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Facioscapulohumeral Muscular Dystrophy

Synonym: FSH Muscular Dystrophy

, PhD, , MD, PhD, and , PhD.

Author Information

Initial Posting: ; Last Revision: March 20, 2014.


Clinical characteristics.

Facioscapulohumeral muscular dystrophy (FSHD) typically presents before age 20 years with weakness of the facial muscles and 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.


Although some controversy remains, FSHD is likely caused by inappropriate expression of the double homeobox-containing gene DUX4 in muscle cells. DUX4 lies in the macrosatellite repeat D4Z4 on chromosome 4q35, which has a length between 11 and 100 repeat units on normal alleles. Approximately 95% of individuals with FSHD have a D4Z4 allele of between one and ten repeat units. The shortening of the D4Z4 allele causes chromatin relaxation at the D4Z4 locus and DUX4 promoter and thereby derepression of DUX4. This common form of FSHD is designated facioscapulohumeral muscular dystrophy 1 (FSHD1). Molecular genetic testing measures the length of the D4Z4 allele. About 5% of individuals with FSHD show chromatin relaxation at D4Z4 without having a D4Z4 contraction. In these individuals with so-called FSHD2, pathogenic variants in the chromatin modifier SMCHD1 cause the chromatin relaxation at D4Z4.


Treatment of manifestations: Consultation with a physical therapist; low-intensity aerobic exercise; management of chronic pain by physical therapy and medication, as necessary; ventilator support for hypoventilation; standard treatment of sensorineural hearing loss; lubricants to prevent drying of the sclera or taping the eyes shut during sleep to treat exposure keratitis; ankle/foot orthoses to improve mobility and prevent falls. Surgical fixation of the scapula to the chest wall may improve range of motion of the arms over the short term.

Surveillance: Pain should be assessed at regular visits to the primary care physician or physical therapist; routine screening for hypoventilation and yearly forced vital capacity in those with moderate to severe disease; periodic hearing screening in affected children; annual dilated ophthalmoscopy in childhood.

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.

GeneReview Scope

Facioscapulohumeral Muscular Dystrophy: Included Disorders
  • Facioscapulohumeral muscular dystrophy 1
  • Facioscapulohumeral muscular dystrophy 2

For synonyms and outdated names see Nomenclature.


Clinical Diagnosis

Two genetic variants of FSHD that are clinically indistinguishable have been identified as FSHD1 and FSHD2 [de Greef et al 2010]. FSHD is suspected in individuals with the following [Tawil et al 1998, Tawil & van der Maarel 2006]:

  • Weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness
  • Onset of signs typically by age 20 years. However, more mildly affected individuals show signs at a later age and some remain asymptomatic.


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 over 1500 IU/L suggests an alternate diagnosis.

EMG usually shows mild myopathic changes.

Muscle biopsy most often shows nonspecific chronic myopathic changes. Mononuclear inflammatory reaction 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 those individuals in whom FSHD is suspected but not confirmed by molecular genetic testing.

Molecular Genetic Testing

Derepression and dysregulation of DUX4 (within the macrosatellite repeat D4Z4) underlie both FSHD1 and FSHD2. For FSHD1 the derepression is a consequence of the contraction of the D4Z4 repeat and for FSHD2 this is caused by pathogenic variants in SMCHD1. (See Table A for chromosome locus and protein name for these genes.)

Evidence for locus heterogeneity. FSHD2 has been identified in two families; about 20% of affected members have D4Z4 hypomethylation without SMCHD1 pathogenic variants, suggesting other modifier loci that affect the structure of D4Z4 [Lemmers et al 2012a].

Organization and regulation of the D4Z4 locus is complex but critical to the understanding of genetic testing issues. The D4Z4 locus of individuals with either FSHD1 or FSHD2 displays chromatin relaxation leading to inappropriate expression of DUX4 in muscle cells resulting in the disorder. In FSHD1, chromatin relaxation occurs via a D4Z4 repeat array contraction below a certain threshold. In FSHD2 chromatin relaxation results from a heterozygous pathogenic variant in SMCHD1, which normally regulates the repression of D4Z4 via DNA CpG methylation.

Each D4Z4 macrosatellite repeat contains a gene with two homeoboxes, called DUX4 [Hewitt et al 1994, Gabriëls et al 1999]. The DUX4 open reading frame is present in each 3.3-kb D4Z4 unit but only transcripts that are spliced with an exon localized immediately distal to the array are stabilized sufficiently for protein production. Recently, transcription analysis showed that DUX4 transcripts from the most distal D4Z4 unit are present in cultured myoblasts from affected individuals in both FSHD1 and FSHD2, but not in control myoblasts [Dixit et al 2007, Snider et al 2009, Lemmers et al 2010a, Lemmers et al 2012b].


Critical region. Approximately 95% of individuals with FSHD have a pathogenic contraction of the D4Z4 macrosatellite array in the subtelomeric region of chromosome 4q35. The pathologic contraction of the D4Z4 repeat array is associated with an opening of the chromatin structure at the D4Z4 locus.

Genetic variation at D4Z4. Roughly, the present authors distinguish two different variants of D4Z4 on chromosome 4: 4A and 4B. This categorization is mainly based on sequence variations telomeric to D4Z4, which contribute to the pathogenicity of a contracted D4Z4 allele [van Geel et al 2002, Lemmers et al 2002]. Distal to the D4Z4 region on the 4A variant, the authors find an extra DUX4 exon that carries the polyadenylation signal of the gene required for stable expression of the gene from the most distal D4Z4 unit [Dixit et al 2007, Lemmers et al 2010a]. Chromosome variants 4A and 4B (sometimes referred to as 4qA and 4qB) are almost equally common in a control population (see Molecular Genetics) and can be further divided into at least nine distinct haplotypes (i.e., different combinations of single-nucleotide variants at one locus that are inherited together) [Lemmers et al 2007, Lemmers et al 2010b].

  • 4A haplotype. FSHD1 is only associated with contractions of the D4Z4 repeat array on the 4A variant FSHD1 [Lemmers et al 2002] because this variant is permissive to DUX4 expression [Lemmers et al 2010a]. 4A161 is the most common 4A haplotype (see Molecular Genetics, DUX4 for haplotype details).
  • 4B haplotype. Contractions of the D4Z4 allele on the 4B haplotypes are non-pathogenic (benign), these alleles lack the exon distal to D4Z4 that stabilizes the DUX4 transcript [Lemmers et al 2004a, Lemmers et al 2010a].
  • D4Z4 variant on chromosome 10. A repeat sequence almost identical to D4Z4 has been identified on chromosome 10q26 but contractions of this repeat are not associated with FSHD. Genetic analysis showed that the distal DUX4-like gene in the D4Z4 array on chromosome 10 has nucleotide variants in the polyadenylation signal, which prevent the production of a stable DUX4 transcript from this locus [Lemmers et al 2010a].

