 methylation levels should always be evaluated with respect to the repeat size. A Southern blot-based method has been developed that measures the total D4Z4 methylation at chromosomes 4q and 10q by using methylation-sensitive restriction enzyme (FseI) in the promoter region of DUX4 [Lemmers et al 2012b]. The average methylation of D4Z4 in control individuals is 45%, while in individuals with FSHD2 the methylation level drops below 25%, with an average of 11% [Lemmers et al 2012b].
- 10.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 11.
51 families of 60 with FSHD2 were found to have an SMCHD1 pathogenic variant with D4Z4 DNA hypomethylation [Lemmers et al 2015].
- 12.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications.
- 13.
Deletions including SMCHD1 and other genes have been reported as 18p- syndrome [Lemmers et al 2015].
- 14.
van den Boogaard et al [2016]
Clinical Characteristics
Clinical Description
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness involving the face, scapular stabilizers, upper arm, lower leg (peroneal muscles), and hip girdle [Wang & Tawil 2016]. Asymmetry of facial, limb, and shoulder weakness is common [Kilmer et al 1995]. Typically, individuals with FSHD become symptomatic in their teens, but age of onset is variable. More than 50% of individuals with FSHD demonstrate findings by age 20 years. Individuals with severe infantile FSHD have muscle weakness at birth. In contrast, some individuals remain asymptomatic throughout their lives. Progression is usually slow; however, many affected individuals describe a stuttering course with periods of disease inactivity followed by periods of rapid deterioration. Eventually 20% of affected individuals require a wheelchair.
Scapular winging is the most common initial finding; preferential weakness of the lower trapezius muscle results in characteristic upward movement of the scapula when attempting to flex or abduct the arms. The shoulders tend to slope forward with straight clavicles and pectoral muscle atrophy.
Affected individuals show facial weakness, with symptoms more pronounced in the lower facial muscles than the upper. Some affected individuals recall having facial weakness before the onset of shoulder weakness. Earliest signs are often difficulty whistling or sleeping with eyes partially open in childhood. Individuals with FSHD are often unable to purse their lips, turn up the corners of their mouth when smiling, or bury their eyelashes when attempting to close their eyelids tightly. Extraocular, eyelid, and bulbar muscles are spared.
The deltoids remain minimally affected until late in the disease; however, the biceps and triceps are selectively involved, resulting in atrophy of the upper arm and sparing of the forearm muscles. The latter results in the appearance of "Popeye arms." In more severely affected individuals, distal upper extremity weakness typically involves the wrist and finger extensors.
Abdominal muscle weakness results in protuberance of the abdomen and exaggerated lumbar lordosis. The lower abdominal muscles are selectively involved, resulting in a Beevor's sign (upward displacement of the umbilicus upon flexion of the neck in a supine position).
The legs are variably involved, with peroneal muscle weakness with or without weakness of the hip girdle muscles, resulting in foot drop.
Sensation is preserved; reflexes are often diminished when the reflex involves weak muscles.
Respiratory dysfunction is relatively uncommon. Individuals who had pulmonary function testing by spirometry showed a restrictive lung disease pattern in 38% [Moreira et al 2017], which was likely due to expiratory weakness. Respiratory support with noninvasive ventilation is uncommon (1%-3%) [Santos et al 2015].
Other manifestations. Retinal vasculopathy characterized by failure of vascularization of the peripheral retina, telangiectatic blood vessels, and microaneurysms can be demonstrated by fluorescein angiography in 40%-60% of affected individuals [Padberg et al 1995]. Vision is usually unaffected by this particular vascular malformation, but an exudative retinopathy clinically indistinguishable from Coats disease that can result in retinal detachment and vision loss has also been described. Bindoff et al [2006] reported two sisters with infantile-onset FSHD who had tortuous retinal vessels, small aneurysms, and yellow exudates.
Approximately 15% of individuals with FSHD have an abnormal audiogram. An abnormal audiogram was identified in up to 32% of individuals with a large pathogenic contraction of D4Z4 (D4Z4 fragments <20 kb) [Lutz et al 2013].
Both the exudative retinopathy and symptomatic sensorineural hearing loss are seen almost exclusively in individuals with a large pathogenic contraction of D4Z4 (1-3) repeats) or in individuals with early-onset disease [Lutz et al 2013, Statland et al 2013].
A predilection for atrial tachyarrhythmias has been reported in about 5% of cases, but symptoms are rarely experienced [Laforêt et al 1998, Galetta et al 2005, Trevisan et al 2006].
Chronic pain is likely underrecognized in affected individuals, with a prevalence as high as 77% [van der Kooi et al 2007].
