Просмотр кода страницы Английская Википедия:Facioscapulohumeral muscular dystrophy

{{Английская Википедия/Панель перехода}}
{{Infobox medical condition
| name            = Facioscapulohumeral muscular dystrophy
| synonyms        = Landouzy–Dejerine muscular dystrophy, FSHMD, FSH
| image           = File:FSHDBodyDiagram.jpg
| image_size      = 300px
| caption         = A diagram showing the muscles commonly affected by FSHD
| pronounce       = {{IPAc-en|ˌ|f|ei|ʃ|iː|oʊ|ˌ|s|k|æ|p|y|ə|l|oʊ|ˈ|h|juː|m|ər|əl}}
{{respell|fay|shee|oh|skap|yə|low|HEW|mər|əl}}<ref name=pronunciation>
The sources listed below differ on pronunciation of the 'u' in 'scapulo'. A 'long u' sound in an unstressed nonfinal syllable is often reduced to a [[schwa]] and varies by speaker.
* {{MerriamWebsterDictionary|Facioscapulohumeral}}
* [https://medical-dictionary.thefreedictionary.com/facioscapulohumeral "Facioscapulohumeral"]. Medical Dictionary, Farlex and Partners, 2009.
</ref>
|pronounce 2      = alt. {{IPAc-en|f|ei|s|-|,_|f|ɑː|ʃ|-|,_|f|ɑː|s|-}}
| field           = [[Neurology]], [[neuromuscular medicine]]
| symptoms        = Facial weakness, scapular winging, foot drop
| complications   = Chronic pain, dry eyes, and shoulder instability; less commonly retinal disease, [[scoliosis]], and respiratory insufficiency
| onset           = Ages 15 – 30 years
| duration        = Lifelong
| types           = Typically classified by genetic cause (FSHD1, FSHD2). Sometimes classified by disease manifestation (eg, infantile-onset)
| causes          = Genetic (inherited or new mutation)
| risks           = Male sex, extent of genetic mutation
| diagnosis       = Genetic testing
| differential    = [[Limb-girdle muscular dystrophy]] (especially [[calpainopathy]]), [[Pompe disease]], [[mitochondrial myopathy]], [[polymyositis]]<ref name="Wagner2019Review" />
| prevention      =
| management      = Physical therapy, bracing, reconstructive surgery
| medication      = Clinical trials ongoing
| prognosis       = Progressive, unaffected life expectancy
| frequency       = Up to 1/8,333<ref name="Wagner2019Review" />
| deaths          =
}}
<!-- Definition and symptoms -->
'''Facioscapulohumeral muscular dystrophy''' ('''FSHD''') is a type of [[muscular dystrophy]], a group of [[heritable disease]]s that cause [[Degenerative disease|degeneration]] of muscle and [[Progressive disease|progressive]] [[muscle weakness|weakness]]. [[List of medical roots, suffixes and prefixes|Per the name]], FSHD tends to sequentially weaken the [[facial muscles|muscles of the face]], [[Scapula#Movements|those that position]] the [[scapula]], and [[Arm#Muscles|those overlying]] the [[humerus]] bone of the upper arm.<ref name="Wagner2019Review" /><ref name="Stedman_1987">{{cite book|last1=Stedman|first1=Thomas|title= Webster's New World/Stedman's Concise Medical Dictionary|date=1987|publisher=Williams & Wilkins |location=Baltimore|isbn=0139481427|page=230|edition=1|url=https://archive.org/details/stedmanspocketme0000sted/page/230/mode/2up?q=facioscapulohumeral}}</ref> These areas can be spared, and muscles of other areas usually are affected, especially those of the [[Pectoral muscles|chest]], [[Abdomen#Muscles|abdomen]], [[List of skeletal muscles of the human body#Back|spine]], and [[List of skeletal muscles of the human body#Anterior compartment 4|shin]]. Almost any [[skeletal muscle]] can be affected in advanced disease. Abnormally positioned, termed [[winged scapula|'winged']], scapulas are common, as is the inability to lift the foot, known as [[foot drop]]. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15 – 30 years.<ref name="Mul2016ClinicalFeatures" /> FSHD can also cause [[hearing loss]] and blood vessel abnormalities at the [[retina|back of the eye]].

<!-- Cause and pathophysiology -->
FSHD is caused by a [[genetics|genetic]] [[mutation]] leading to deregulation of the ''[[DUX4]]'' [[gene]].<ref name="Robbins2018Pathology">{{cite book |editor1-last=Kumar |editor1-first=Vinay |editor2-last=Abbas |editor2-first=Abul |editor3-last=Aster |editor3-first=Jon |title=Robbins Basic Pathology |date=2018 |publisher=Elsevier |location=Philadelphia, Pennsylvania |isbn=978-0-323-35317-5 |page=844 |edition=Tenth}}</ref> Normally, ''DUX4'' is [[gene expression|expressed]] (i.e., turned on) in [[cell (biology)|cell]]s of the [[ovary]] and in very early [[Development of the human body|human development]], becoming repressed (i.e., turned off) by the time an [[embryo]] is several days old.<ref name="Laco2017DUX_ZGA">{{cite journal |last1=De Iaco |first1=A |last2=Planet |first2=E |last3=Coluccio |first3=A |last4=Verp |first4=S |last5=Duc |first5=J |last6=Trono |first6=D |title=DUX-family transcription factors regulate zygotic genome activation in placental mammals. |journal=Nature Genetics |date=June 2017 |volume=49 |issue=6 |pages=941–945 |doi=10.1038/ng.3858 |pmid=28459456|pmc=5446900 }}</ref><ref name="Snider2010retrotransposed">{{cite journal |last1=Snider |first1=L |last2=Geng |first2=LN |last3=Lemmers |first3=RJ |last4=Kyba |first4=M |last5=Ware |first5=CB |last6=Nelson |first6=AM |last7=Tawil |first7=R |last8=Filippova |first8=GN |last9=van der Maarel |first9=SM |last10=Tapscott |first10=SJ |last11=Miller |first11=DG |title=Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. |journal=PLOS Genetics |date=28 October 2010 |volume=6 |issue=10 |pages=e1001181 |doi=10.1371/journal.pgen.1001181 |pmid=21060811|pmc=2965761 |doi-access=free }}</ref> In FSHD, ''DUX4'' is inadequately repressed, allowing sporadic expression throughout life. [[Deletion (genetics)|Deletion]] of [[DNA]] in the region surrounding ''DUX4'' is the causative mutation in 95% of cases, termed "[[#D4Z4|D4Z4 contraction]]" and defining FSHD type 1 (FSHD1).<ref name="Unifying">{{cite journal|vauthors=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 |title=A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy|journal=Science|date=19 August 2010|pmid=20724583|doi=10.1126/science.1189044|volume=329|issue=5999|pages=1650–3|pmc=4677822|bibcode=2010Sci...329.1650L|hdl=1887/117104|url=https://bms.ucsf.edu/sites/ucsf-bms.ixm.ca/files/russelljonathan_12092010.pdf |archive-url=https://web.archive.org/web/20140605033041/https://bms.ucsf.edu/sites/ucsf-bms.ixm.ca/files/russelljonathan_12092010.pdf |url-status=dead |archive-date = 2014-06-05}}</ref> FSHD caused by other mutations is FSHD type 2 (FSHD2). For disease to develop, also required is a 4qA [[allele]], which is a common variation in the DNA next to ''DUX4''. The chances of a D4Z4 contraction with a 4qA allele [[heredity|being passed on]] to a child is 50% ([[autosomal dominant]]);<ref name="Wagner2019Review" /> in 30% of cases, the mutation arose spontaneously.<ref name="Mul2016ClinicalFeatures" /> Mutations of FSHD cause inadequate ''DUX4'' repression by [[Euchromatin|unpacking]] the DNA around ''DUX4'', making it accessible to be [[transcription (biology)|copied]] into [[messenger RNA]] (mRNA). The 4qA allele stabilizes this ''DUX4'' mRNA, allowing it to be used for [[translation (biology)|production]] of DUX4 [[protein]].<ref name="pmid17924332">{{cite journal  |vauthors=Lemmers RJ, Wohlgemuth M, van der Gaag KJ, etal |title=Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy |journal=Am. J. Hum. Genet. |volume=81 |issue=5 |pages=884–94 |date=November 2007 |pmid=17924332 |pmc=2265642 |doi=10.1086/521986 }}</ref> DUX4 protein is a [[Regulation of gene expression|modulator]] of hundreds of other genes, many of which are involved in muscle function.<ref name="Wagner2019Review" /><ref name="Robbins2018Pathology" /> How this genetic modulation causes muscle damage remains unclear.<ref name="Wagner2019Review" />

<!-- Diagnosis, treatment, epidemiology, and prognosis -->
Signs, symptoms, and diagnostic tests can suggest FSHD; [[genetic testing]] usually provides definitive diagnosis.<ref name="Wagner2019Review" /> FSHD can be presumptively diagnosed in an individual with signs/symptoms and an established family history. No intervention has proven effective for slowing progression of weakness.<ref name="Mul2022Review" /> [[Screening (medicine)|Screening]] allows for early detection and intervention for various disease complications. Symptoms can be addressed with physical therapy, bracing, and [[reconstructive surgery]] such as surgical fixation of the scapula to the thorax.<ref name="Eren2020ScapFusionStaging" /> FSHD affects up to 1 in 8,333 people,<ref name="Wagner2019Review">{{cite journal |last1=Wagner |first1=Kathryn R. |s2cid=208531681 |title=Facioscapulohumeral Muscular Dystrophies |journal=CONTINUUM: Lifelong Learning in Neurology |date=December 2019 |volume=25 |issue=6 |pages=1662–1681 |doi=10.1212/CON.0000000000000801|pmid=31794465 }}</ref> putting it in the three most common muscular dystrophies with [[myotonic dystrophy]] and [[Duchenne muscular dystrophy]].<ref name="Theadom2014MD_Epidemiology">{{cite journal |last1=Theadom |first1=A |last2=Rodrigues |first2=M |last3=Roxburgh |first3=R |last4=Balalla |first4=S |last5=Higgins |first5=C |last6=Bhattacharjee |first6=R |last7=Jones |first7=K |last8=Krishnamurthi |first8=R |last9=Feigin |first9=V |title=Prevalence of muscular dystrophies: a systematic literature review. |journal=Neuroepidemiology |date=2014 |volume=43 |issue=3–4 |pages=259–68 |doi=10.1159/000369343 |pmid=25532075|s2cid=2426923 |doi-access=free |hdl=10292/13206 |hdl-access=free }}</ref><ref name="Mah2016MD_Epidemiology">{{cite journal |last1=Mah |first1=JK |last2=Korngut |first2=L |last3=Fiest |first3=KM |last4=Dykeman |first4=J |last5=Day |first5=LJ |last6=Pringsheim |first6=T |last7=Jette |first7=N |title=A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies. |journal=The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques |date=January 2016 |volume=43 |issue=1 |pages=163–77 |doi=10.1017/cjn.2015.311 |pmid=26786644|s2cid=24936950 |doi-access=free }}</ref> Prognosis is variable. Many are not significantly limited in daily activity, whereas a wheel chair or scooter is required in 20% of cases.<ref name="Tawil2006Review" /> [[Life expectancy]] is not affected, although death can rarely be attributed to [[respiratory insufficiency]] due to FSHD.<ref name="Statland and Tawil Review article 2016">{{cite journal |last1=Statland |first1=JM |last2=Tawil |first2=R |title=Facioscapulohumeral Muscular Dystrophy. |journal=Continuum (Minneapolis, Minn.) |date=December 2016 |volume=22 |issue=6, Muscle and Neuromuscular Junction Disorders |pages=1916–1931 |doi=10.1212/CON.0000000000000399 |pmid=27922500|pmc=5898965 }}</ref>