Number of D4Z4 repeat units in the subtelomeric region of chromosome 4q35. The D4Z4 array consists of single D4Z4 units of 3.3 kilobases (kb) repeated in a head-to-tail array (depicted by triangles in Figure 1).

Figure 1. . Schematic comparison of the structure of the normal D4Z4 allele and the pathogenic contracted D4Z4 allele that causes FSHD1.

Figure 1.

Schematic comparison of the structure of the normal D4Z4 allele and the pathogenic contracted D4Z4 allele that causes FSHD1. The normal D4Z4 allele has between 11 and 100 units of the 3.3-kb repeat sequence (depicted by triangles), whereas the pathogenic (more...)

  • Unaffected individuals. Both chromosome 4 D4Z4 alleles have 11-100 repeat units.
  • Individuals with FSHD

FSHD2. Among FSH-positive specimens received by a diagnostic laboratory, most are FSHD1 (95%); the remainder (5%) are FSHD2. Individuals with FSHD2 did not have a D4Z4 contraction but were shown to have an open chromatin structure at the D4Z4 locus that was marked by a loss of CpG methylation at all D4Z4 repeat arrays on chromosomes 4 and 10. For FSHD2, an epigenetic FSHD variant, the chromatin relaxation in 80% of the cases is caused by mutation of SMCHD1, the structural maintenance of chromosomes flexible hinge domain containing gene 1, which is encoded by 48 exons. SMCHD1 regulates chromatin repression at the inactive X chromosome and autosomal transgenes, like D4Z4, by CpG DNA methylation [Blewitt et al 2008]. Similar to FSHD1, FSHD2 requires an allele that is permissive to DUX4 transcription. SMCHD1 can also be a modifier in FSHD1 families, as has been shown for three FSHD families in which pathogenic variants for both FSHD1 as well as for FSHD2 have been identified. Individuals that carried both pathogenic variants were shown to be more affected than family members with either of the two pathogenic variants [Sacconi et al 2013]. Due to the requirement of inheriting altered alleles from two independently-segregating genes (an SMCHD1 pathogenic variant and a DUX4 permissive allele) FSHD2 displays a digenic inheritance pattern.

Clinical testing


The guidelines for genetic diagnosis of FSHD were discussed at a Best Practice meeting held in The Netherlands in 2010. At the end of this meeting all participants came to a consensus regarding the molecular diagnosis of FSHD1; see Lemmers et al [2012a] (full text) and Figure 2.

Figure 2.

Figure 2.

Flowchart analysis of FSHD Standard analysis: Best practice guidelines [Lemmers et al 2012a] recommend standard analysis (steps 1 and 2), which can confirm or exclude a diagnosis for the majority of individuals tested.

Allele sizes. Molecular genetic testing to determine the length or number of repeat units of the D4Z4 locus relies on Southern blot analysis, typically with a probe (e.g., p13E-11) that is localized immediately proximal to D4Z4. Standard DNA diagnostic testing (defined here as linear gel electrophoresis and Southern blot analysis) uses the restriction enzyme EcoRI that recognizes the D4Z4 locus on chromosomes 4 and 10.

Note: 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.

  • Normal alleles. A D4Z4 locus with 11 to 100 repeat units (i.e., fragments of 43 kb or greater using EcoRI and the p13E-11 probe)
  • Borderline alleles. A D4Z4 locus with ten or 11 repeat units
    Note: (1) To date, it has not been possible to establish a definitive diagnostic cut-off for the number of repeat units of the D4Z4 locus; thus, caution should be exercised in assigning the diagnosis of FSHD to persons whose clinical findings are atypical and whose molecular genetic test results are within this borderline ("gray") zone. (2) Interpretation of the significance of fragments of this length requires correlation with clinical findings: In a study of 39 unrelated individuals having a D4Z4 allele in this size range, Butz et al [2003] identified individuals representing the complete phenotypic spectrum, from typical and atypical FSHD, to facial-sparing FSHD, to non-FSHD myopathy, to healthy without signs or symptoms. The authors consider 35-40 kb fragments to be FSHD-associated if the person has clinical features of FSHD.
  • FSHD-associated alleles. A D4Z4 locus that has one to ten repeat units AND is on a chromosome 4A haplotype. When such a fragment is not visible in the DNA sample, the person is said to have tested negative for FSHD1.
  • 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 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 2004b].
    Depending on when in embryogenesis the pathogenic contraction occurs at the D4Z4 locus and the proportion of cells with the contracted D44Z 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].
    Note: In the other half of cases of de novo FSHD, the pathogenic contraction of the D4Z4 array likely occurs within the germline, prior to fertilization.
  • Translocated alleles. Approximately 20% of the general population carries either a chromosome 4q35-type D4Z4 repeat array on chromosome 10 or a D4Z4 array that consists of both 4q35- and 10q26-type sequence repeats on chromosome 4q35 [van Deutekom et al 1996, Lemmers et al 2010b]. Translocated arrays on chromosome 10q are non-permissive to FSHD, while the contractions on the hybrid arrays on chromosome 4q35 cause FSHD [Buzhov et al 2005, Lemmers et al 2010a].
    Therefore, the finding of a D4Z4 array that appears to be contracted in an individual who carries these translocations must be interpreted with caution and reconciled with clinical findings [Lemmers et al 2010b, Lemmers et al 2012b].
    Note: Although these are commonly known as "translocated alleles," the mechanism is unknown.
  • Haplotype analysis. To prevent a false positive diagnosis, the clinician should know whether a laboratory test can distinguish between contracted D4Z4 arrays that occur on either the permissive 4A161 haplotype or the non-permissive 4A166 and 4B haplotypes (see Molecular Genetic Testing), telomeric to the D4Z4 region.
    Sometimes a D4Z4 array from chromosome 4 that appears to have a pathogenic contraction is detected in unaffected control individuals. In most of these cases, the contracted D4Z4 array is on the non-permissive 4B haplotype and is therefore non-penetrant. Lemmers et al developed a clinically available diagnostic test to discriminate both haplotype variants using HindIII-digested DNA and specific probes for 4qA and 4qB [Lemmers et al 2002, Lemmers et al 2007].
    Note: More specific genotyping to distinguish different 4A haplotypes is not yet possible.
  • Alleles deleted for the molecular probe p13E-11. 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].
  • Alternative diagnostic methods are being developed to improve detection of pathogenic alleles (see Molecular Genetics).


