Facioscapulohumeral Dystrophy

Updated: Mar 19, 2019
  • Author: Naganand Sripathi, MD; Chief Editor: Amy Kao, MD  more...
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Facioscapulohumeral dystrophy (FSHD) is one of the most common types of muscular dystrophy.3133 It has distinct regional involvement and progression. FSHD is an autosomal dominant disorder in as many as 90% of affected patients. Landouzy and Dejerine first described FSHD in 1884. Tyler and Stephens described an extensive family from Utah in which 6 generations were affected. Walton and Nattrass established FSHD as a distinct muscular dystrophy with specific diagnostic criteria.



It is an autosomal dominant disease in 70-90% of patients and is sporadic in the rest. One of the FSHD genes has been localized to chromosome band 4q35, but the gene or genes that are affected in FSHD are still unknown. Patients with FSHD have a shorter Eco RI digestion fragment detected by the chromosome-4qter DNA marker p13E-11. About 2% of FSHD patients are not linked to the locus at 4q35. [1]

The probe p13E-11 identifies 2 polymorphic loci at 4q35 and 10q26. The Eco R1 fragment of 4q is composed of repetitive DNA sequences that are 3.3-kilobase (kb) Kpn I tandem repeats identified as D4Z4. In control subjects, the D4Z4 repeat consists of 11-100 KpnI units, each 3.3 kb, whereas in FSHD this is shortened; the shortened Eco RI fragment in FSHD is 1-10 units. Diagnostic difficulties arise as these fragments also may come from chromosome 10, as already described. 4-Type units are resistant to Bln I and 10-type units are resistant to Xap I. The combined use of EcoRI, BlnI, and XapI in pulsed-field gel electrophoresis–based DNA separation techniques allows detection of 4q fragments.

  • FSHD is caused by a contraction mutation of D4Z4 macrosatellite repeats in the subtelomeric region of the 4qA161 haplotype of chromosome 4 in 95% of patients.

  • Those without FSHD have approximately 11-100 D4Z4 units, whereas patients with FSHD have 1-10 D4Z4 units. [2]

  • At least 1 copy of D4Z4 is required to develop FSHD.

  • Mosaic males are mostly affected, where as mosaic females with an equal complement of affected cells are more often asymptomatic carriers.

  • A bi-allelic variation of chromosome 4qter is known, designated as 4qA and 4qB. FSHD alleles are exclusively of the 4qter type (4qA161).

  • Although the genetic lesion is well described in FSHD, the causal gene and the protein products are not known.

  • Additional testing may be needed in patients without D4Z4 contraction for a deletion encompassing the region.

  • Patients with FSHD and no contraction of D4Z4 repeats may show loss of DNA methylation and heterochromatin markers of D4Z4 repeat.

  • The most extensively studies candidate genes for FSHD on 4q35 are ANT1, PDLIM3, FRG1, TUBB4q, FRG2, and DUX4.

Disease mechanisms

The actual genetic defect in FSHD is unknown. Possible disease mechanisms include the following:

  • Position variegation effect on a proximal candidate gene or genes

  • Direct and indirect evidence points to epigenetic modifications in the DNA. A local deficit of a repressor complex due to the contraction of D4Z4 may cause inappropriate expression of genes. This may account for upregulation of FRG2, FRG1, and ANT1 in FSHD muscle.

  • The most common modification of mammalian DNA is cytosine methylation that is necessary for many regulatory processes. D4Z4 was found to be hypomethylated in FSHD.

  • Myoblasts from patients with FSHD also demonstrate increased susceptibility to oxidative stress.

  • Misexpression of FRG1 (FSHD region gene 1) may lead to the development of FSHD. Knockdown of FRG1 in Xenopus led to the decreased angiogenesis and reduced expression of DAB2 (angiogenic regulator). Of patients with FSHD, 50-75% exhibit retinal vasculopathy and increased expression of vascular or endothelial-related FRG1 transcripts in the muscle. Thus FRG1 may be at least crucial for angiogenesis.

  • Deletion of D4Z4 macrosatellites results in aberrant gene expression. DUX4 transcript from the last D4Z4 (most telomeric) unit generates small si/miRNA-sized fragments; uncapped, polyadenylated 3-prime fragments encoding C-terminal portion of DUX4; capped and polyadenylated mRNAs containing the double-homeobox domain of DUX4, but splice-out the C-terminal polypeptide. C-terminal polypeptide produced by transfection studies inhibits myogenesis. [3]

  • DUX4 is a retrogene contained within D4Z4 repeats and is normally epigenetically silenced in somatic cells. D4Z4 contraction leads to loss of DNA methylation and heterochromatin markers in D4Z4 region, resulting in relaxation of chromatin structure and release DUX4 repression. [4]



Old content


United States

FSHD is the third most common muscular dystrophy. Estimated prevalence of FSHD is 1 case in 20,000 persons. [5]


Most of the patients have normal life expectancy.


Frequency is higher in males; however, asymptomatic cases are more common in females.


See the list below:

  • The usual presentation is between the first and third decades. Ninety-five percent of patients show clinical features before age 20 years. As many as one third of patients are asymptomatic.

  • Infantile onset has been described, but is rare.

New content

FSHD is considered one of the more common hereditary muscular disorders with a prevalence of ~1 in 8,000. It appears to affect males and females in relatively equal numbers. The estimated prevalence is between four and ten per 100,000 people. [6, 7]