<!-- History and research -->
FSHD was first distinguished as a disease in the 1870s and 1880s when French physicians [[Louis Théophile Joseph Landouzy]] and [[Joseph Jules Dejerine]] followed a family affected by it, thus the initial name '''Landouzy–Dejerine muscular dystrophy'''. Their work is predated by descriptions of probable individual FSHD cases.<ref name="Cruveilhier1852Firstdescription" /><ref name="Rogers2004TextbookHistory" /><ref name="Landouzy1885Review" /> The significance of D4Z4 contraction on chromosome 4 was established in the 1990s. The ''DUX4'' gene was discovered in 1999, found to be expressed and toxic in 2007, and in 2010 the genetic mechanism causing its expression was elucidated. In 2012, the gene most frequently mutated in FSHD2 was identified. In 2019, the first drug designed to counteract ''DUX4'' expression entered clinical trials.<ref name="Cohen2020Therapeutics" />

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== Signs and symptoms ==
Classically, weakness develops in the face, then the [[shoulder girdle]], then the [[upper arm]].<ref name="Mul2022Review">{{cite journal |last1=Mul |first1=K |title=Facioscapulohumeral Muscular Dystrophy. |journal=Continuum (Minneapolis, Minn.) |date=1 December 2022 |volume=28 |issue=6 |pages=1735–1751 |doi=10.1212/CON.0000000000001155 |pmid=36537978|s2cid=254883066 }}</ref> These muscles can be spared and other muscles usually are affected. The order of muscle involvement can cause the appearance of weakness "descending" from the face to the legs.<ref name="Mul2022Review" /> Distribution and degree of muscle weakness is extremely variable, even between identical twins.<ref name="Tupler1998Twins"/><ref>{{cite journal |last1=Tawil |first1=R |last2=Storvick |first2=D |last3=Feasby |first3=TE |last4=Weiffenbach |first4=B |last5=Griggs |first5=RC |s2cid=44422140 |title=Extreme variability of expression in monozygotic twins with FSH muscular dystrophy. |journal=Neurology |date=February 1993 |volume=43 |issue=2 |pages=345–8 |doi=10.1212/wnl.43.2.345 |pmid=8094896}}</ref> Musculoskeletal pain is very common, most often described in the neck, shoulders, lower back, and the back of the knee.<ref>{{cite web |last1=Pandya |first1=Shree |last2=Eichinger |first2=Kate |title=Physical Therapy for Facioscapulohumeral Muscular Dystrophy |url=https://www.fshdsociety.org/wp-content/uploads/2019/08/FSH-Society-PT-for-FSHD-Brochure.pdf |publisher=FSHD Society |access-date=14 April 2020 |archive-url=https://web.archive.org/web/20200414192559/https://www.fshdsociety.org/wp-content/uploads/2019/08/FSH-Society-PT-for-FSHD-Brochure.pdf |archive-date=14 April 2020}}</ref><ref name="Mul2016ClinicalFeatures" /> [[Fatigue]] is also common.<ref name="Mul2016ClinicalFeatures" /> Muscle weakness usually becomes noticeable on one side of the body before the other, a hallmark of the disease.<ref name="Tawil2006Review" /> The right shoulder and arm muscles are more often affected than the left upper extremity muscles, independent of [[handedness]].<ref name="Padberg1982thesis" />{{rp|139}}<ref name="Padberg2004Textbook" /><ref name="Rijken2014CTWholeBody" /><ref>{{cite journal |last1=Bergsma |first1=A |last2=Cup |first2=EH |last3=Janssen |first3=MM |last4=Geurts |first4=AC |last5=de Groot |first5=IJ |title=Upper limb function and activity in people with facioscapulohumeral muscular dystrophy: a web-based survey. |journal=Disability and Rehabilitation |date=February 2017 |volume=39 |issue=3 |pages=236–243 |doi=10.3109/09638288.2016.1140834 |pmid=26942834|s2cid=4237308 |doi-access=free }}</ref> Otherwise, neither side of the body has been found to be at more risk. Classically, symptoms appear in those 15 – 30 years of age, although infantile onset, adult onset, and absence of symptoms despite having the causal genetics also occur.<ref name="Mul2016ClinicalFeatures" /> FSHD1 with a very large D4Z4 deletion ([[#Genetic testing|''Eco''RI 10-11 kb]]) is more strongly associated with infantile onset and severe weakness.<ref name="Tawil2014PathophysConsensus" /> On average, FSHD2 presents 10 years later than FSHD1.<ref name="Jia2021FSHD2Review">{{cite journal |last1=Jia |first1=FF |last2=Drew |first2=AP |last3=Nicholson |first3=GA |last4=Corbett |first4=A |last5=Kumar |first5=KR |title=Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings. |journal=Neuromuscular Disorders |date=2 October 2021 |volume=31 |issue=11 |pages=1101–1112 |doi=10.1016/j.nmd.2021.09.010 |pmid=34711481|s2cid=238246093 |doi-access=free }}</ref> Otherwise, FSHD1 and FSHD2 are indistinguishable on the basis of weakness.<ref name="Tawil2014PathophysConsensus" /> Disease progression is slow, and long static phases, in which no progression is apparent, is not uncommon.<ref name="Upadhyaya2004FSHDTextbook">{{cite book |editor-last1=Upadhyaya |editor-first1=Meena |editor-last2=Cooper |editor-first2=David |title=FSHD Facioscapulohumeral Muscular Dystrophy : Clinical Medicine and Molecular Cell Biology |date=March 2004 |publisher=BIOS Scientific Publishers |isbn=0203483677}}</ref> Less commonly, individual muscles rapidly deteriorate over several months.<ref name="Wagner2019Review" /> The symptom burden of FSHD is typically more severe than it is perceived to be by those without the disease.<ref name=":3">The [[Food and Drug Administration|FDA]] held an externally-led Patient-Focused Drug Development meeting with about 400 FSHD patients on June 29, 2020, resulting in a seminal document called the "[https://www.fshdsociety.org/wp-content/uploads/2020/11/Voice-of-the-Patient-Report-FINAL.pdf Voice of the Patient Report]."  The report captures the impact of FSHD on the daily lives of those with the disease as conveyed by the patients themselves. While FSHD is often perceived to be "mild," the report shows that over 80% of patients report being "moderately" or "severely" limited in daily activities.
*{{Cite web |last=Society |first=FSHD |title=FSHD Society releases Voice of the Patient Report on FSH muscular dystrophy |url=https://www.prweb.com/releases/fshd-society-releases-voice-of-the-patient-report-on-fsh-muscular-dystrophy-860368992.html |access-date=2024-01-31 |website=www.prweb.com |language=en}}</ref><ref name=":0">{{Cite web |last=Society |first=FSHD |title=Facioscapulohumeral muscular dystrophy community speaks to the FDA |url=https://www.prweb.com/releases/facioscapulohumeral-muscular-dystrophy-community-speaks-to-the-fda-880417266.html |access-date=2024-01-31 |website=www.prweb.com |language=en}}</ref><ref name=":1">{{Citation |title=Voice of the Patient Forum - Patient-Focused Drug Development Meeting |url=https://www.youtube.com/watch?v=l6YB-X5pJ4c |access-date=2024-01-31 |language=en}}</ref><ref name=":2">{{Cite web |last=Overman |first=Debbie |date=2020-11-13 |title=People Living with FSHD Tell Their Stories in New Report |url=https://rehabpub.com/conditions/neurological/muscular-dystrophy-conditions/people-living-with-fshd-tell-their-stories-in-new-report/ |access-date=2024-01-31 |website=Rehab Management |language=en-US}}</ref>

===Face===
Weakness of the muscles of the face is the most distinguishing sign of FSHD.<ref name="Mul2016ClinicalFeatures" /> It is typically the earliest sign, although it is rarely the initial complaint.<ref name="Mul2016ClinicalFeatures" /> At least mild facial weakness can be found in 90% or more with FSHD.<ref name="Upadhyaya2004FSHDTextbook"/><ref name="Padberg2004Textbook" /> One of the most common deficits is inability to close the eyelids, which can result in sleeping with the eyelids open and dry eyes.<ref name="Mul2016ClinicalFeatures" /> The implicated muscle is the [[orbicularis oculi muscle|orbicularis oculi]] muscle.<ref name="Mul2016ClinicalFeatures" /> Another common deficit is inability to purse the lips, causing inability to pucker, whistle, or blow up a balloon.<ref name="Mul2016ClinicalFeatures" /> The implicated muscle is the [[orbicularis oris muscle|orbicularis oris]] muscle.<ref name="Mul2016ClinicalFeatures" /> A third common deficit is inability raise the corners of the mouth, causing a "horizontal smile," which looks more like a grin.<ref name="Mul2016ClinicalFeatures" /> Responsible is the [[zygomaticus major]] muscle.<ref name="Mul2016ClinicalFeatures" />

Weakness of facial muscles contributes to difficulty [[Manner of articulation|pronouncing words]].<ref name="Mul2019Dysphagia" /> Facial expressions can appear diminished, arrogant, grumpy, or fatigued.<ref name="Mul2016ClinicalFeatures" /> Muscles used for [[Muscles of mastication|chewing]] and [[Extraocular muscles|moving the eyes]] are not affected.<ref name="Padberg2004Textbook" /><ref name="Tawil2006Review">{{cite journal |last1=Tawil |first1=R |last2=Van Der Maarel |first2=SM |title=Facioscapulohumeral muscular dystrophy. |journal=Muscle & Nerve |date=July 2006 |volume=34 |issue=1 |pages=1–15 |doi=10.1002/mus.20522 |pmid=16508966|s2cid=43304086 |url=https://hal.archives-ouvertes.fr/hal-00480367/file/PEER_stage2_10.1016%252Fj.bbadis.2006.05.009.pdf }}</ref> [[Dysphagia|Difficulty swallowing]] is not typical, although can occur in advanced cases.<ref name="Wohlgemuth2006Dysphagia">{{cite journal |last1=Wohlgemuth |first1=M |last2=de Swart |first2=BJ |last3=Kalf |first3=JG |last4=Joosten |first4=FB |last5=Van der Vliet |first5=AM |last6=Padberg |first6=GW |title=Dysphagia in facioscapulohumeral muscular dystrophy. |journal=Neurology |date=27 June 2006 |volume=66 |issue=12 |pages=1926–8 |doi=10.1212/01.wnl.0000219760.76441.f8 |pmid=16801662|s2cid=7695047 }}</ref><ref name="Mul2019Dysphagia">{{cite journal |last1=Mul |first1=K |last2=Berggren |first2=KN |last3=Sills |first3=MY |last4=McCalley |first4=A |last5=van Engelen |first5=BGM |last6=Johnson |first6=NE |last7=Statland |first7=JM |title=Effects of weakness of orofacial muscles on swallowing and communication in FSHD. |journal=Neurology |date=26 February 2019 |volume=92 |issue=9 |pages=e957–e963 |doi=10.1212/WNL.0000000000007013 |pmid=30804066|pmc=6404471 }}</ref> FSHD is generally progressive, but it is not established whether facial weakness is progressive or stable throughout life.<ref name="Padberg2020Regrets" />