Table 1.

Molecular Genetic Testing Used in Facioscapulohumeral Muscular Dystrophy

DisorderGene 1/LocusTest MethodVariant Detected 2Variant Detection Frequency 3
FSHD1D4Z4Targeted analysis for pathogenic variantsPathogenic contraction of number of D4Z4 repeats95%
Haplotype analysisAnalysis to confirm that the D4Z4 pathogenic contraction occurred on a permissive haplotype 4Not applicable
FSHD2D4Z4Methylation analysisD4Z4 hypomethylation (<25% methylation)<5%
SMCHD1Sequence analysis 5SMCHD1 sequence variants<5%

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene/locus


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.


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.

Interpretation of test results

  • Molecular genetic test results should always be interpreted within the context of clinical findings.
  • FSHD1. 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.
  • FSHD2. D4Z4 methylation values below the threshold of 25% are indicative for FSHD2. 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
  • Variant alleles of uncertain clinical significance may be investigated further by D4Z4 methylation analysis and/or SMCHD1 transcription analysis.

Testing Strategy

To confirm/establish the diagnosis of either FSHD1 or FSHD2 in a proband follow the Figure 2 algorithm.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

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 [Tawil et al 1998]. Asymmetry of limb and/or 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 90% of affected individuals 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 and continuous; 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 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."

Abdominal muscle weakness results in protuberance of the abdomen and exaggerated lumbar lordosis. The lower abdominal muscles are selectively involved, resulting in 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.

Respiratory function is usually normal [Tawil & Griggs 1997] but occasionally compromised [Kilmer et al 1995].

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 60% of individuals with FSHD have an abnormal audiogram with high-tone sensorineural hearing loss [Brouwer et al 1991, Padberg et al 1995]. Subclinical sensorinerural hearing loss occurs in up to 75% of affected individuals.

Both the exudative retinopathy and the sensorineural hearing loss are seen more commonly in people with small (1-2 repeat) arrays or in individuals with early onset disease [Trevisan et al 2008].

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 a frequent and likely under-recognized complaint 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 with facial sparing
  • Slowly progressive FSHD with progressive external ophthalmoplegia [Krasnianski et al 2003]. This kindred presents a departure from previously described atypical FSHD kindreds. Given the complexity of interpreting FSHD molecular genetic test results, more comprehensive molecular testing of this kindred is necessary before progressive external ophthalmoplegia can be included with certainty in the clinical spectrum of FSHD.
  • 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 cases with infantile onset. Mild to moderate cognitive deficiency and possible epilepsy have been reported in early-onset cases often with associated deafness and retinopathy [Bindoff et al 2006, Hobson-Webb & Caress 2006, Quarantelli et al 2006].The affected parent frequently had mild disease and was mosaic for a pathogenic contraction of the D4Z4 locus.

Genotype-Phenotype Correlations

FSHD1. 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 et al 1995], 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 the D4Z4 locus tend to have 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]. However, others have not been able to confirm a correlation between disease severity and degree of D4Z4 pathogenic contractions [Butz et al 2003].

De novo pathogenic variants are associated with larger contractions of D4Z4 (on average) compared to the size of D4Z4 pathogenic contractions observed segregating in families; hence, individuals with de novo pathogenic variants tend to have findings at the more severe end of the phenotypic spectrum. 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.

Zatz et al [1998] have reported reduced penetrance in females with large pathogenic contractions of D4Z4, compared to the penetrance in males with similar-sized pathogenic contractions; these results support their previous findings (see Penetrance).

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 in comparison to other family members.

Homozygosity. Tonini et al [2004b] reported an individual homozygous for the contraction on two D4Z4 4qA 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.


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]. This finding was confirmed by Tonini et al [2004a]. The sex difference in penetrance is unexplained [Zatz et al 1998].

Tonini et al [2004a] suggest that non-penetrance may cluster in families, with other genetic factors contributing to the severity of clinical presentation. Goto et al [2004] drew similar conclusions in an analysis of penetrance in 85 kindreds.


The existence and putative mechanism for anticipation in FSHD remains controversial. Anticipation in FSHD was originally suggested by Zatz et al [1995] based on the observation in multigenerational families that parents were frequently less affected than their offspring. Substantiation for this idea can be found in the reports of Lunt et al [1995] and Tawil et al [1996].

However, further data suggest that this apparent anticipation may be the result of the gender differences in penetrance described above [Zatz et al 1998]. Thus, affected male offspring of affected mothers are likely to be more severely affected as a function of gender difference rather than anticipation.

It has also been suggested that late ascertainment bias among maternal relatives contributed to the apparent anticipation.

Absence of anticipation in large multigenerational families has also been reported [Flanigan et al 2001].


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 of scapulo-humeral or scapulo-peroneal syndromes.


The estimated prevalence of FSHD is between four and ten per 100,000 population. Sposito et al [2005] found a prevalence in central Italy of 4.6 per 100,000, a much higher prevalence than found in a previous study from the same region done in the pre-molecular diagnosis era (1981).

Differential Diagnosis

Disorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) but easily differentiated by their distinct muscle histopathology include the following:

More troublesome are the following disorders in which the distribution of weakness and pathologic findings can be difficult to distinguish easily from FSHD:

  • The 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. Molecular genetic testing allows definitive diagnosis of these two conditions.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with facioscapulohumeral muscular dystrophy (FSHD), the following evaluations are recommended:

  • Physical examination to assess strength and functional limitations
  • Evaluation for physical therapy and need for assistive devices
  • Assessment of hearing if the individual has symptomatic hearing loss
  • Ophthalmologic evaluation for the presence of retinal telangiectasias
  • Clinical genetics consultation

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 below:

Physical therapy and rehabilitation

  • Consultation with a physical therapist is indicated.
  • Establishment of follow-up frequency is important at the time of diagnosis. Individuals with FSHD should be seen at a frequency based on their disease severity, which for some will be frequent initially, and may include occupational and speech therapy in infantile onset forms of FSHD. For others with mild involvement, annual visits would be appropriate.
  • Physical therapy and rehabilitation consultations can help establish appropriate exercise regimens and assistive devices that may enhance mobility and reduce the risk of falls in home environments.