Atypical presentations. Clinical variants of typical FSHD in individuals with a pathogenic contraction of the D4Z4 locus in the subtelomeric region of chromosome 4q35 include the following:
- Scapulohumeral dystrophy onset with facial sparing
- Infantile onset with severe rapidly progressive disease and a large pathogenic contraction of D4Z4 (D4Z4 fragments in the 9-21 kb range) was observed in 4% of individuals studied [Klinge et al 2006]. Felice et al [2005] and Bindoff et al [2006] have also reported individuals with infantile onset and mild-to-moderate cognitive deficiency and possible epilepsy [Bindoff et al 2006, Hobson-Webb & Caress 2006, Quarantelli et al 2006].
Mosaicism for FSHD-associated alleles. Approximately half of de novo cases of FSHD (i.e., affected offspring of unaffected parents) show a mosaic distribution of D4Z4 repeat array lengths in peripheral blood. This mosaicism likely results from a postzygotic array contraction during the first few cell divisions in embryogenesis. In such cases, a proportion of cells have two normal-sized D4Z4 alleles, while the remaining cells have one normal-sized D4Z4 allele and one pathogenic contracted D4Z4 allele [Lemmers et al 2004]. Depending on when in embryogenesis the pathogenic contraction occurs at the D4Z4 locus and the proportion of cells with the contracted D4Z4 repeat, individuals with mosaicism can be affected or asymptomatic. FSHD with somatic mosaicism of D4Z4 array lengths is more penetrant in males than in females [van der Maarel et al 2000].
Genotype-Phenotype Correlations
D4Z4 repeat array contraction size. Evidence-based guidelines published in 2015 recommend that a large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) should alert clinicians to the increased likelihood of significant disability, earlier onset of symptoms, and increased likelihood of extramuscular manifestations [Tawil et al 2015].
Allele size explains roughly 10% of variability in phenotype [Mul et al 2018]. A correlation has been reported between the degree of the pathogenic contraction of the D4Z4 locus and the age at onset of symptoms [Zatz et al 1995], age at loss of ambulation [Lunt & Harper 1991], and muscle strength as measured by quantitative isometric myometry [Tawil et al 1996], particularly in affected females [Tonini et al 2004a]. Individuals with a large contraction of D4Z4 (1-3 repeats) have a higher probability of earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus [Bindoff et al 2006, Hobson-Webb & Caress 2006, Klinge et al 2006, Nikolic et al 2016, Goselink et al 2019]. However, significant variation exists even with small repeats, and others have not been able to confirm a correlation between disease severity and degree of D4Z4 pathogenic contractions [Butz et al 2003].
A study of Italy’s National Registry concluded that 76% of early-onset (age <10 years) disease was due to de novo pathogenic variants. However, neither de novo pathogenic variants nor earlier disease onset were associated with a more severe phenotype [Nikolic et al 2016], contrasting with other studies showing that earlier onset is associated with more severe symptoms [Mah et al 2018, Goselink et al 2019]. Caution must be noted as this correlation may represent an ascertainment bias, where more mild forms of FSHD are detected when inheritance of a known pathogenic variant in a family is suspected.
Mosaicism. The phenotypic severity of individuals with mosaic distributions of one or more array sizes, which is typically less than that of individuals without mosaicism, may reflect the proportion of cells carrying the pathogenic contracted D4Z4 locus in addition to the degree of the contraction of the D4Z4 locus in those cells.
Compound heterozygosity. Two unrelated affected individuals homozygous for a D4Z4 pathogenic contraction were reported by Wohlgemuth et al [2003], suggesting that the presence of two FSHD-associated alleles can be compatible with life. However, both families demonstrated reduced penetrance for FSHD, leaving open the possibility that in other genetic/environmental settings, compound heterozygosity could be a lethal condition. In support of this possibility, the authors report a phenotypic dosage effect in both of the compound heterozygotes, compared to other family members.
Homozygosity. Tonini et al [2004b] reported an individual homozygous for the contraction on two D4Z4 4A alleles whose clinical phenotype is not more severe than those of some of his heterozygous relatives. Within the same family, the authors also observed a large number of asymptomatic or minimally affected heterozygotes, reflecting the wide range of clinical variability that can occur in a given kindred.
Penetrance
Penetrance is increased with smaller D4Z4 repeat arrays; however, significant variation exists. In one study, penetrance of FSHD was found to vary by age and gender; it was 83% by age 30 years, but significantly greater for males (95%) than for females (69%) [Zatz et al 1998, Wohlgemuth et al 2018]. The effect of gender on penetrance and disease variability is uncertain, with data showing a lack of significant effect of lifetime estrogen exposures [Mul et al 2018], or methylation status between genders [Lemmers et al 2015]. Effects from epigenetic factors such as methylation status (for both FSHD1 and 2) and other unknown environmental or genetic factors likely contribute [Mul et al 2018].
Anticipation
Absence of anticipation in large multigenerational families has been reported [Flanigan et al 2001].
Nomenclature
The term "Landouzy-Dejerine muscular dystrophy," used in the past for a syndrome similar or identical to FSHD, is no longer in use.
