understanding of the great variability in the disease and a growing understanding of the genetic and pathophysiological complexities. by the late 1990s, researchers were finally beginning to understand the regions of chromosome 4 associated with fshd. since the publication of the unifying theory in 2010, researchers continued to refine their understanding of dux4. with increasing confidence in this work, researchers proposed the first a consensus view in 2014 of the pathophysiology of the disease and potential approaches to therapeutic intervention based on that model. alternate and historical names for fshd include the following: facioscapulohumeral disease faciohumeroscapular landouzy-dejerine disease (or 'syndrome' or 'type of muscular dystrophy') erb-landouzy-dejerine syndrome chronology of important fshd-related genetic research 1861person with muscular dystrophy depicted by duchenne. based on the muscles involved, this person could have had fshd. 1884landouzy and dejerine describe a form of childhood progressive muscle atrophy with a characteristic involvement of facial muscles and distinct from pseudohypertrophic (duchenne's md) and spinal muscle atrophy in adults. two brothers with fshd followed by landouzy and dejerinephotograph of one brother at age 21. the right scapula is protracted, downwardly rotated, and laterally displaced.drawing of another brother at age 17. visible is lumbar hyperlordosis. the upper arm and pectoral muscles appear atrophied. 1886landouzy and dejerine describe progressive muscular atrophy of the scapulo-humeral type. 1950tyler and stephens study 1249 individuals from a single kindred with fshd traced to a single ancestor and describe a typical mendelian inheritance pattern with complete penetrance and highly variable expression. the term facioscapulohumeral dystrophy is introduced. 1982padberg provides the first linkage studies to determine the genetic locus for fshd in his seminal thesis "facioscapulohumeral disease." 1987the complete sequence of the dystrophin gene (duchenne's md) is determined. 1991the genetic defect in fshd is linked to a region (4q35) near the tip of the long arm of chromosome 4. 1992fshd, in both familial and de novo cases, is found to be linked to a recombination event that reduces the size of 4q ecor1 fragment to < 28 kb (50–300 kb normally). 19934q ecor1 fragments are found to contain tandem arrangement of multiple 3.3-kb units (d4z4), and fshd is associated with the presence of < 11 d4z4 units. a study of seven families with fshd reveals evidence of genetic heterogeneity in fshd. 1994the heterochromatic structure of 4q35 is recognized as a factor that may affect the expression of fshd, possibly via position-effect variegation. dna sequencing within d4z4 units shows they contain an open reading frame corresponding to two homeobox domains, but investigators conclude that d4z4 is unlikely to code for a functional transcript. 1995the terms fshd1a and fshd1b are introduced to describe 4q-linked and non-4q-linked forms of the disease. 1996fshd region gene1 (frg1) is discovered 100 kb proximal to d4z4. 1998monozygotic twins with vastly different clinical expression of fshd are described. 1999complete sequencing of 4q35 d4z4 units reveals a promoter region located 149 bp 5' from the open reading frame for the two homeobox domains, indicating a gene that encodes a protein of 391 amino acid protein (later corrected to 424 aa), given the name dux4. 2001investigators assessed the methylation state (heterochromatin is more highly methylated than euchromatin) of dna in 4q35 d4z4. an examination of smai, mlui, sacii, and eagi restriction fragments from multiple cell types, including skeletal muscle, revealed no evidence for hypomethylation in cells from fshd1 patients relative to d4z4 from unaffected control cells or relative to homologous d4z4 sites on chromosome 10. however, in all instances, d4z4 from sperm was hypomethylated relative to d4z4 from somatic tissues. 2002a polymorphic segment of 10 kb directly distal to d4z4 is found to exist in two allelic forms, designated 4qa and 4qb. fshd1 is associated solely with the 4qa allele. three genes (frg1, frg2, ant1) located in the region just centromeric to d4z4 on chromosome 4 are found in isolated muscle cells from individuals with fshd at levels 10 to 60 times greater than normal, showing a linkage between d4z4 contractions and altered expression of 4q35 genes. 