Exercise in FSHD

  • Exercise with moderate weights is not detrimental to individuals with FSHD [Milner-Brown & Miller 1988, van der Kooi et al 2004].
  • Aerobic training (when possible) has been beneficial to affected individuals [Olsen et al 2005].
  • Any type of exercise regimen should be instituted under the guidance of a physical therapist and personalized according to the individual’s disease symptoms, age, and cardiovascular status.

Pain. Chronic pain should be managed by physical therapy and medication as necessary.

Respiratory dysfunction. Ventilatory support such as BiPAP should be considered as necessary for those with hypoventilation.

Hearing loss. Standard therapies for hearing loss, including amplification if necessary, are appropriate.

Ophthalmologic disease. Exposure keratitis may occur in individuals who sleep with their eyes partially open. Use of lubricants to prevent drying of the sclera or in more severe cases taping the eyes shut during sleep may be required.

Orthopedic intervention

  • Ankle/foot orthoses can improve mobility and prevent falls in individuals with foot drop.
  • Surgical fixation of the scapula to the chest wall often improves range of motion of the arms, although this gain can be short-lived in individuals with rapidly progressive disease [Diab et al 2005, Krishnan et al 2005, Giannini et al 2006]. Evaluation of such individuals prior to surgery is warranted to assure a functional and sustained benefit.


For those with a confirmed diagnosis of FSHD, the following surveillance applies:

Pain. Pain should be assessed at regular visits to primary care physicians and physical therapists.

Respiratory dysfunction

  • Affected individuals with moderate to severe FSHD, defined as those with proximal lower extremity weakness, should be routinely screened for hypoventilation.
  • Yearly forced vital capacity (FVC) measurements should be monitored for all affected individuals who are wheelchair bound, have pelvic girdle weakness and superimposed pulmonary disease, and/or have moderate to severe kyphoscoliosis, lumbar hyperlordosis, or chest wall deformities.

Hearing loss

  • As in children who are at risk for hearing loss for other reasons, hearing can be followed routinely by periodic assessment as part of school-based testing.
  • Hearing screens are particularly important in severe infantile onset forms of FSHD, as hearing loss can result in delayed language acquisition.
  • Adults should have a formal hearing evaluation based purely on symptoms. No additional audiometry screening of asymptomatic individuals is necessary.

Ophthalmologic disease

  • Annual dilated ophthalmoscopy in childhood is indicated.
  • In adults, a dilated retinal exam should be performed at the time of diagnosis; if vascular disease is absent, follow-up exams are only necessary if visual symptoms develop.

In children known to be at risk for FSHD (because of family history) but for whom the diagnosis has not yet been confirmed, annual dilated ophthalmoscopy is indicated.

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

MYO-029, an antibody designed to inhibit the activity of myostatin and enhance the growth and strength of muscles, has been developed. Because results in animal models of muscular dystrophy indicated that this could result in increased strength, a clinical trial was initiated in 2005 and completed in 2007. The study was designed primarily as a safety study for antibody injection into humans and identification of side effects. The study had four treatment groups on increasing doses of MYO-029 and a group that received a placebo for comparison. Side effects from the highest dose of MYO-029 caused that group to be discontinued from the study. The injections were fairly well tolerated; hypersensitivity reactions (rashes, itching, and occasionally more systemic reactions) limiting the dose that could be injected were the most common reactions. Such reactions are generally expected for the injection of biologically active proteins into the blood stream.

With respect to FSHD, 22 people who received MYO-29 injections of various doses finished the study. A total of five withdrew voluntarily and four were in the high-dose cohort and were discontinued from the study. People who received the MYO-029 injections and placebo injections were evaluated for muscle strength (6 months of dosing and 3 months of follow-up for a total of 9 months). Using a number of both quantitative and subjective parameters, no difference in strength was measured or perceived by subjects in the study regardless of dose. The study authors [Wagner et al 2008] did state that many more subjects would have been necessary (160 with FSHD) to demonstrate a significant difference in strength, thus it cannot be concluded that the treatment was completely unsuccessful; further, the primary goal of the study was determination of safety rather than demonstration of increase in strength.

Muscle biopsies from subjects who received MYO-029 showed no significant adverse effect by several measures. A dose-dependent increase in fiber size diameter (essentially an increase in muscle size) was observed (low dose: 2% increase; medium dose: 2.2% increase; high dose: 5.3% increase in size). Thus, the MYO-029 appeared to have an effect on muscle.

The study also indicated that more potent inhibitors of myostatin are being developed [Wagner et al 2008].

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions.


A 24-week trial of dilitazem did not improve findings in individuals with FSHD [Elsheikh et al 2007].

Steroids, albuterol, and creatine have not proven effective [Tawil & van der Maarel 2006].

  • Two controlled studies of oral albuterol in FSHD [Kissel et al 2001, van der Kooi et al 2004] did not show significant global improvement in strength despite a modest increase in muscle mass. A Cochrane review concluded that further study of albuterol in FSHD is needed [Rose & Tawil 2004].
  • Corticosteroids have been used in individuals who have evidence of inflammation on muscle biopsy. Although transient improvement in strength has been reported, a natural history-controlled study in eight individuals with FSHD revealed no improvement after 12 weeks of treatment with prednisone [Tawil et al 1997].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Facioscapulohumeral muscular dystrophy 1 (FSHD1) is inherited in an autosomal dominant manner. Facioscapulohumeral muscular dystrophy 2 (FSHD2) is inherited in a digenic manner.

Risk to Family Members – FSHD1 (Autosomal Dominant Inheritance)

Parents of a proband

  • Most individuals diagnosed with FSHD have a parent with clinical findings of FSHD and one D4Z4 allele with a pathogenic contraction (70%-90% of individuals with FSHD).
  • However, approximately 10%-30% of probands with FSHD have the disorder as the result of a D4Z4 de novo pathogenic contraction [Bakker et al 1996, Köhler et al 1996].
  • It is appropriate to evaluate the parents of a proband clinically and with molecular genetic testing.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: The family history may appear to be negative because of failure to recognize the disorder in family members, an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative), early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the parents.
  • If a parent of the proband is affected or has the pathogenic contraction, the risk to the sibs of inheriting the D4Z4 pathogenic contraction is 50%.
  • When neither parent has the D4Z4 pathogenic contraction, the risk to the sibs of a proband appears to be low.
  • If neither parent of the proband has a detectable D4Z4 pathogenic contraction, two possible explanations are germline mosaicism in a parent or a de novo D4Z4 pathogenic contraction in the proband. Germline mosaicism has been reported [Köhler et al 1996] but the incidence is unknown.