===Shoulder, chest, and arm===
[[File:Facioscapulohumeral muscular dystrophy - Scapular winging.png|thumb|right|Bilateral scapular winging, right moreso than left. Left image showing wall push test, right image showing attempted shoulder flexion.]]
After the facial weakness, weakness usually develops in the muscles of the chest and those that span from scapula to thorax. Symptoms involving the shoulder, such as difficulty working with the arms overhead, are the initial complaint in 80% of cases.<ref name="Padberg2004Textbook" /><ref name="Tawil2006Review" /> Predominantly, the [[serratus anterior muscle|serratus anterior]] and [[trapezius muscle|middle and lower trapezii]] muscles are affected;<ref name="Mul2016ClinicalFeatures" /> the upper trapezius is often spared.<ref name="Tawil2006Review" /> Trapezius weakness causes the scapulas to become [[Scapula#Movements|downwardly rotated]] and [[Scapula#Movements|protracted]], resulting in [[winged scapula]]s, horizontal clavicles, and sloping shoulders; [[Shoulder#Function|arm abduction]] is impaired. Serratus anterior weaknesss impairs [[Shoulder#Function|arm flexion]], and worsening of winging can be demonstrated when pushing against a wall. Muscles spanning from the scapula to the arm are generally spared, which include deltoid and the [[rotator cuff]] muscles.<ref name="Tasca2014MRIUpperGirdle" /><ref name="Gerevini2016MRIWholeBody" /> The deltoid can be affected later on, especially the upper portion.<ref name="Mul2016ClinicalFeatures" />

Severe muscle wasting can make bones and spared shoulder muscles very visible, a characteristic example being the "poly-hill" sign elicited by arm elevation.<ref name="Mul2016ClinicalFeatures" /> The first "hill" or bump is the [[Scapula#Angles|upper corner of scapula]] appearing to "herniate" up and over the rib cage. The second hill is the [[AC joint]], seen between a wasted upper trapezius and wasted upper deltoid. The third hill is the lower deltoid, distinguishable between the wasted upper deltoid and wasted humeral muscles.<ref name="Mul2016ClinicalFeatures" /> Shoulder weakness and pain can in turn lead to shoulder instability, such as recurrent [[Dislocated shoulder|dislocation]], [[subluxation]], or downward translation of the [[humeral head]].<ref name="Nightingale2021Shoulder">{{cite journal |last1=Faux-Nightingale |first1=Alice |last2=Kulshrestha |first2=Richa |last3=Emery |first3=Nicholas |last4=Pandyan |first4=Anand |last5=Willis |first5=Tracey |last6=Philp |first6=Fraser |title=Upper limb rehabilitation in fascioscapularhumeral dystrophy (FSHD): a patients' perspective |journal=Archives of Rehabilitation Research and Clinical Translation |date=September 2021 |volume=3 |issue=4 |pages=100157 |doi=10.1016/j.arrct.2021.100157|pmid=34977539 |pmc=8683863 |issn=2590-1095 |doi-access=free }}</ref>

Also affected is the chest, particularly the parts of the [[pectoralis major muscle]] that connect to the [[sternum]] and ribs. The part that connects to the clavicle is less often affected. This muscle wasting pattern can contribute to a prominent horizontal [[Axilla#Boundaries|anterior axillary fold]].<ref name="Tawil Update 2008">{{cite journal |last1=Pandya |first1=Shree |last2=King |first2=Wendy M |last3=Tawil |first3=Rabi |title=Facioscapulohumeral Dystrophy |journal=Physical Therapy |date=1 January 2008 |volume=88 |issue=1 |pages=105–113 |doi=10.2522/ptj.20070104|pmid=17986494 |doi-access=free }}</ref><ref name="Mul2016ClinicalFeatures">{{cite journal |last1=Mul |first1=Karlien |last2=Lassche |first2=Saskia |last3=Voermans |first3=Nicol C |last4=Padberg |first4=George W |last5=Horlings |first5=Corinne GC |last6=van Engelen |first6=Baziel GM |s2cid=4481678 |title=What's in a name? The clinical features of facioscapulohumeral muscular dystrophy |journal=Practical Neurology |date=June 2016 |volume=16 |issue=3 |pages=201–207 |doi=10.1136/practneurol-2015-001353|pmid=26862222 }}</ref> Beyond this point the disease does not progress further in 30% of familial cases.<ref name="Padberg2004Textbook" /><ref name="Tawil2006Review" /> After upper torso weakness, weakness can "descend" to the upper arms ([[biceps muscle]] and, particularly, the [[triceps muscle]]).<ref name="Padberg2004Textbook" /> The forearms are usually spared, resulting in an appearance some compare to the fictional character [[Popeye]],<ref name="Mul2016ClinicalFeatures" /> although when the forearms are affected in advanced disease, the [[Extrinsic extensor muscles of the hand|wrist extensor]]s are more often affected.<ref name="Padberg2004Textbook" />

===Lower body and trunk===
After the upper body, weakness can next appear in either the pelvis, or it "skips" the pelvis and involves the [[tibialis anterior]] (shin muscle), causing [[foot drop]]. One author considers the pelvic and thigh muscles to be the last group affected.<ref name="Padberg2004Textbook" /> Pelvic weakness can manifest as a [[Trendelenburg's sign]].<ref name="Mul2016ClinicalFeatures" /> Weakness of the back of the thigh (hamstrings) is more common than weakness of the front of the thigh (quadriceps).<ref name="Mul2016ClinicalFeatures" /> In more severe cases, especially infantile FSHD, there can be anterior [[pelvic tilt]], with associated hyperextension of the knees.<ref name="Liew2015NeonatalHyptonia">{{cite book |last1=Liew |first1=Wendy K.M. |last2=van der Maarel |first2=Silvère M. |last3=Tawil |first3=Rabi |title=Neuromuscular Disorders of Infancy, Childhood, and Adolescence |chapter=Facioscapulohumeral Dystrophy |date=2015 |pages=620–630 |doi=10.1016/B978-0-12-417044-5.00032-9|isbn=9780124170445 }}</ref>

Weakness can also occur in the [[abdominal muscle]]s and [[Erector spinae muscles|paraspinal muscles]], which can manifest as a protuberant abdomen and lumbar [[Lordosis#Lumbar hyperlordosis|hyperlordosis]].<ref name="Wagner2019Review" /><ref name="Mul2016ClinicalFeatures" /> Abdominal weakness can cause inability to do a sit-up or the inability to turn from one side to the other while lying on one's back.<ref name="Mul2016ClinicalFeatures" /> Of the [[rectus abdominis muscle]], the lower portion is preferentially affected, manifesting as a positive [[Beevor's sign]].<ref name="Mul2016ClinicalFeatures" /><ref name="Wagner2019Review" /> In advanced cases, neck extensor weakness can cause the head to lean towards the chest, termed head drop.<ref name="Padberg2004Textbook" />

===Non-muscular===
[[File:Retinal vessel tortuosity.jpg|thumb|left|235px|[[Funduscopy]] of the retinal: (A) normal blood vessels (B) tortuous blood vessels, as often seen with FSHD]]
The most common non-musculoskeletal manifestation of FSHD is abnormalities in the small arteries ([[arteriole]]s) in the [[retina]]. Tortuosity of the arterioles is seen in approximately 50% of those with FSHD. Less common arteriole abnormalities include [[telangiectasia]]s and [[aneurysm|microaneurysms]].<ref name="Goselink2019Ophthalmologic">{{cite journal |last1=Goselink |first1=RJM |last2=Schreur |first2=V |last3=van Kernebeek |first3=CR |last4=Padberg |first4=GW |last5=van der Maarel |first5=SM |last6=van Engelen |first6=BGM |last7=Erasmus |first7=CE |last8=Theelen |first8=T |title=Ophthalmological findings in facioscapulohumeral dystrophy. |journal=Brain Communications |date=2019 |volume=1 |issue=1 |pages=fcz023 |doi=10.1093/braincomms/fcz023 |pmid=32954265|pmc=7425335 }}</ref><ref name="Padbert1995Retinopathy">{{cite journal |last1=Padberg |first1=G. W. |last2=Brouwer |first2=O. F. |last3=de Keizer |first3=R. J. W. |last4=Dijkman |first4=G. |last5=Wijmenga |first5=C. |last6=Grote |first6=J. J. |last7=Frants |first7=R. R. |title=On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy |journal=Muscle & Nerve |date=1995 |volume=18 |issue=S13 |pages=S73–S80 |doi=10.1002/mus.880181314|hdl=2066/20764 |s2cid=27523889 |hdl-access=free }}</ref> These abnormalities of arterioles usually do not affect vision or health, although a severe form of it mimics [[Coat's disease]], a condition found in about 1% of FSHD cases and more frequently associated with large 4q35 deletions.<ref name="Wagner2019Review" /><ref>{{Cite journal|last1=Lindner|first1=Moritz|last2=Holz|first2=Frank G|last3=Charbel Issa|first3=Peter|date=2016-04-27|title=Spontaneous resolution of retinal vascular abnormalities and macular oedema in facioscapulohumeral muscular dystrophy|journal=Clinical & Experimental Ophthalmology|language=en|volume=44|issue=7|pages=627–628|doi=10.1111/ceo.12735|pmid=26933772|s2cid=204996841|issn=1442-6404}}</ref> High-frequency [[sensorineural hearing loss]] can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population.<ref name="Wagner2019Review" /> Large 4q35 deletion can lead to various other rare manifestations.<ref>{{cite journal |last1=Trevisan |first1=CP |last2=Pastorello |first2=E |last3=Tomelleri |first3=G |last4=Vercelli |first4=L |last5=Bruno |first5=C |last6=Scapolan |first6=S |last7=Siciliano |first7=G |last8=Comacchio |first8=F |title=Facioscapulohumeral muscular dystrophy: hearing loss and other atypical features of patients with large 4q35 deletions. |journal=European Journal of Neurology |date=December 2008 |volume=15 |issue=12 |pages=1353–8 |doi=10.1111/j.1468-1331.2008.02314.x |pmid=19049553|s2cid=26276887 }}</ref>