2003a further examination of dna methylation in different 4q35 d4z4 restriction fragments (bsaai and fsei) showed significant hypomethylation at both sites for individuals with fshd1, non-fshd-expressing gene carriers, and individuals with phenotypic fshd relative to unaffected controls. 2004contraction of the d4z4 region on the 4qb allele to < 38 kb does not cause fshd. 2006transgenic mice overexpressing frg1 are shown to develop severe myopathy. 2007the dux4 open reading frame is found to have been conserved in the genome of primates for over 100 million years, supporting the likelihood that it encodes a required protein. researchers identify dux4 mrna in primary fshd myoblasts and identify in d4z4-transfected cells a dux4 protein, the overexpression of which induces cell death. dux4 mrna and protein expression are reported to increase in myoblasts from fshd patients, compared to unaffected controls. stable dux4 mrna is transcribed only from the most distal d4z4 unit, which uses an intron and a polyadenylation signal provided by the flanking plam region. dux4 protein is identified as a transcription factor, and evidence suggests overexpression of dux4 is linked to an increase in the target paired-like homeodomain transcription factor 1 (pitx1). 2009the terms fshd1 and fshd2 are introduced to describe d4z4-deletion-linked and non-d4z4-deletion-linked genetic forms, respectively. in fshd1, hypomethylation is restricted to the short 4q allele, whereas fshd2 is characterized by hypomethylation of both 4q and both 10q alleles. splicing and cleavage of the terminal (most telomeric) 4q d4z4 dux4 transcript in primary myoblasts and fibroblasts from fshd patients is found to result in the generation of multiple rnas, including small noncoding rnas, antisense rnas and capped mrnas as new candidates for the pathophysiology of fshd. 2010a unifying genetic model of fshd is established: d4z4 contractions only cause fshd when in the context of a 4qa allele due to stabilization of dux4 rna transcript, allowing dux4 expression. several organizations including the new york times highlighted this research (see fshd society). dr. francis collins, who oversaw the first sequencing of the human genome with the national institutes of health stated: "if we were thinking of a collection of the genome's greatest hits, this would go on the list," daniel perez, co-founder of the fshd society, hailed the new findings saying: "this is a long-sought explanation of the exact biological workings of " the mda stated that: "now, the hunt is on for which proteins or genetic instructions (rna) cause the problem for muscle tissue in fshd." one of the report's co-authors, silvère van der maarel of the university of leiden, stated that "it is amazing to realize that a long and frustrating journey of almost two decades now culminates in the identification of a single small dna variant that differs between patients and people without the disease. we finally have a target that we can go after." dux4 is found actively transcribed in skeletal muscle biopsies and primary myoblasts. fshd-affected cells produce a full-length transcript, dux4-fl, whereas alternative splicing in unaffected individuals results in the production of a shorter, 3'-truncated transcript (dux4-s). the low overall expression of both transcripts in muscle is attributed to relatively high expression in a small number of nuclei (~ 1 in 1000). higher levels of dux4 expression in human testis (~100 fold higher than skeletal muscle) suggest a developmental role for dux4 in human development. higher levels of dux4-s (vs dux4-fl) are shown to correlate with a greater degree of dux-4 h3k9me3-methylation. 2012some instances of fshd2 are linked to mutations in the smchd1 gene on chromosome 18, and a genetic/mechanistic intersection of fshd1 and fshd2 is established. the prevalence of fshd-like d4z4 deletions on permissive alleles is significantly higher than the prevalence of fshd in the general population, challenging the criteria for molecular diagnosis of fshd. when expressed in primary myoblasts, dux4-fl acted as a transcriptional activator, producing a > 3-fold change in the expression of 710 genes. a subsequent study using a larger number of samples identified dux4-fl expression in myogenic cells and muscle tissue from unaffected relatives of fshd patients, per se, is not sufficient to cause pathology, and that additional modifiers are determinants of disease progression. mechanism proposed of dbe-t (d4z4 regulatory element transcript) leading to de-repression of 4q35 genes. 