Offspring of a proband. Each offspring of an affected individual has a 50% chance of inheriting the D4Z4 pathogenic contraction.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected and/or has a D4Z4 pathogenic contraction, his or her family members are at risk.

Risk to Family Members – FSHD2 (Digenic Inheritance)

Facioscapulohumeral muscular dystrophy 2 is reported to result from inheritance of both one pathogenic SMCHD1 allele and an FSHD-permissive DUX4 allele (SMCHD1 and the DUX4-permissive allele segregate independently).

Parents of a proband

Sibs of a proband

  • At conception, each sib has a 25% chance of having FSHD2, a 50% chance of having an SMCHD1 pathogenic variant or an FSHD-permissive DUX4 allele, and a 25% chance of being unaffected and having neither an SMCHD1 pathogenic variant nor an FSHD-permissive DUX4 allele.
  • Once an at-risk sib is known to be unaffected, the chance of his/her having either an SMCHD1 pathogenic variant or an FSHD-permissive DUX4 allele is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. Assuming that the proband's reproductive partner is not affected and not a carrier of either an SMCHD1 pathogenic variant or an FSHD-permissive DUX4 allele, each child of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Other family members of a proband. Each sib of an obligate heterozygote has a 50% chance of having either an SMCHD1 pathogenic variant or an FSHD-permissive DUX4 allele.

Related Genetic Counseling Issues

Testing of at-risk individuals. Molecular genetic testing for asymptomatic at-risk adult family members is possible. The testing of unaffected at-risk children younger than age 18 years is discouraged because no treatment is available. In a family with an established diagnosis of FSHD, it is appropriate to consider testing of symptomatic individuals regardless of age.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Considerations in families with apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant has been identified in an affected family member, prenatal diagnosis for a preganancy at increased is possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the pathogenic variant has been identified. However, no method for PGD is currently reliable.

The current diagnostic method for FSHD1 is based on genetic linkage and requires detailed chromosome analysis including D4Z4 array sizing of both parents, after which the segregation of a pathogenic chromosome in the fetal material is followed using DNA markers. However, one study tested several polymorphic markers in the D4Z4 region at a considerable distance from the array (0.55-1.88 Mb) that showed a relatively high recombination risk, making the application to PGD unreliable [Barat-Houari et al 2010]. Another study used DNA markers much closer to the D4Z4 repeat array with a very low risk of recombination [Tsumagari et al 2010]. This method enables the detection of the permissive haplotype but does not distinguish between a person carrying the common 4A161 permissive haplotype and those carrying the haplotype and associated FSHD-causing array contraction, thus reducing the sensitivity of this approach considerably, given the high frequency of permissive haplotypes in European and Asian populations.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Facioscapulohumeral Muscular Dystrophy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Facioscapulohumeral Muscular Dystrophy (View All in OMIM)


Molecular Genetic Pathogenesis

See Molecular Genetic Testing.

Alternative diagnostic methods for FSHD1. Because the current Southern blot based molecular diagnosis for FSHD1 is expensive and labor intensive, and requires large amounts of high molecular-weight DNA, some alternative molecular diagnostic methods are being investigated.

For example, D4Z4 sizing can be performed by long-range polymerase chain reaction (LR-PCR), which is faster and requires less DNA than the Southern blot-based method [Goto et al 2006]. However, the method does not allow the identification of repeat arrays of more than six repeat units, making the LR-PCR method unsuitable for the identification of FSHD1 in a large proportion of European families with FSHD. False negative results are a significant concern, as a negative result could occur when the DNA available was unsuitable for PCR amplification due to protein and salt impurities or due to low DNA quality.

Recently, molecular combing (MC) was developed for FSHD1; MC is based on fluorescence in situ hybridization (FISH) of stretched DNA molecules [Nguyen et al 2011]. By this method D4Z4 fragments are visualized and sized with different fluorescence-labeled probes which enable discrimination between arrays on chromosomes 4 and 10 and the 4A and 4B haplotypes. Detection of the different chromosomes by MC is currently time consuming and the technology needs further automation to warrant replacing the Southern blot-based method. However, if D4Z4 repeat array sizing by MC proves to be accurate and if the microscopic analysis is further automated MC may become a useful diagnostic method for FSHD.


Benign variants. Each D4Z4 repeat unit has an open reading frame (named DUX4) that encodes two homeoboxes. See Figure 2. The transcript is approximately 1300 nucleotides and is stabilized sufficiently for protein production only when spliced with an exon localized immediately distal to the array. See Molecular Genetic Testing. For a detailed summary of gene and protein information, see Table A, Gene.

  • 4A haplotype. In general, contractions of the D4Z4 allele in the 4A haplotype causes FSHD1 [Lemmers et al 2002] because it is permissive to DUX4 expression [Lemmers et al 2010a]. 4A161 is the most common 4A haplotype; less common FSHD permissive haplotypes are 4A159, 4A163, 4A166H, and 4A168 [Lemmers et al 2007, Lemmers et al 2010a]. A study in two Dutch families showed that D4Z4 contraction in the less common 4A haplotype (designated 4A166) is not associated with FSHD (see Molecular Genetic Testing, Genetic variation at D4Z4).

Pathogenic variants. See Molecular Genetic Testing, FSHD1.

Normal gene product. Normal DUX4 alleles are not expressed; no protein is produced.

Abnormal gene product. The DUX4 protein (NP_149418.4) is 424 amino acids in length and functions as a transcriptional activator.


Gene structure. SMCHD1 has a transcript of 8672 nucleotides and 48 exons (NM_015295.2). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic missense, frameshift, and splicing variants have been identified in FSHD2 families [Lemmers et al 2012b].

Normal gene product. The protein product of SMCHD1 is a 226 kd with 2005 amino acids. It is necessary for D4Z4 hypermethylation and remains associated with the array in skeletal muscle cells.

Abnormal gene product. Haploinsufficiency for SMCHD1 protein appears to be the cause of reduced D4Z4 methylation and variegated expression of Dux 4 [Lemmers et al 2012b].


Published Guidelines/Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 10-9-18. [PubMed: 23428972]
  • Lemmers RJ, O'Shea S, Padberg GW, Lunt PW, van der Maarel SM. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: Workshop 9th June 2010, LUMC, Leiden, The Netherlands. Available online. 2012. Accessed 10-9-18. [PubMed: 22177830]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 10-9-18.