[[Scoliosis]] can occur, thought to result from weakness of abdominal, hip extensor, and spinal muscles.<ref name="Eren2020SpinalFusion">{{cite journal |last1=Eren |first1=İ |last2=Abay |first2=B |last3=Günerbüyük |first3=C |last4=Çakmak |first4=ÖÖ |last5=Şar |first5=C |last6=Demirhan |first6=M |title=Spinal fusion in facioscapulohumeral dystrophy for hyperlordosis: A case report. |journal=Medicine |date=February 2020 |volume=99 |issue=8 |pages=e18787 |doi=10.1097/MD.0000000000018787 |pmid=32080072|pmc=7034682 }}</ref><ref name="Huml2015Review">{{cite book |last1=Huml |first1=Raymond A. |last2=Perez |first2=Daniel P. |title=Muscular Dystrophy |chapter=FSHD: The Most Common Type of Muscular Dystrophy? |date=2015 |pages=9–19 |doi=10.1007/978-3-319-17362-7_3|isbn=978-3-319-17361-0 }}</ref> Conversely, scoliosis can be viewed as a compensatory mechanism to weakness.<ref name="Eren2020SpinalFusion" /> Breathing can be affected, associated with [[kyphoscoliosis]] and wheelchair use; it is seen in one-third of wheelchair-using patients.<ref name="Wagner2019Review" /> However, ventilator support (nocturnal or diurnal) is needed in only 1% of cases.<ref name="Wagner2019Review" /><ref>{{cite journal |vauthors=Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW | s2cid = 31335126 | year = 2004 | title = Ventilatory support in facioscapulohumeral muscular dystrophy | journal = Neurology | volume = 63 | issue = 1| pages = 176–8 | pmid = 15249635 | doi=10.1212/01.wnl.0000133126.86377.e8| citeseerx = 10.1.1.543.2968 }}</ref> Although there are reports of increased risk of cardiac arrhythmias, general consensus is that the heart is not affected.<ref name="Tawil2006Review" />

==Genetics==
[[File:DUX4-FL Protein.png|thumb|right|[[Protein structure|Structure]] of DUX4 protein full-length (FL), with short (S) version indicated.]]
The genetics of FSHD is complex.<ref name="Wagner2019Review" /> FSHD and the myotonic dystrophies have unique genetic mechanisms that differ substantially from the rest of genetic myopathies.<ref name="Weihl2021myopathies">{{cite journal |last1=Dowling |first1=JJ |last2=Weihl |first2=CC |last3=Spencer |first3=MJ |title=Molecular and cellular basis of genetically inherited skeletal muscle disorders. |journal=Nature Reviews. Molecular Cell Biology |date=November 2021 |volume=22 |issue=11 |pages=713–732 |doi=10.1038/s41580-021-00389-z |pmid=34257452|pmc=9686310 |s2cid=235822532 }}</ref> The ''[[DUX4]]'' gene is the focal point of FSHD genetics. Normally, ''DUX4'' is expressed during [[embryogenesis]] and later [[Regulation of gene expression|repressed]] in all tissues except the [[testes]]. In FSHD, there is failure of ''DUX4'' repression and continued production of DUX4 protein, which is [[toxic]] to muscles.<ref name="Wagner2019Review" /><ref name="Unifying" /> The mechanism of failed ''DUX4'' repression is [[DNA methylation|hypomethylation]] of ''DUX4'' and its surrounding [[DNA]] on the tip of chromosome 4 (4q35), allowing [[transcription (biology)|transcription]] of ''DUX4'' into [[messenger RNA]] (mRNA). Several mutations can result in disease, upon which FSHD is sub-classified into FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2).<ref name="Tawil2014PathophysConsensus" /> Disease can only result when a mutation is present in combination with select, commonly found variations of 4q35, termed [[haplotype]] [[Gene polymorphism|polymorphisms]]. There are at least 17 4q35 haplotype polymorphisms,<ref name="Lemmers2012GeneticGuidelines">{{cite journal |last1=Lemmers |first1=Richard J.L.F. |last2=O'Shea |first2=Suzanne |last3=Padberg |first3=George W. |last4=Lunt |first4=Peter W. |last5=van der Maarel |first5=Silvère M. |title=Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: Workshop 9th June 2010, LUMC, Leiden, The Netherlands |journal=Neuromuscular Disorders |date=May 2012 |volume=22 |issue=5 |pages=463–470 |doi=10.1016/j.nmd.2011.09.004|pmid=22177830 |s2cid=39898514 |doi-access=free }}</ref> roughly dividable into the groups 4qA and 4qB.<ref name="Lemmers2012GeneticGuidelines" /> A 4qA haplotype polymorphism, often referred to as a 4qA [[allele]], is necessary for disease, as it contains a [[polyadenylation]] sequence that allows ''DUX4'' mRNA to resist degradation long enough to be [[Translation (biology)|translated]] into DUX4 protein.<ref name="Unifying" />
{{anchor|D4Z4}} <!-- Anchor point to allow easy linking to D4Z4 information, since this is not found in any other WP article. -->

===DUX4 and the D4Z4 repeat array===
[[File:A schematic of D4Z4 locus on chromosome 4.jpg|thumb|right|alt=D4Z4 array diagram|400px|D4Z4 array with three D4Z4 repeats and the 4qA allele.<ref name="Tawil2014PathophysConsensus" />
{|  style="width: 100%"
|-
| '''CEN''' || [[centromeric]] end || '''TEL''' || [[telomeric]] end
|-
| '''NDE box''' || non-deleted element || '''PAS''' || [[polyadenylation]] site
|-
| '''triangle''' || D4Z4 repeat|| '''trapezoid''' || partial D4Z4 repeat
|-
| '''white box''' || pLAM || '''gray boxes''' || DUX4 exons 1, 2, 3
|-
|  colspan="4" style="text-align: center; background: #cccdcf;" | '''arrows'''
|-
|  '''corner''' || [[Promoter (genetics)|promoters]] || '''straight''' ||  [[Transcription (biology)|RNA transcripts]]
|-
|  '''black''' || [[Sense (molecular biology)|sense]] || '''red''' || [[Cis-natural antisense transcript|antisense]]
|-
| '''blue''' || DBE-T || '''dashes''' || dicing sites
|}
]]
''DUX4'' resides within the D4Z4 [[macrosatellite]] repeat array, a series of [[Tandem repeat|tandemly repeated]] DNA segments in the [[subtelomeric]] region (4q35) of [[chromosome 4]].<ref>
The name "D4Z4" is derived from an obsolete nomenclature system used for DNA segments of unknown significance during the [[human genome project]]: '''D''' for DNA, '''4''' for chromosome 4, '''Z''' indicates it is a repetitive sequence, and '''4''' is a serial number assigned based on the order of submission.
* {{cite journal |last1=White |first1=J.A. |last2=McAlpine |first2=P.J. |last3=Antonarakis |first3=S. |last4=Cann |first4=H. |last5=Eppig |first5=J.T. |last6=Frazer |first6=K. |last7=Frezal |first7=J. |last8=Lancet |first8=D. |last9=Nahmias |first9=J. |last10=Pearson |first10=P. |last11=Peters |first11=J. |last12=Scott |first12=A. |last13=Scott |first13=H. |last14=Spurr |first14=N. |last15=Talbot |first15=C. |last16=Povey |first16=S. |title=NOMENCLATURE |journal=Genomics |date=October 1997 |volume=45 |issue=2 |pages=468–471 |doi=10.1006/geno.1997.4979|pmid=9344684 |doi-access=free }}
* {{cite journal |last1=Fasman |first1=KH |last2=Letovsky |first2=SI |last3=Cottingham |first3=RW |last4=Kingsbury |first4=DT |title=Improvements to the GDB Human Genome Data Base. |journal=Nucleic Acids Research |date=1 January 1996 |volume=24 |issue=1 |pages=57–63 |doi=10.1093/nar/24.1.57 |pmid=8594601|pmc=145602 |doi-access=free }}
</ref> Each D4Z4 repeat is 3.3 [[base pair|kilobase pairs]] (kb) long and is the site of epigenetic regulation, containing both [[heterochromatin]] and [[euchromatin]] structures.<ref name="Quest March–April 2007"/><ref>{{cite journal  |vauthors=Dixit M, Ansseau E, Tassin A, etal |title=DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=46 |pages=18157–62 |date=November 2007 |pmid=17984056 |pmc=2084313 |doi=10.1073/pnas.0708659104 |bibcode=2007PNAS..10418157D |doi-access=free }}</ref> In FSHD, the heterochromatin structure is lost, becoming euchromatin,<ref name="Quest March–April 2007"/> which consists of less methylation of DNA, and altered methylation of [[histones]].<ref name="Sikrova2023FSHD2Genetics" /> Histone methylation patterns differ slightly between FSHD1 and FSHD2.<ref name="Sikrova2023FSHD2Genetics" />

The subtelomeric region of chromosome 10q contains a tandem repeat structure highly [[Sequence homology|homologous]] (99% identical) to 4q35,<ref name="Unifying" /><ref name="Lemmers2012GeneticGuidelines" /> containing "D4Z4-like" repeats with protein-coding regions identical to ''DUX4'' (D10Z10 repeats and ''DUX4L10'', respectively).<ref name="Unifying" /><ref name="Coppee2004TextbookDUXgeneFamily">{{cite book |last1=Coppée |first1=Frédérique |last2=Mattéotti |first2=Christel |last3=Anssaeu |first3=Eugénie |last4= Sauvage |first4=Sébastien |last5=Leclercq |first5=India |last6=Leroy |first6=Axelle |last7=Marcowycz |first7=Aline |last8=Gerbaux |first8=Cécile |last9=Figlewicz |first9=Denise |last10=Ding |first10=Hao |last11=Belayew |first11=Belayew |editor1-last=Upadhyaya |editor1-first=Meena |editor2-last=Cooper |editor2-first=David N. |title=FSHD facioscapulohumeral muscular dystrophy : clinical medicine and molecular cell biology |date=2004 |publisher=BIOS Scientific Publishers |isbn=1-85996-244-0 |chapter=The DUX gene family and FSHD}}</ref> Because 10q usually lacks a polyadenylation sequence, it is usually not implicated in disease. However, [[homologous recombination|chromosomal rearrangements]] can occur between 4q and 10q repeat arrays, and involvement in disease is possible if a 4q D4Z4 repeat and polyadenylation signal are transferred onto 10q,<ref name="pmid17335567">{{cite journal  |vauthors=Rossi M, Ricci E, Colantoni L, etal |title=The Facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure |journal=BMC Med. Genet. |volume=8|pages=8 |year=2007 |pmid=17335567 |pmc=1821008 |doi=10.1186/1471-2350-8-8 |doi-access=free }}</ref><ref name="Unifying" /><ref name="Lemmers2021FSHD_10q">{{cite journal |last1=Lemmers |first1=RJLF |last2=van der Vliet |first2=PJ |last3=Blatnik |first3=A |last4=Balog |first4=J |last5=Zidar |first5=J |last6=Henderson |first6=D |last7=Goselink |first7=R |last8=Tapscott |first8=SJ |last9=Voermans |first9=NC |last10=Tawil |first10=R |last11=Padberg |first11=GWAM |last12=van Engelen |first12=BG |last13=van der Maarel |first13=SM |title=Chromosome 10q-linked FSHD identifies ''DUX4'' as principal disease gene. |journal=Journal of Medical Genetics |date=12 January 2021 |volume=59 |issue=2 |pages=jmedgenet-2020-107041 |doi=10.1136/jmedgenet-2020-107041 |pmid=33436523|pmc=8273184 |s2cid=231589589 }}</ref> or if rearrangement causes FSHD1.