Persons with FSHD are sometimes included under the descriptive terms "scapulo-humeral" or "scapulo-peroneal syndromes."
Prevalence
The estimated prevalence of FSHD is between four and ten per 100,000 population. Sposìto et al [2005] found a prevalence in central Italy of 4.6:100,000. Lunt and Harper noted reports of 1:435,000 population in Wisconsin and figures for Europe from 1:17,000 to 1:250,000 population [Lunt & Harper 1991]. In Wales, the prevalence was 4.4:100,000 population. In Netherlands, the prevalence of FSHD may be 2.4:20,000 population, higher than prior estimates [Deenen et al 2014].
Differential Diagnosis
Disorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) but easily differentiated by their distinct muscle histopathology include the following:
- Myofibrillar myopathy (previously called desmin-storage myopathy)
- Inclusion body myositis including inclusion body myopathy 2 (See GNE-Related Myopathy.)
- Mitochondrial myopathies
- Adult acid maltase deficiency (See Pompe Disease.)
- Congenital myopathies
- Polymyositis
More troublesome are the following disorders in which the distribution of weakness and pathologic findings can be difficult to distinguish easily from FSHD. Molecular genetic testing allows definitive diagnosis of these conditions:
- Limb-girdle muscular dystrophies
- Scapuloperoneal muscular dystrophy syndromes, including myotonic dystrophy type 1 and myotonic dystrophy type 2 (also known as PROMM), which have mild facial weakness and nonspecific histopathologic changes that cannot be differentiated from FSHD
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with facioscapulohumeral muscular dystrophy (FSHD), the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 2.
Recommended Evaluations Following Initial Diagnosis in Individuals with Facioscapulohumeral Muscular Dystrophy
| System/Concern | Evaluation | Comment |
|---|---|---|
| Musculoskeletal | Physical examination | To assess strength & functional limitations |
| Evaluation for PT & need for assistive devices | ||
| Neurodevelopmental | OT & speech therapy assessment | In individuals w/infantile onset |
| Respiratory | Evaluation for hypoventilation, screen for daytime somnolence, nonrestorative sleep |
|
| Ophthalmologic | Ophthalmologic evaluation |
|
| Audiologic | Assessment of hearing |
|
| Other | Consultation w/clinical geneticist &/or genetic counselor |
OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy
Treatment of Manifestations
Standards of care and management of facioscapulohumeral muscular dystrophy were agreed upon at the 171st ENMC International Workshop. A consensus on the following topics and the recommendations from that conference [Tawil et al 2010] are outlined in Table 3.
Table 3.
Treatment of Manifestations in Individuals with Facioscapulohumeral Muscular Dystrophy
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Weakness | PT |
|
| Ankle/foot orthoses | To improve mobility &prevent falls in individuals with foot drop | |
| OT & speech therapy | In individuals w/infantile onset | |
| Limited range of motion | Surgical fixation of the scapula to chest wall | Offered cautiously w/careful consideration of risk & benefit in context of affected individual's symptoms |
| Pain | PT; pain medication |
|
| Hypoventilation | Ventilatory support (e.g., BiPAP) | As necessary |
| Exposure keratitis | Ocular lubricants | In severe cases taping the eyes shut during sleep may be required. |
| Exudative retinopathy | Treatment per ophthalmologist | May be prevented by early intervention w/laser treatment |
| Hearing loss | Standard therapies | Incl amplification if necessary |
OT = occupational therapy; PT = physical therapy
Surveillance
Table 4.
Recommended Surveillance for Individuals with Facioscapulohumeral Muscular Dystrophy
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Musculoskeletal | PT assessment | Annually or more frequently as determined by disease severity |
| Pain assessment | W/each visit to primary care physician & PT | |
| Respiratory | Screening for hypoventilation |
|
| Ophthalmologic | Dilated ophthalmoscopy |
|
| Audiology | Audiometry |
|
| Cardiology | Cardiac evaluation | If overt signs or symptoms of cardiac disease (regular screening not required) |
FVC = forced vital capacity; PFT = pulmonary function test; PT = physical therapy/therapist
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Outcome of 105 pregnancies in 38 women with FSHD was generally favorable [Ciafaloni et al 2006]. However, rates for low-birth-weight infants, augmented extraction procedures such as forceps and vacuum assisted deliveries, delivery by cesarean section, and anesthetic complications were higher than for the general population. Worsening of weakness occurred in 24% of the pregnancies, beginning during the pregnancy and generally not resolving after delivery.
Therapies Under Investigation
Genetic treatments such as RNAi treatment to silence DUX4 have been evaluated in preclinical studies, though no human trials are currently underway [Wallace et al 2017]. Losmapimod is an inhibitor of p38α/β mitogen-activated protein kinase (MAPK) shown in preclinical studies to reduced DUX4 expression. The medication has been previously studied in Phase I trials in other diseases, and Phase II trials are currently enrolling for FSHD [Ino et al 2015, Oliva et al 2019].
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.