Literature Cited

  • Bakker E, van der Wielen MJ, Voorhoeve E, Ippel PF, Padberg GW, Frants RR, Wijmenga C. Diagnostic, predictive, and prenatal testing for facioscapulohumeral muscular dystrophy: diagnostic approach for sporadic and familial cases. J Med Genet. 1996;33:29–35. [PMC free article: PMC1051808] [PubMed: 8825045]
  • Barat-Houari M, Nguyen K, Bernard R, Fernandez C, Vovan C, Bareil C, Khau Van Kien P, Thorel D, Tuffery-Giraud S, Vasseur F, Attarian S, Pouget J, Girardet A, Lévy N, Claustres M. New multiplex PCR-based protocol allowing indirect diagnosis of FSHD on single cells: can PGD be offered despite high risk of recombination? Eur J Hum Genet. 2010;18:533–8. [PMC free article: PMC2987324] [PubMed: 19935833]
  • Bindoff LA, Mjellem N, Sommerfelt K, Krossnes BK, Roberts F, Krohn J, Tranheim RS, Haggerty ID. Severe fascioscapulohumeral muscular dystrophy presenting with Coats' disease and mental retardation. Neuromuscul Disord. 2006;16:559–63. [PubMed: 16935506]
  • Blewitt ME, Gendrel AV, Pang Z, Sparrow DB, Whitelaw N, Craig JM, Apedaile A, Hilton DJ, Dunwoodie SL, Brockdorff N, Kay GF, Whitelaw E. SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet. 2008;40:663–9. [PubMed: 18425126]
  • Brouwer OF, Padberg GW, Ruys CJ, Brand R, de Laat JA, Grote JJ. Hearing loss in facioscapulohumeral muscular dystrophy. Neurology. 1991;41:1878–81. [PubMed: 1745341]
  • Butz M, Koch MC, Muller-Felber W, Lemmers RJ, van der Maarel SM, Schreiber H. Facioscapulohumeral muscular dystrophy. Phenotype-genotype correlation in patients with borderline D4Z4 repeat numbers. J Neurol. 2003;250:932–7. [PubMed: 12928911]
  • Buzhov BT, Lemmers RJ, Tournev I, Dikova C, Kremensky I, Petrova J, Frants RR, van der Maarel SM. Genetic confirmation of facioscapulohumeral muscular dystrophy in a case with complex D4Z4 rearrangments. Hum Genet. 2005;116:262–6. [PubMed: 15645183]
  • Ciafaloni E, Pressman EK, Loi AM, Smirnow AM, Guntrum DJ, Dilek N, Tawil R. Pregnancy and birth outcomes in women with facioscapulohumeral muscular dystrophy. Neurology. 2006;67:1887–9. [PubMed: 17130433]
  • de Greef JC, Lemmers RJ, Camaño P, Day JW, Sacconi S, Dunand M, van Engelen BG, Kiuru-Enari S, Padberg GW, Rosa AL, Desnuelle C, Spuler S, Tarnopolsky M, Venance SL, Frants RR, van der Maarel SM, Tawil R. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology. 2010;75:1548–54. [PMC free article: PMC2974464] [PubMed: 20975055]
  • de Greef JC, Lemmers RJ, van Engelen BG, Sacconi S, Venance SL, Frants RR, Tawil R, van der Maarel SM. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum Mutat. 2009;30:1449–59. [PubMed: 19728363]
  • Diab M, Darras BT, Shapiro F. Scapulothoracic fusion for facioscapulohumeral muscular dystrophy. J Bone Joint Surg Am. 2005;87:2267–75. [PubMed: 16203893]
  • Dixit M, Ansseau E, Tassin A, Winokur S, Shi R, Qian H, Sauvage S, Mattéotti C, van Acker AM, Leo O, Figlewicz D, Barro M, Laoudj-Chenivesse D, Belayew A, Coppée F, Chen YW. DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc Natl Acad Sci U S A. 2007;104:18157–62. [PMC free article: PMC2084313] [PubMed: 17984056]
  • Ehrlich M, Jackson K, Tsumagari K, Camaño P, Lemmers RJ. Hybridization analysis of D4Z4 repeat arrays linked to FSHD. Chromosoma. 2007;116:107–16. [PMC free article: PMC1828046] [PubMed: 17131163]
  • Elsheikh BH, Bollman E, Peruggia M, King W, Galloway G, Kissel JT. Pilot trial of diltiazem in facioscapulohumeral muscular dystrophy. Neurology. 2007;68:1428–9. [PubMed: 17452589]
  • Felice KJ, Jones JM, Conway SR. Facioscapulohumeral dystrophy presenting as infantile facial diplegia and late-onset limb-girdle myopathy in members of the same family. Muscle Nerve. 2005;32:368–72. [PubMed: 15880682]
  • Flanigan KM, Coffeen CM, Sexton L, Stauffer D, Brunner S, Leppert MF. Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscul Disord. 2001;11:525–9. [PubMed: 11525880]
  • Gabriëls J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A. Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene. 1999;236:25–32. [PubMed: 10433963]
  • Galetta F, Franzoni F, Sposito R, Plantinga Y, Femia FR, Galluzzi F, Rocchi A, Santoro G, Siciliano G. Subclinical cardiac involvement in patients with facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2005;15:403–8. [PubMed: 15907286]
  • Giannini S, Ceccarelli F, Faldini C, Pagkrati S, Merlini L. Scapulopexy of winged scapula secondary to facioscapulohumeral muscular dystrophy. Clin Orthop Relat Res. 2006;(449):288–94. [PubMed: 16672903]
  • Goto K, Nishino I, Hayashi YK. Rapid and accurate diagnosis of facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2006;16:256–61. [PubMed: 16545566]
  • Goto K, Nishino I, Hayashi YK. Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A. J Med Genet. 2004;41:e12. [PMC free article: PMC1757263] [PubMed: 14729852]
  • Hewitt JE, Lyle R, Clark LN, Valleley EM, Wright TJ, Wijmenga C, van Deutekom JC, Francis F, Sharpe PT, Hofker M, Frants RR, Williamson R. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet. 1994;3:1287–95. [PubMed: 7987304]
  • Hobson-Webb LD, Caress JB. Facioscapulohumeral muscular dystrophy can be a cause of isolated childhood cognitive dysfunction. J Child Neurol. 2006;21:252–3. [PubMed: 16901430]
  • Kilmer DD, Abresch RT, McCrory MA, Carter GT, Fowler WM Jr, Johnson ER, McDonald CM. Profiles of neuromuscular diseases. Facioscapulohumeral muscular dystrophy. Am J Phys Med Rehabil. 1995;74:S131–9. [PubMed: 7576420]
  • Kissel JT, McDermott MP, Mendell JR, King WM, Pandya S, Griggs RC, Tawil R. Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology. 2001;57:1434–40. [PubMed: 11673585]
  • Klinge L, Eagle M, Haggerty ID, Roberts CE, Straub V, Bushby KM. Severe phenotype in infantile facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2006;16:553–8. [PubMed: 16934468]
  • Köhler J, Rupilius B, Otto M, Bathke K, Koch MC. Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occurring predominantly in oogenesis. Hum Genet. 1996;98:485–90. [PubMed: 8792827]
  • Krasnianski M, Eger K, Neudecker S, Jakubiczka S, Zierz S. Atypical phenotypes in patients with facioscapulohumeral muscular dystrophy 4q35 deletion. Arch Neurol. 2003;60:1421–5. [PubMed: 14568813]
  • Krishnan SG, Hawkins RJ, Michelotti JD, Litchfield R, Willis RB, Kim YK. Scapulothoracic arthrodesis: indications, technique, and results. Clin Orthop Relat Res. 2005;(435):126–33. [PubMed: 15930929]
  • Laforêt P, de Toma C, Eymard B, Becane HM, Jeanpierre M, Fardeau M, Duboc D. Cardiac involvement in genetically confirmed facioscapulohumeral muscular dystrophy. Neurology. 1998;51:1454–6. [PubMed: 9818880]
  • Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet. 2002;32:235–6. [PubMed: 12355084]
  • Lemmers RJL, de Kievit P, van Geel M, van der Wielen MJ, Bakker E, Padberg GW, Frants RR, van der Maarel SM. Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis. Ann Neurol. 2001; 50:816.9. [PubMed: 11761483]
  • Lemmers RJ, Osborn M, Haaf T, Rogers M, Frants RR, Padberg GW, Cooper DN, van der Maarel SM, Upadhyaya M. D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection. Neurology. 2003;61:178–83. [PubMed: 12874395]
  • Lemmers RJ, O'Shea S, Padberg GW, Lunt PW, van der Maarel SM. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: Workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscul Disord. 2012a;22:463–70. [PubMed: 22177830]
  • Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC, Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN, Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012b;44:1370–4. [PMC free article: PMC3671095] [PubMed: 23143600]
  • Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010a;329:1650–3. [PMC free article: PMC4677822] [PubMed: 20724583]