''DUX4'' consists of three [[exon]]s. Exons 1 and 2 are in each repeat. Exon 3 is in the pLAM region telomeric to the last partial repeat.<ref name="Unifying" /><ref name="Snider2010retrotransposed"/> Multiple RNA transcripts are produced from the D4Z4 repeat array, both sense and antisense. Some transcripts might be degraded in areas to produce si-like small RNAs.<ref name="Tawil2014PathophysConsensus" /> Some transcripts that originate centromeric to the D4Z4 repeat array at the non-deleted element (NDE), termed D4Z4 regulatory element transcripts (DBE-T), could play a role in ''DUX4'' derepression.<ref name="Tawil2014PathophysConsensus" /><ref name="Himeda2019(Epi)genetics">{{cite journal |last1=Himeda |first1=CL |last2=Jones |first2=PL |title=The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy. |journal=Annual Review of Genomics and Human Genetics |date=31 August 2019 |volume=20 |pages=265–291 |doi=10.1146/annurev-genom-083118-014933 |pmid=31018108|s2cid=131775712 |doi-access=free }}</ref> One proposed mechanism is that DBE-T leads to the recruitment of the [[trithorax-group protein]] [[ASH1L|Ash1L]], an increase in [[H3K36me2]]-methylation, and ultimately de-repression of 4q35 genes.<ref name = Cabianca2012DBE-T>{{Cite journal|title = A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy|last1 = Cabianca|first1 = DS|date = May 11, 2012|journal = Cell|doi = 10.1016/j.cell.2012.03.035|volume = 149|issue = 4|pages = 819–831|last2 = Casa|first2 = Casa|last3 = Bodega|first3 = B|pmid=22541069|pmc=3350859|display-authors=etal}}</ref>
{| class="wikitable" style="float:right"
|+ Chromatin profiles<ref name="Sikrova2023FSHD2Genetics" />
|-
! !! {{vert header|DNA methylation}} !! {{vert header|[[H3K4me3|H3K4me2]]}} !! {{vert header|[[H3K9me3]]}} !! {{vert header|[[H3K27me3]]}}
|-
| FSHD1 || ↓ || ↑ || ↓ || 
|-
| FSHD2* || ↓ || ↑ || ↓ || ↑
|-
| colspan = "5" style='border: 1px solid white; background: #ffffff;' | <small>*Chromatin profiles not fully<br /> characterized for ''DNMT3B'' mutation<ref name="Sikrova2023FSHD2Genetics" /></small>
|}

===FSHD1===
FSHD involving deletion of D4Z4 repeats (termed 'D4Z4 contraction') on 4q is classified as FSHD1, which accounts for 95% of FSHD cases.<ref name="Wagner2019Review" /> Typically, chromosome 4 includes between 11 and 150 D4Z4 repeats.<ref name="Quest March–April 2007"/><ref name="Unifying" /> In FSHD1, there are 1–10 D4Z4 repeats.<ref name="Unifying" /> The number of repeats is roughly [[Negative relationship|inversely related]] to disease severity. Namely, those with 8 - 10 repeats tend to have the mildest presentations, sometimes with no symptoms; those with 4 - 7 repeats have moderate disease that is highly variable; and those with 1 - 3 repeats are more likely to have severe, atypical, and early-onset disease.<ref name="Sacconi2019Continuum" /> Deletion of the entire D4Z4 repeat array does not result in FSHD because then there are no complete copies of ''DUX4'' to be expressed, although other birth defects result.<ref>{{cite journal |last1=Tupler |first1=R |last2=Berardinelli |first2=A |last3=Barbierato |first3=L |last4=Frants |first4=R |last5=Hewitt |first5=JE |last6=Lanzi |first6=G |last7=Maraschio |first7=P |last8=Tiepolo |first8=L |title=Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy. |journal=Journal of Medical Genetics |date=May 1996 |volume=33 |issue=5 |pages=366–70 |doi=10.1136/jmg.33.5.366 |pmid=8733044|pmc=1050603 }}</ref><ref name="Unifying" /> One contracted D4Z4 repeat array with an adjoining 4qA allele is sufficient to cause disease, so inheritance is [[autosomal dominant]]. [[De novo mutation|''De novo'' (new) mutations]] are implicated in 10 - 30% of cases,<ref name="Mul2016ClinicalFeatures" /> up to 40% of which exhibit [[somatic mosaicism]].<ref name="Tawil2006Review" /> In an individual with mosaic FSHD, the severity of disease is correlated to the proportion of their cells carrying the mutation.<ref name="Tawil2006Review" />

It has been proposed that FSHD1 undergoes [[anticipation (genetics)|anticipation]], a phenomenon primarily associated with [[trinucleotide repeat disorders]] in which disease manifestation worsens with each subsequent generation.<ref name="Tawil1996anticipation">{{cite journal |last1=Tawil |first1=R |last2=Forrester |first2=J |last3=Griggs |first3=RC |last4=Mendell |first4=J |last5=Kissel |first5=J |last6=McDermott |first6=M |last7=King |first7=W |last8=Weiffenbach |first8=B |last9=Figlewicz |first9=D |title=Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. |journal=Annals of Neurology |date=June 1996 |volume=39 |issue=6 |pages=744–8 |doi=10.1002/ana.410390610 |pmid=8651646|s2cid=84518968 }}</ref> As of 2019, more detailed studies are needed to definitively show whether or not anticipation occurs.<ref name="Zernov2019genPhenCorrelations">{{cite journal |last1=Zernov |first1=N |last2=Skoblov |first2=M |title=Genotype-phenotype correlations in FSHD. |journal=BMC Medical Genomics |date=13 March 2019 |volume=12 |issue=Suppl 2 |pages=43 |doi=10.1186/s12920-019-0488-5 |pmid=30871534|pmc=6416831 |doi-access=free }}</ref> If anticipation does occur in FSHD, the mechanism is different than that of trinucleotide repeat disorders, since D4Z4 repeats are much larger than trinucleotide repeats, an underabundance of repeats (rather than overabundance) causes disease, and the repeat array size in FSHD is stable across generations.<ref name="Sacconi2015Review">{{cite journal |last1=Sacconi |first1=S |last2=Salviati |first2=L |last3=Desnuelle |first3=C |title=Facioscapulohumeral muscular dystrophy. |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |date=April 2015 |volume=1852 |issue=4 |pages=607–14 |doi=10.1016/j.bbadis.2014.05.021 |pmid=24882751|doi-access=free }}</ref>
[[File:FSHD genetics and epigenetics.png|thumb|left|350px|alt=FSHD genetics and epigenetics.png|D4Z4 array examples, with each D4Z4 repeat represented by a triangle. The circles above the triangles represent DNA methylation, which determine DNA packaging as represented by the circles in line with the triangles.]]

=== FSHD2 ===
FSHD without D4Z4 contraction is classified as FSHD2, which constitutes 5% of FSHD cases.<ref name="Wagner2019Review" /> Various mutations cause FSHD2, all of [[chromatin]] modifier genes that result in D4Z4 hypomethylation, at which the genetic mechanism converges with FSHD1.<ref name="Lemmers 1370–1374" /><ref name="Mul2022Review" /> Approximately 80% of FSHD2 cases are due to deactivating mutations in the gene ''[[SMCHD1]]'' (structural maintenance of chromosomes flexible hinge domain containing 1) on [[chromosome 18]]. ''SMCHD1'' is responsible for DNA methylation, and its deactivation results in hypomethylation of the D4Z4 repeat array.<ref name="Wagner2019Review" /> Specific mutations of ''SMCHD1'' are also associated with [[Syndromic microphthalmia|Bosma arhinia and microphtalmia syndrome]].<ref name="Sikrova2023FSHD2Genetics">{{cite journal |last1=Šikrová |first1=D |last2=Testa |first2=AM |last3=Willemsen |first3=I |last4=van den Heuvel |first4=A |last5=Tapscott |first5=SJ |last6=Daxinger |first6=L |last7=Balog |first7=J |last8=van der Maarel |first8=SM |title=SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action. |journal=Communications Biology |date=28 June 2023 |volume=6 |issue=1 |pages=677 |doi=10.1038/s42003-023-05053-0 |pmid=37380887|pmc=10307901 }}</ref> Another cause of FSHD2 is mutation in ''[[DNMT3B]]'' (DNA methyltransferase 3B), which also plays a role in DNA methylation.<ref name="vanDenBoogaard2016_DNMT3B">{{cite journal |last1=van den Boogaard |first1=ML |last2=Lemmers |first2=RJLF |last3=Balog |first3=J |last4=Wohlgemuth |first4=M |last5=Auranen |first5=M |last6=Mitsuhashi |first6=S |last7=van der Vliet |first7=PJ |last8=Straasheijm |first8=KR |last9=van den Akker |first9=RFP |last10=Kriek |first10=M |last11=Laurense-Bik |first11=MEY |last12=Raz |first12=V |last13=van Ostaijen-Ten Dam |first13=MM |last14=Hansson |first14=KBM |last15=van der Kooi |first15=EL |last16=Kiuru-Enari |first16=S |last17=Udd |first17=B |last18=van Tol |first18=MJD |last19=Nishino |first19=I |last20=Tawil |first20=R |last21=Tapscott |first21=SJ |last22=van Engelen |first22=BGM |last23=van der Maarel |first23=SM |title=Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy. |journal=American Journal of Human Genetics |date=5 May 2016 |volume=98 |issue=5 |pages=1020–1029 |doi=10.1016/j.ajhg.2016.03.013 |pmid=27153398|pmc=4863565 |doi-access=free }}</ref><ref name="Johnson2019FSHD1&2Review">{{cite journal |last1=Johnson |first1=NE |last2=Statland |first2=JM |s2cid=111390628 |title=FSHD1 or FSHD2: That is the question: The answer: It's all just FSHD. |journal=Neurology |date=7 May 2019 |volume=92 |issue=19 |pages=881–882 |doi=10.1212/WNL.0000000000007446 |pmid=30979855}}</ref> Mutations in ''DNMT3B'' can also cause [[ICF syndrome]].<ref name="Sikrova2023FSHD2Genetics" /> As of 2020, early evidence indicates that a third cause of FSHD2 is mutation in both copies of the ''LRIF1'' gene, which encodes the protein [[ligand-dependent nuclear receptor-interacting factor 1]] (LRIF1).<ref name="Hamanaka2020_LRIF1">{{cite journal |last1=Hamanaka |first1=Kohei |last2=Šikrová |first2=Darina |last3=Mitsuhashi |first3=Satomi |last4=Masuda |first4=Hiroki |last5=Sekiguchi |first5=Yukari |last6=Sugiyama |first6=Atsuhiko |last7=Shibuya |first7=Kazumoto |last8=Lemmers |first8=Richard J.L.F. |last9=Goossens |first9=Remko |last10=Ogawa |first10=Megumu |last11=Nagao |first11=Koji |last12=Obuse |first12=Chikashi |last13=Noguchi |first13=Satoru |last14=Hayashi |first14=Yukiko K. |last15=Kuwabara |first15=Satoshi |last16=Balog |first16=Judit |last17=Nishino |first17=Ichizo |last18=van der Maarel |first18=Silvère M. |s2cid=218982743 |title=Homozygous nonsense variant in associated with facioscapulohumeral muscular dystrophy |journal=Neurology |date=28 May 2020 |volume=94 |issue=23 |pages=e2441–e2447 |doi=10.1212/WNL.0000000000009617|pmid=32467133 |pmc=7455367 }}</ref> LRIF1 is known to interact with the SMCHD1 protein.<ref name="Hamanaka2020_LRIF1" /> As of 2019, there are presumably additional mutations at other unidentified genetic locations that can cause FSHD2.<ref name="Wagner2019Review" />