2013mutations in smchd1 are shown to increase the severity of fshd1. transgenic mice carrying d4z4 arrays from an fshd1 allele (with 2.5 d4z4 units), although lacking an obvious fshd-like skeletal muscle phenotype, are found to recapitulate important genetic expression patterns and epigenetic features of fshd. 2014dux4-fl and downstream target genes are expressed in skeletal muscle biopsies and biopsy-derived cells of fetuses with fshd-like d4z4 arrays, indicating that molecular markers of fshd are already expressed during fetal development. researchers "review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease" and articulate how the unifying genetic model and subsequent research represent a "pivot-point in fshd research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology." they describe the consensus mechanism of pathophysiology for fshd as an "inefficient repeat-mediated epigenetic repression of the d4z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the dux4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle." past pharmaceutical development early drug trials, before the pathogenesis involving dux4 was discovered, were untargeted and largely unsuccessful. compounds were trialed with goals of increasing muscle mass, decreasing inflammation, or addressing provisional theories of disease mechanism. the following drugs failed to show efficacy: prednisone, a steroid, based on its antiinflammatory properties and therapeutic effect in duchenne muscular dystrophy. oral albuterol, a β2 agonist, on the basis of its anabolic properties. although it improved muscle mass and certain measures of strength in those with fshd, it did not improve global strength or function. interestingly, β2 agonists were later shown to reduce dux4 expression. diltiazem, a calcium channel blocker, on the bases of anecdotal reports of benefit and the theory that calcium dysregulation played a part in muscle cell death. myo-029 (stamulumab), an antibody that inhibits myostatin, was developed to promote muscle growth. myostatin is a protein that inhibits the growth of muscle tissue. ace-083, a tgf-β inhibitor, was developed to promote muscle growth. society and culture media in the amazon video series the man in the high castle, obergruppenführer john smith's son, thomas, is diagnosed with landouzy-dejerine syndrome. in the biography stuart: a life backwards, the protagonist was affected by muscular dystrophy, presumably fshd. patient and research organizations the fshd society (named "fsh society" until 2019) was founded in 1991 on the east coast by two individuals with fshd, daniel perez and stephen jacobsen. the fshd society claims to have advocated for the standardization of the disease name facioscapulohumeral muscular dystrophy and its abbreviation fshd. the fshd society claims to have raised funding for seed grants for fshd research and co-wrote the md-care act of 2001, which provided federal funding for all muscular dystrophies. the fshd society has grown into the world's largest grassroots organization advocating for patient education and scientific and medical research for fshd. one notable spokesperson for fshd society has been max adler, an actor on the tv series glee. friends of fsh research is a research-oriented nonprofit organization founded in 2004 by terry and rick colella from kirkland, washington after their son was diagnosed with fshd. the fshd global research foundation was founded in 2007 by bill moss in australia, a former macquarie bank executive affected by fshd. it is currently directed by moss's daughter. it was named australian charity of the year for 2017. it is the largest funder of fshd medical research outside of the united states as of 2018. fshd europe was founded in 2010. spanning multiple countries in europe, it has launched the european trial network. notable cases chip wilson is a canadian billionaire and founder of lululemon. he has pledged 100 million canadian dollars to research through the venture 'solve fshd'. chris carrino is the radio voice of the brooklyn nets. he founded the 'chris carrino foundation for fshd', oriented towards research funding. morgan hoffman is an american professional golfer. he started the morgan hoffman foundation, oriented towards research funding. research directions pharmaceutical development after achieving consensus on fshd pathophysiology in 2014, researchers proposed four approaches for therapeutic intervention: enhance the epigenetic repression of the d4z4