  • Lemmers RJ, van der Vliet PJ, van der Gaag KJ, Zuniga S, Frants RR, de Knijff P, van der Maarel SM. Worldwide population analysis of the 4q and 10q subtelomeres identifies only four discrete interchromosomal sequence transfers in human evolution. Am J Hum Genet. 2010b;86:364–77. [PMC free article: PMC2833386] [PubMed: 20206332]
  • Lemmers RJ, van der Wielen MJ, Bakker E, Padberg GW, Frants RR, van der Maarel SM. Somatic mosaicism in FSHD often goes undetected. Ann Neurol. 2004a;55:845–50. [PubMed: 15174019]
  • Lemmers RJ, Van Overveld PG, Sandkuijl LA, Vrieling H, Padberg GW, Frants RR, van der Maarel SM. Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2004b;75:44–53. [PMC free article: PMC1182007] [PubMed: 15154112]
  • Lemmers RJ, Wohlgemuth M, van der Gaag KJ, van der Vliet PJ, van Teijlingen CM, de Knijff P, Padberg GW, Frants RR, van der Maarel SM. Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2007;81:884–94. [PMC free article: PMC2265642] [PubMed: 17924332]
  • Lunt PW, Jardine PE, Koch M, Maynard J, Osborn M, Williams M, Harper PS, Upadhyaya M. Phenotypic-genotypic correlation will assist genetic counseling in 4q35-facioscapulohumeral muscular dystrophy. Muscle Nerve. 1995;2:S103–9. [PubMed: 7739619]
  • Milner-Brown HS, Miller RG. Muscle strengthening through high-resistance weight training in patiens with neuromuscular disorders. Arch Phys Med Rehabil. 1988;69:14–19. [PubMed: 3337636]
  • Nguyen K, Walrafen P, Bernard R, Attarian S, Chaix C, Vovan C, Renard E, Dufrane N, Pouget J, Vannier A, Bensimon A, Lévy N. Molecular combing reveals allelic combinations in facioscapulohumeral dystrophy. Ann Neurol. 2011;70:627–33. [PubMed: 22028222]
  • Olsen DB, Orngreen MC, Vissing J. Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology. 2005;64:1064–6. [PubMed: 15781829]
  • Padberg GW, Brouwer OF, de Keizer RJW, Dijkman G, Wijmenga C, Grote JJ, Frants RR. On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy. Muscle Nerve. 1995;2:S73–80. [PubMed: 7739630]
  • Quarantelli M, Lanzillo R, Del Vecchio W, Mollica C, Prinster A, Iadicicco L, Iodice V, Santoro L, Salvatore M. Modifications of brain tissue volumes in facioscapulohumeral dystrophy. Neuroimage. 2006;32:1237–42. [PubMed: 16806975]
  • Rose MR, Tawil R. Drug treatment for facioscapulohumeral muscular dystrophy. Cochrane Database Syst Rev. 2004;2:CD002276. [PubMed: 15106171]
  • Sacconi S, Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P, van Nieuwenhuizen MP, Straasheijm KR, Debipersad RD, Vos-Versteeg M, Salviati L, Casarin A, Pegoraro E, Tawil R, Bakker E, Tapscott SJ, Desnuelle C, van der Maarel SM. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet. 2013;93:744–51. [PMC free article: PMC3791262] [PubMed: 24075187]
  • Snider L, Asawachaicharn A, Tyler AE, Geng LN, Petek LM, Maves L, Miller DG, Lemmers RJ, Winokur ST, Tawil R, van der Maarel SM, Filippova GN, Tapscott SJ. RNA transcripts, miRNA-sized fragments, and proteins produced from d4z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy. Hum Mol Genet. 2009;18:2414–30. [PMC free article: PMC2694690] [PubMed: 19359275]
  • Sposito R, Pasquali L, Galluzzi F, Rocchi A, Solito B, Soragna D, Tupler R, Siciliano G. Facioscapulohumeral muscular dystrophy type 1A in northwestern Tuscany: a molecular genetics-based epidemiological and genotype-phenotype study. Genet Test. 2005;9:30–6. [PubMed: 15857184]
  • Tawil R, Figlewicz DA, Griggs RC, Weiffenbach B. Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. FSH Consortium. Ann Neurol. 1998;43:279–82. [PubMed: 9506542]
  • Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J, McDermott M, King W, Weiffenbach B, Figlewicz D. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol. 1996;39:744–8. [PubMed: 8651646]
  • Tawil R, Griggs RC. Facioscapulohumeral muscular dystrophy. In: Rosenberg RN, Pruisner SB, DiMaurio S, Barchi R. eds. The Molecular and Genetic Basis of Neurological Disease. Boston, MA: Butterworth-Heinemann; 1997:931-8.
  • Tawil R, McDermott MP, Pandya S, King W, Kissel J, Mendell JR, Griggs RC. A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology. 1997;48:46–9. [PubMed: 9008492]
  • Tawil R, van der Maarel S, Padberg GW, van Engelen BGM. 171st ENMC International Workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscular Disorders. 2010;20:471–5. [PubMed: 20554202]
  • Tawil R, van der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2006;34:1–15. [PubMed: 16508966]
  • Tonini MM, Passos-Bueno MR, Cerqueira A, Matioli SR, Pavanello R, Zatz M. Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord. 2004a;14:33–8. [PubMed: 14659410]
  • Tonini MM, Pavanello RC, Gurgel-Giannetti J, Lemmers RJ, van der Maarel SM, Frants RR, Zatz M. Homozygosity for autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) does not result in a more severe phenotype. J Med Genet. 2004b;41:e17. [PMC free article: PMC1735661] [PubMed: 14757867]
  • Trevisan CP, Pastorello E, Armani M, Angelini C, Nante G, Tomelleri G, Tonin P, Mongini T, Palmucci L, Galluzzi G, Tupler RG, Barchitta A. Facioscapulohumeral muscular dystrophy and occurrence of heart arrhythmia. Eur Neurol. 2006;56:1–5. [PubMed: 16804309]
  • Trevisan CP, Pastorello E, Tomelleri G, Vercelli L, Bruno C, Scapolan S, Siciliano G, Comacchio F. Facioscapulohumeral muscular dystrophy: hearing loss and other atypical features of patients with large 4q35 deletions. Eur J Neurol. 2008;15:1353–8. [PubMed: 19049553]
  • Tsumagari K, Chen D, Hackman JR, Bossler AD, Ehrlich M. FSH dystrophy and a subtelomeric 4q haplotype: a new assay and associations with disease. J Med Genet. 2010;47:745–51. [PMC free article: PMC3043595] [PubMed: 20710047]
  • van der Kooi EL, Kalkman JS, Lindeman E, Hendriks JC, van Engelen BG, Bleijenberg G, Padberg GW. Effects of training and albuterol on pain and fatigue in facioscapulohumeral muscular dystrophy. J Neurol. 2007;254:931–40. [PMC free article: PMC2779375] [PubMed: 17361345]
  • van der Kooi EL, Vogels OJ, van Asseldonk RJ, Lindeman E, Hendriks JC, Wohlgemuth M, van der Maarel SM, Padberg GW. Strength training and albuterol in facioscapulohumeral muscular dystrophy. Neurology. 2004;63:702–8. [PubMed: 15326246]
  • van der Maarel SM, Deidda G, Lemmers RJ, van Overveld PG, van der Wielen M, Hewitt JE, Sandkuijl L, Bakker B, van Ommen GJ, Padberg GW, Frants RR. De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet. 2000;66:26–35. [PMC free article: PMC1288331] [PubMed: 10631134]
  • van Deutekom JC, Bakker E, Lemmers RJ, van der Wielen MJ, Bik E, Hofker MH, Padberg GW, Frants RR. Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1. Hum Mol Genet. 1996;5:1997–2003. [PubMed: 8968754]
  • van Geel M, Dickson MC, Beck AF, Bolland DJ, Frants RR, van der Maarel SM, de Jong PJ, Hewitt JE. Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin. Genomics. 2002;79:210–7. [PubMed: 11829491]
  • van Overveld PG, Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003;35:315–7. [PubMed: 14634647]
  • Wagner KR, Fleckenstein JL, Amato AA, Barohn RJ, Bushby K, Escolar DM, Flanigan KM, Pestronk A, Tawil R, Wolfe GI, Eagle M, Florence JM, King WM, Pandya S, Straub V, Juneau P, Meyers K, Csimma C, Araujo T, Allen R, Parsons SA, Wozney JM, Lavallie ER, Mendell JR. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008;63:561–71. [PubMed: 18335515]
  • Wohlgemuth M, Lemmers RJ, van der Kooi EL, van der Wielen MJ, van Overveld PG, Dauwerse H, Bakker E, Frants RR, Padberg GW, van der Maarel SM. Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles. Neurology. 2003;61:909–13. [PubMed: 14557558]
  • Zatz M, Marie SK, Cerqueira A, Vainzof M, Pavanello RC, Passos-Bueno MR. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am J Med Genet. 1998;77:155–61. [PubMed: 9605290]
  • Zatz M, Marie SK, Passos-Bueno MR, Vainzof M, Campiotto S, Cerqueira A, Wijmenga C, Padberg G, Frants R. High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families. Am J Hum Genet. 1995;56:99–105. [PMC free article: PMC1801310] [PubMed: 7825608]