Mutation of a single allele of ''SMCHD1'' or ''DNMT3B'' can cause disease. Mutation of both copies ''LRIF1'' has been tentatively shown to cause disease in a single person as of 2020.<ref name="Hamanaka2020_LRIF1" /> As in FSHD1, a 4qA allele must be present for disease to result. However, unlike the D4Z4 array, the genes implicated in FSHD2 are not in proximity with the 4qA allele, and so they are [[Genetic linkage|inherited independently]] from the 4qA allele, resulting in a digenic inheritance pattern. For example, one parent without FSHD can pass on an ''SMCHD1'' mutation, and the other parent, also without FSHD, can pass on a 4qA allele, bearing a child with FSHD2.<ref name="Lemmers 1370–1374">{{Cite journal|title = Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2|last1 = Lemmers|first1 = RJ|date = Dec 2012|journal = Nature Genetics|doi = 10.1038/ng.2454|last2 = Tawil|first2 = R|volume = 44|pages = 1370–1374|last3 = Petek|first3 = LM|issue=12|display-authors=etal|pmid=23143600|pmc=3671095}}</ref><ref name="Johnson2019FSHD1&2Review" />

=== Two ends of a disease spectrum ===

FSHD1 and FSHD2 have been traditionally viewed as separate entities with distinct genetic causes (albeit, the downstream genetic mechanisms merge).<ref name="Caputo2022MolecularUpdate">{{cite journal |last1=Caputo |first1=V |last2=Megalizzi |first2=D |last3=Fabrizio |first3=C |last4=Termine |first4=A |last5=Colantoni |first5=L |last6=Caltagirone |first6=C |last7=Giardina |first7=E |last8=Cascella |first8=R |last9=Strafella |first9=C |title=Update on the Molecular Aspects and Methods Underlying the Complex Architecture of FSHD. |journal=Cells |date=29 August 2022 |volume=11 |issue=17 |page=2687 |doi=10.3390/cells11172687 |pmid=36078093|pmc=9454908 |doi-access=free }}</ref> Alternatively, the genetic causes of FSHD1 and FSHD2 can be viewed as [[risk factor]]s, each contributing to an FSHD disease spectrum.<ref name="Caputo2022MolecularUpdate" /> Not rarely, an affected individual seems to have contributions from both.<ref name="Sacconi2019Continuum">{{cite journal |last1=Sacconi |first1=S |last2=Briand-Suleau |first2=A |last3=Gros |first3=M |last4=Baudoin |first4=C |last5=Lemmers |first5=RJLF |last6=Rondeau |first6=S |last7=Lagha |first7=N |last8=Nigumann |first8=P |last9=Cambieri |first9=C |last10=Puma |first10=A |last11=Chapon |first11=F |last12=Stojkovic |first12=T |last13=Vial |first13=C |last14=Bouhour |first14=F |last15=Cao |first15=M |last16=Pegoraro |first16=E |last17=Petiot |first17=P |last18=Behin |first18=A |last19=Marc |first19=B |last20=Eymard |first20=B |last21=Echaniz-Laguna |first21=A |last22=Laforet |first22=P |last23=Salviati |first23=L |last24=Jeanpierre |first24=M |last25=Cristofari |first25=G |last26=van der Maarel |first26=SM |title=FSHD1 and FSHD2 form a disease continuum. |journal=Neurology |date=7 May 2019 |volume=92 |issue=19 |pages=e2273–e2285 |doi=10.1212/WNL.0000000000007456 |pmid=30979860|pmc=6537132 }}</ref> For example, in those with FSHD2, although they have do not have a 4qA allele with D4Z4 repeat number less than 11, they still often have one less than 17 (relatively short compared to the general population), suggesting that a large number of D4Z4 repeats can prevent the effects of an ''SMCHD1'' mutation.<ref name="Sacconi2019Continuum" /> Further studies are needed to determine the upper limit of D4Z4 repeats in FSHD2.<ref name="Sacconi2019Continuum" />

In those with FSHD1 and FSHD2, that is, having 10 or fewer repeats with an adjacent 4qA allele and an ''SMCHD1'' mutation, the disease manifests more severely, illustrating that the effects of each mutation are additive.<ref name = "Sacconi2013SMCHD1Modify">{{Cite journal|title = The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1|last1 = Sacconi|first1 = S|date = Oct 3, 2013|journal = The American Journal of Human Genetics|doi = 10.1016/j.ajhg.2013.08.004|volume = 93|issue = 4|pages = 744–751|last2 = Lemmers|first2 = RJ|last3 = Balog|first3 = J|display-authors=etal|pmid=24075187|pmc=3791262}}</ref> A combined FSHD1/FSHD2 presentation is most common in those with 9 - 10 repeats. A possible explanation is that a sizable portion of the general population has 9 - 10 repeats with difficult to detect or no disease, yet with the additive effect of an ''SMCHD1'' mutation, symptoms are severe enough for a diagnosis to be made.<ref name="Sacconi2019Continuum" /> The 9 - 10 repeat size can be considered as an overlap zone between FSHD1 and FSDH2.<ref name="Sacconi2019Continuum" />

==Pathophysiology==
===Molecular===
[[File:DUX4 Signalling in FSHD.png|thumb|DUX4 signaling in FSHD-affected skeletal muscle.|400px]]
As of 2020, there seems to be a consensus that aberrant expression of ''DUX4'' in muscle is the cause of FSHD.<ref name="Lim2020PathogenesisReview" /> ''DUX4'' is expressed in extremely small amounts, detectable in 1 out of every 1000 [[Myocyte#Development|immature muscle cells (myoblast)]], which appears to increase after myoblast maturation, in part because the cells fuse as they mature, and a single [[cell nucleus|nucleus]] expressing ''DUX4'' can provide ''DUX4'' protein to neighboring nuclei from fused cells.<ref name="Bosnakovski2020DUX4FAP">{{cite journal |last1=Bosnakovski |first1=Darko |last2=Shams |first2=Ahmed S. |last3=Yuan |first3=Ce |last4=da Silva |first4=Meiricris T. |last5=Ener |first5=Elizabeth T. |last6=Baumann |first6=Cory W. |last7=Lindsay |first7=Angus J. |last8=Verma |first8=Mayank |last9=Asakura |first9=Atsushi |last10=Lowe |first10=Dawn A. |last11=Kyba |first11=Michael |title=Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice |journal=Journal of Clinical Investigation |date=6 April 2020 |volume=130 |issue=5 |pages=2465–2477 |doi=10.1172/JCI133303|pmid=32250341 |pmc=7190912 |doi-access=free }}</ref>

It remains an area of active research how DUX4 protein causes muscle damage.<ref name="Mocciaro2021DUX4">{{cite journal |last1=Mocciaro |first1=Emanuele |last2=Runfola |first2=Valeria |last3=Ghezzi |first3=Paola |last4=Pannese |first4=Maria |last5=Gabellini |first5=Davide |title=DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy |journal=Cells |date=26 November 2021 |volume=10 |issue=12 |pages=3322 |doi=10.3390/cells10123322|pmid=34943834 |pmc=8699294 |doi-access=free }}</ref> DUX4 protein is a transcription factor that regulates many other genes. Some of these genes are involved in [[apoptosis]], such as [[p53]], [[p21]], [[MYC]], and [[β-catenin]], and indeed it seems that DUX4 protein makes muscle cells more prone to apoptosis. Other DUX4 protein-regulated genes are involved in [[oxidative stress]], and indeed it seems that ''DUX4'' expression lowers muscle cell tolerance of oxidative stress. Variation in the ability of individual muscles to handle oxidative stress could partially explain the muscle involvement patterns of FSHD. DUX4 protein downregulates many genes involved in muscle development, including [[MyoD]], [[myogenin]], [[desmin]], and [[PAX7]], and indeed ''DUX4'' expression has shown to reduce [[muscle cell]] proliferation, differentiation, and fusion. DUX4 protein regulates a few genes that are involved in [[RNA]] quality control, and indeed ''DUX4'' expression has been shown to cause accumulation of RNA with subsequent apoptosis.<ref name="Lim2020PathogenesisReview">{{cite journal |last1=Lim |first1=KRQ |last2=Nguyen |first2=Q |last3=Yokota |first3=T |title=DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy. |journal=International Journal of Molecular Sciences |date=22 January 2020 |volume=21 |issue=3 |pages=729 |doi=10.3390/ijms21030729 |pmid=31979100|pmc=7037115 |doi-access=free }}</ref> [[Estrogen]] seems to play a role in modifying DUX4 protein effects on muscle differentiation, which could explain why females are lesser affected than males, although it remains unproven.<ref name="Schatzl2021GeneticsReview" />

The cellular [[hypoxia (medical)|hypoxia]] response has been reported in a single study to be the main driver of DUX4 protein-induced muscle cell death. The [[hypoxia-inducible factors]] (HIFs) are upregulated by DUX4 protein, possibly causing pathologic signaling leading to cell death.<ref>{{cite journal |last1=Lek |first1=Angela |last2=Zhang |first2=Yuanfan |last3=Woodman |first3=Keryn G. |last4=Huang |first4=Shushu |last5=DeSimone |first5=Alec M. |last6=Cohen |first6=Justin |last7=Ho |first7=Vincent |last8=Conner |first8=James |last9=Mead |first9=Lillian |last10=Kodani |first10=Andrew |last11=Pakula |first11=Anna |last12=Sanjana |first12=Neville |last13=King |first13=Oliver D. |last14=Jones |first14=Peter L. |last15=Wagner |first15=Kathryn R. |last16=Lek |first16=Monkol |last17=Kunkel |first17=Louis M. |title=Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy |journal=Science Translational Medicine |date=25 March 2020 |volume=12 |issue=536 |pages=eaay0271 |doi=10.1126/scitranslmed.aay0271 |pmid=32213627|pmc=7304480 }}</ref>

Another study found that ''DUX4'' expression in muscle cells led to the recruitment and alteration of [[fibroblast|fibrous]]/[[adipocyte|fat]] progenitor cells, which helps explain why muscles become replaced by fat and [[fibrous tissue]].<ref name="Bosnakovski2020DUX4FAP" />

A single study implicated ''[[RIPK3]]'' in DUX4-mediated cell death.<ref>{{cite journal |last1=Mariot |first1=Virginie |last2=Joubert |first2=Romain |last3=Le Gall |first3=Laura |last4=Sidlauskaite |first4=Eva |last5=Hourde |first5=Christophe |last6=Duddy |first6=William |last7=Voit |first7=Thomas |last8=Bencze |first8=Maximilien |last9=Dumonceaux |first9=Julie |title=RIPK3-mediated cell death is involved in DUX4-mediated toxicity in facioscapulohumeral dystrophy |journal=Journal of Cachexia, Sarcopenia and Muscle |date=22 October 2021 |volume=12 |issue=6 |pages=2079–2090 |doi=10.1002/jcsm.12813|pmid=34687171 |pmc=8718031 |s2cid=239471655 }}</ref>

===Muscle histology===
[[File:Facioscapulohumeral muscular dystrophy histology.jpg|thumb|right|Microscopic cross-sectional views of FSHD-affected [[muscle fiber]]s. Visible is inflammation and fibrosis, as well as muscle fiber shape change, death, and regeneration.]]
Unlike other muscular dystrophies, early muscle biopsies show only mild degrees of [[fibrosis]], muscle fiber [[hypertrophy]], and displacement of [[cell nucleus|nuclei]] from myofiber peripheries (central nucleation).<ref name="Tawil2014PathophysConsensus" /> More often found is inflammation.<ref name="Tawil2014PathophysConsensus" /> There can be [[Endomysium|endomysial]] inflammation, primarily composed of [[CD8+ T-cell]]s, although these cells do not seem to directly cause muscle fiber death.<ref name="Tawil2014PathophysConsensus" /> Endomysial blood vessels can be surrounded by inflammation, which is relatively unique to FSHD, and this inflammation contains [[T helper cell|CD4+ T-cells]].<ref name="Tawil2014PathophysConsensus" /> Inflammation is succeeded by deposition of fat (fatty infiltration), then fibrosis.<ref name="Wang2019MRI">{{cite journal |last1=Wang |first1=LH |last2=Friedman |first2=SD |last3=Shaw |first3=D |last4=Snider |first4=L |last5=Wong |first5=CJ |last6=Budech |first6=CB |last7=Poliachik |first7=SL |last8=Gove |first8=NE |last9=Lewis |first9=LM |last10=Campbell |first10=AE |last11=Lemmers |first11=RJFL |last12=Maarel |first12=SM |last13=Tapscott |first13=SJ |last14=Tawil |first14=RN |title=MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD. |journal=Human Molecular Genetics |date=2019-02-01 |volume=28 |issue=3 |pages=476–486 |doi=10.1093/hmg/ddy364 |pmid=30312408|pmc=6337697 }}</ref><ref name="Tawil2014PathophysConsensus" /> Individual muscle fibers can appear whorled, moth-eaten, and, especially, lobulated.<ref name="Gherardi2019Neuropathology_textbook">{{cite book |last1=Gherardi |first1=Romain |last2=Amato |first2=Anthony A. |last3=Lidov |first3=Hart G. |last4=Girolami |first4=Umberto De |editor1-last=Gray |editor1-first=Francoise |editor2-last=Duyckaerts |editor2-first=Charles |editor3-last=Girolami |editor3-first=Umberto de |title=Escourolle and Poirier's manual of basic neuropathology |date=Nov 2018 |publisher=Oxford University Press |location=New York, NY |isbn=9780190675011 |edition=Sixth |chapter=Pathology of Skeletal Muscle | doi = 10.1093/med/9780190675011.001.0001}}</ref>

===Muscle involvement pattern===
Why certain muscles are preferentially affected in FSHD remains unknown. There are multiple trends of involvement seen in FSHD, possibly hinting at underlying pathophysiology. Individual muscles can weaken while adjacent muscles remain strong.<ref name="vanDerMaarel2012chromatinRelaxation">{{cite journal |last1=van der Maarel |first1=SM |last2=Miller |first2=DG |last3=Tawil |first3=R |last4=Filippova |first4=GN |last5=Tapscott |first5=SJ |title=Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation. |journal=Current Opinion in Neurology |date=October 2012 |volume=25 |issue=5 |pages=614–20 |doi=10.1097/WCO.0b013e328357f22d |pmid=22892954|pmc=3653067 }}</ref> The right shoulder and arm muscles are more often affected than the left upper extremity muscles, a pattern also seen in [[Poland syndrome]] and [[hereditary neuralgic amyotrophy]]; this could reflect a genetic, developmental/anatomic, or functional-related mechanism.<ref name="Padberg2004Textbook" /><ref name="Rijken2014CTWholeBody" /> The deltoid is often spared, which is not seen in any other condition that affects the muscles around the scapula.<ref name="Padberg2020Regrets">{{cite web | title=A giant of FSHD research shares his "regrets"|url=https://www.fshdsociety.org/2020/09/30/a-giant-of-fshd-research-shares-his-regrets/ |website=FSHD Society |access-date=11 March 2021 |archive-url=https://web.archive.org/web/20201024082949/https://www.fshdsociety.org/2020/09/30/a-giant-of-fshd-research-shares-his-regrets/ |archive-date=24 October 2020 |location=Way Back Machine |date=30 September 2020 |quote=Another striking aspect of FSHD is that muscles weakness seems to vary so much from patient to patient. Nonetheless, "there is a highly characteristic pattern of muscle weakness, otherwise we would never have been able to recognize FSHD as a specific disease," Padberg said. "Strong deltoid muscle does not occur in any other condition that involves weakness of scapular stabilizers. No other muscle disease with shoulder girdle involvement has this pattern." Unfortunately, "an explanation is beyond our grasp as we don't know how muscle are laid down" during the early stages of human gestation.}}</ref>
[[File:FSHD Muscle MRI T1 and T2.png|thumb|Examples of MRI imaging in FSHD. The white within the muscles of the STIR (T2) image represents muscle edema. The white within the muscles of the T1 images represents fatty infiltration.]]
Medical imaging (CT and MRI) have shown muscle involvement not readily apparent otherwise<ref name="Tasca2014MRIUpperGirdle">{{cite journal |last1=Tasca |first1=G |last2=Monforte |first2=M |last3=Iannaccone |first3=E |last4=Laschena |first4=F |last5=Ottaviani |first5=P |last6=Leoncini |first6=E |last7=Boccia |first7=S |last8=Galluzzi |first8=G |last9=Pelliccioni |first9=M |last10=Masciullo |first10=M |last11=Frusciante |first11=R |last12=Mercuri |first12=E |last13=Ricci |first13=E |title=Upper girdle imaging in facioscapulohumeral muscular dystrophy. |journal=PLOS ONE |date=2014 |volume=9 |issue=6 |pages=e100292 |doi=10.1371/journal.pone.0100292 |pmid=24932477|pmc=4059711 |bibcode=2014PLoSO...9j0292T |doi-access=free }}</ref> 
* A single MRI study shows the [[teres major muscle]] to be commonly affected.<ref name="Gerevini2016MRIWholeBody">{{cite journal |last1=Gerevini |first1=S |last2=Scarlato |first2=M |last3=Maggi |first3=L |last4=Cava |first4=M |last5=Caliendo |first5=G |last6=Pasanisi |first6=B |last7=Falini |first7=A |last8=Previtali |first8=SC |last9=Morandi |first9=L |s2cid=24650482 |title=Muscle MRI findings in facioscapulohumeral muscular dystrophy |journal=European Radiology |date=March 2016 |volume=26 |issue=3 |pages=693–705 |doi=10.1007/s00330-015-3890-1 |pmid=26115655}}</ref> 
* The [[semimembranosus muscle]], part of the [[hamstrings]], is commonly affected,<ref name="Rijken2014CTWholeBody">{{cite journal |last1=Rijken |first1=NH |last2=van der Kooi |first2=EL |last3=Hendriks |first3=JC |last4=van Asseldonk |first4=RJ |last5=Padberg |first5=GW |last6=Geurts |first6=AC |last7=van Engelen |first7=BG |s2cid=101093 |title=Skeletal muscle imaging in facioscapulohumeral muscular dystrophy, pattern and asymmetry of individual muscle involvement. |journal=Neuromuscular Disorders |date=December 2014 |volume=24 |issue=12 |pages=1087–96 |doi=10.1016/j.nmd.2014.05.012 |pmid=25176503|doi-access=free }}</ref><ref name="Mair2017MRILeg">{{cite journal |last1=Mair |first1=D |last2=Huegens-Penzel |first2=M |last3=Kress |first3=W |last4=Roth |first4=C |last5=Ferbert |first5=A |s2cid=25005883 |title=Leg Muscle Involvement in Facioscapulohumeral Muscular Dystrophy: Comparison between Facioscapulohumeral Muscular Dystrophy Types 1 and 2. |journal=European Neurology |date=2017 |volume=77 |issue=1–2 |pages=32–39 |doi=10.1159/000452763 |pmid=27855411}}</ref><ref name="Olsen2006MRILeg">{{cite journal |last1=Olsen |first1=DB |last2=Gideon |first2=P |last3=Jeppesen |first3=TD |last4=Vissing |first4=J |s2cid=19421344 |title=Leg muscle involvement in facioscapulohumeral muscular dystrophy assessed by MRI. |journal=Journal of Neurology |date=November 2006 |volume=253 |issue=11 |pages=1437–41 |doi=10.1007/s00415-006-0230-z |pmid=16773269}}</ref>  deemed by one author to be "the most frequently and severely affected muscle."<ref name="Wagner2019Review" />
* Of the quadriceps muscles, the [[rectus femoris]] is preferentially affected<ref name="Mair2017MRILeg" /> 
* Of the  [[gastrocnemius]], the medial section is preferentially affected;<ref name="Mair2017MRILeg" /><ref name="Olsen2006MRILeg" />
* The [[iliopsoas]], a hip flexor muscle, is very often spared.<ref name="Olsen2006MRILeg" /><ref name="Wagner2019Review" />

===Retinopathy===
Tortuosity of the retinal arterioles, and less often microaneurysms and telangiectasia, are commonly found in FSHD.<ref name="Goselink2019Ophthalmologic" /> Abnormalities of the capillaries and venules are not observed.<ref name="Goselink2019Ophthalmologic" /> One theory for why the arterioles are selectively affected is that they contain [[smooth muscle]].<ref name="Goselink2019Ophthalmologic" /> The degree of D4Z4 contraction correlates to the severity of tortuosity of arterioles.<ref name="Goselink2019Ophthalmologic" /> It has been hypothesized that retinopathy is due to DUX4-protein-induced modulation of the [[CXCR4]]–[[Stromal cell-derived factor 1|SDF1]] axis, which has a role in endothelial tip cell morphology and vascular branching.<ref name="Goselink2019Ophthalmologic" />

== Diagnosis ==
[[File:FSHDDiagnosticTree.png|thumb|left|American Academy of Neurology (ANN) guidelines for genetic testing for suspected FSHD. Not all laboratories follow this workflow.]]FSHD can be presumptively diagnosed in many cases based on signs, symptoms, and/or non-genetic medical tests, especially if a [[first-degree relative]] has genetically confirmed FSHD.<ref name="Mul2022Review" /> Genetic testing can provide definitive diagnosis.<ref name="Mul2016ClinicalFeatures" /> In the absence of an established family history of FSHD, diagnosis can be difficult due to the variability in how FSHD manifests.<ref name="Sacconi2006DiagnosticDifficulty">{{cite journal |last1=Sacconi |first1=S |last2=Salviati |first2=L |last3=Bourget |first3=I |last4=Figarella |first4=D |last5=Péréon |first5=Y |last6=Lemmers |first6=R |last7=van der Maarel |first7=S |last8=Desnuelle |first8=C |title=Diagnostic challenges in facioscapulohumeral muscular dystrophy. |journal=Neurology |date=2006-10-24 |volume=67 |issue=8 |pages=1464–6 |doi=10.1212/01.wnl.0000240071.62540.6f |pmid=17060574|hdl=11577/1565214 |s2cid=25693278 |hdl-access=free }}</ref>