Suggested Reading

  • Kang PB,Kunkel LM. The muscular dystrophies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 216. New York, NY: McGraw-Hill.
  • Upadhyaya M, Cooper DN. FSHD: Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology. New York, NY: Garland Science/BIOS Scientific Publishers Ltd; 2004.

Chapter Notes


The authors would like to acknowledge their colleagues in the FSH-Dystrophy Group, based at the University of Rochester and Ohio State University. Our research is funded in part by grants from the MDA-USA; NIH; NYS Department of Education; and FSH Society, Inc.

Author History

Denise A Figlewicz, PhD; University of Michigan Medical School (1998-2009)
Richard JLF Lemmers, PhD (2009-present)
Daniel G Miller, MD, PhD (2012-present)
Rabi Tawil, MD; University of Rochester Medical School (1998-2009)
Silvere M van der Maarel, MD (2009-present)

Revision History

  • 20 March 2014 (aa) Revision: FSHD2 added
  • 21 June 2012 (me) Comprehensive update posted live
  • 9 July 2009 (me) Comprehensive update posted live
  • 17 March 2005 (me) Comprehensive update posted live
  • 18 March 2003 (me) Comprehensive update posted live
  • 8 March 1999 (pb) Review posted live
  • 10 July 1998 (df) Original submission
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