=== Genetic testing ===
Genetic testing is the [[gold standard (test)|gold standard]] for FSHD diagnosis, as it is the most [[sensitivity and specificity|sensitive and specific]] test available.<ref name="Wagner2019Review" /> Commonly, FSHD1 is tested for first.<ref name="Wagner2019Review" /> A shortened D4Z4 array length (''Eco''RI length of 10 kb to 38 kb) with an adjacent 4qA allele supports FSHD1.<ref name="Wagner2019Review" /> If FSHD1 is not present, commonly FSHD2 is tested for next by assessing methylation at 4q35.<ref name="Wagner2019Review" /> Low methylation (less than 20%) in the context of a 4qA allele is sufficient for diagnosis.<ref name="Wagner2019Review" /> The specific mutation, usually one of various SMCHD1 mutations, can be identified with [[next-generation sequencing]] (NGS).<ref>{{cite journal |last1=Strafella |first1=Claudia |last2=Caputo |first2=Valerio |last3=Galota |first3=Rosaria Maria |last4=Campoli |first4=Giulia |last5=Bax |first5=Cristina |last6=Colantoni |first6=Luca |last7=Minozzi |first7=Giulietta |last8=Orsini |first8=Chiara |last9=Politano |first9=Luisa |last10=Tasca |first10=Giorgio |last11=Novelli |first11=Giuseppe |last12=Ricci |first12=Enzo |last13=Giardina |first13=Emiliano |last14=Cascella |first14=Raffaella |title=The variability of SMCHD1 gene in FSHD patients: evidence of new mutations |journal=Human Molecular Genetics |date=1 December 2019 |volume=28 |issue=23 |pages=3912–3920 |doi=10.1093/hmg/ddz239|pmid=31600781 |pmc=6969370 }}</ref>

==== Assessing D4Z4 length ====
Measuring D4Z4 length is technically challenging due to the D4Z4 repeat array consisting of long, repetitive elements.<ref name="Zampatti2019MolecularDiagnosis(NGS)">{{cite journal |last1=Zampatti |first1=S |last2=Colantoni |first2=L |last3=Strafella |first3=C |last4=Galota |first4=RM |last5=Caputo |first5=V |last6=Campoli |first6=G |last7=Pagliaroli |first7=G |last8=Carboni |first8=S |last9=Mela |first9=J |last10=Peconi |first10=C |last11=Gambardella |first11=S |last12=Cascella |first12=R |last13=Giardina |first13=E |title=Facioscapulohumeral muscular dystrophy (FSHD) molecular diagnosis: from traditional technology to the NGS era. |journal=Neurogenetics |date=May 2019 |volume=20 |issue=2 |pages=57–64 |doi=10.1007/s10048-019-00575-4 |pmid=30911870|s2cid=85495566 }}</ref> For example, NGS is not useful for assessing D4Z4 length, because it breaks DNA into fragments before reading them, and it is unclear from which D4Z4 repeat each sequenced fragment came.<ref name="Mul2016ClinicalFeatures" /> In 2020, [[optical mapping]] became available for measuring D4Z4 array length, which is more precise and less labor-intensive than southern blot.<ref name="Kinoshita2020opticalmapping">{{cite web |last1=Kinoshita |first1=June |title=Genetic testing for FSHD—a new frontier |url=https://www.fshdsociety.org/2020/03/11/genetic-testing-for-fshd-a-new-frontier/ |website=FSHD Society |access-date=8 April 2020 |archive-url=https://web.archive.org/web/20200408155512/https://www.fshdsociety.org/2020/03/11/genetic-testing-for-fshd-a-new-frontier/ |archive-date=8 April 2020 |date=11 March 2020}}</ref> 
[[Chromosome combing|Molecular combing]] is also available for assessing D4Z4 array length.<ref name="Vasale2015MolecularCombing">{{cite journal |last1=Vasale |first1=J |last2=Boyar |first2=F |last3=Jocson |first3=M |last4=Sulcova |first4=V |last5=Chan |first5=P |last6=Liaquat |first6=K |last7=Hoffman |first7=C |last8=Meservey |first8=M |last9=Chang |first9=I |last10=Tsao |first10=D |last11=Hensley |first11=K |last12=Liu |first12=Y |last13=Owen |first13=R |last14=Braastad |first14=C |last15=Sun |first15=W |last16=Walrafen |first16=P |last17=Komatsu |first17=J |last18=Wang |first18=JC |last19=Bensimon |first19=A |last20=Anguiano |first20=A |last21=Jaremko |first21=M |last22=Wang |first22=Z |last23=Batish |first23=S |last24=Strom |first24=C |last25=Higgins |first25=J |title=Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD. |journal=Neuromuscular Disorders |date=December 2015 |volume=25 |issue=12 |pages=945–51 |doi=10.1016/j.nmd.2015.08.008 |pmid=26420234|s2cid=6871094 }}</ref> These methods, which physical measure the size of the D4Z4 repeat array, require specially prepared high quality and high molecular weight genomic DNA (gDNA) from serum, increasing cost and reducing accessibility to testing.<ref name="Gould2021Testing">{{cite journal |last1=Gould |first1=T |last2=Jones |first2=TI |last3=Jones |first3=PL |title=Precise Epigenetic Analysis Using Targeted Bisulfite Genomic Sequencing Distinguishes FSHD1, FSHD2, and Healthy Subjects. |journal=Diagnostics (Basel, Switzerland) |date=13 August 2021 |volume=11 |issue=8 |page=1469 |doi=10.3390/diagnostics11081469 |pmid=34441403|pmc=8393475 |doi-access=free }}</ref>

[[File:FSHD Restriction enzyme digestion.png|thumb|Diagram showing restriction enzyme sites used to differentiate between D4Z4 repeat arrays of 4q and 10q.]]
[[Restriction fragment length polymorphism]] (RFLP) analysis was the first genetic test developed and is still used as of 2020, although it is being phased out by newer methods. It involves dicing the DNA with [[restriction enzymes]] and sorting the resulting [[restriction fragment]]s by size using [[southern blot]]. The restriction enzymes ''Eco''RI and ''Bln''I are commonly used. ''Eco''RI isolates the 4q and 10q repeat arrays, and ''Bln''I dices the 10q sequence into small pieces, allowing 4q to be distinguished.<ref name="Mul2016ClinicalFeatures" /><ref name="Lemmers2012GeneticGuidelines" /> The ''Eco''RI restriction fragment is composed of three parts: 1) 5.7 kb proximal part, 2) the central, variable size D4Z4 repeat array, and 3) the distal part, usually 1.25 kb.<ref name="vanDeutekom1993D4Z4" /> The proximal portion has a sequence of DNA stainable by the probe p13E-11, which is commonly used to visualize the EcoRI fragment during southern blot.<ref name="Lemmers2012GeneticGuidelines" /> The name "p13E-11" reflects that it is a [[subcloning|subclone]] of a DNA sequence designated as [[cosmid]] 13E during the human genome project.<ref name="Wijmenga1992p13E-11" /><ref name="Frants2004MappingTextbook">{{cite book |last1=Frants |first1=Rune R. |last2=Sandkuijl |first2=Lodewijk A. |last3=van der Maarel |first3=Silvere M. |last4=Padberg |first4=George W. |editor1-last=Upadhyaya |editor1-first=Meena |editor2-last=Cooper |editor2-first=David N. |title=FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology |date=2004 |publisher=BIOS Scientific Publishers |isbn=1-85996-244-0 |chapter=Mapping of the FSHD gene and the discovery of the pathognomonic deletion}}</ref> Considering that each D4Z4 repeat is 3.3 kb, and the ''Eco''RI fragment contains about 5 kb of DNA that is not part of the D4Z4 repeat array, the number of D4Z4 units can be calculated.<ref name="Schatzl2021GeneticsReview">{{cite journal |last1=Schätzl |first1=T |last2=Kaiser |first2=L |last3=Deigner |first3=HP |title=Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update. |journal=Orphanet Journal of Rare Diseases |date=12 March 2021 |volume=16 |issue=1 |pages=129 |doi=10.1186/s13023-021-01760-1 |pmid=33712050|pmc=7953708 |s2cid=232202360 |doi-access=free }}</ref>
:D4Z4 repeats = (''Eco''RI length - 5) / 3.3

Sometimes 4q or 10q will have a combination of D4Z4 and D4Z4-like repeats due to DNA exchange between 4q and 10q, which can yield erroneous results, requiring more detailed workup.<ref name="Lemmers2012GeneticGuidelines" /> Sometimes D4Z4 repeat array deletions can include the p13E-11 binding site, warranting use of alternate probes.<ref name="Lemmers2012GeneticGuidelines" /><ref>{{cite journal |last1=Lemmers |first1=Richard J L F |last2=Vliet |first2=Patrick J |last3=Granado |first3=David San Leon |last4=Stoep |first4=Nienke |last5=Buermans |first5=Henk |last6=Schendel |first6=Robin |last7=Schimmel |first7=Joost |last8=Visser |first8=Marianne |last9=Coster |first9=Rudy |last10=Jeanpierre |first10=Marc |last11=Laforet |first11=Pascal |last12=Upadhyaya |first12=Meena |last13=Engelen |first13=Baziel |last14=Sacconi |first14=Sabrina |last15=Tawil |first15=Rabi |last16=Voermans |first16=Nicol C |last17=Rogers |first17=Mark |last18=van der Maarel |first18=Silvère M |title=High resolution breakpoint junction mapping of proximally extended D4Z4 deletions in FSHD1 reveals evidence for a founder effect. |journal=Human Molecular Genetics |date=24 September 2021 |volume=31 |issue=5 |pages=748–760 |doi=10.1093/hmg/ddab250|pmid=34559225 |pmc=8895739 }}</ref>

====Assessing methylation status====
Methylation status of 4q35 is traditionally assessed after FSHD1 testing is negative. [[Epigenetics#Methylation-sensitive restriction enzymes|Methylation sensitive restriction enzyme]] (MSRE) digestion showing hypomethylation has long been considered diagnostic of FSHD2.<ref name="Gould2021Testing" /> Other methylation assays have been proposed or used in research settings, including [[methylated DNA immunoprecipitation]] and [[bisulfite sequencing]], but are not routinely used in clinical practice.<ref name="Gaillard2014Immunoprecipitation">{{cite journal |last1=Gaillard |first1=MC |last2=Roche |first2=S |last3=Dion |first3=C |last4=Tasmadjian |first4=A |last5=Bouget |first5=G |last6=Salort-Campana |first6=E |last7=Vovan |first7=C |last8=Chaix |first8=C |last9=Broucqsault |first9=N |last10=Morere |first10=J |last11=Puppo |first11=F |last12=Bartoli |first12=M |last13=Levy |first13=N |last14=Bernard |first14=R |last15=Attarian |first15=S |last16=Nguyen |first16=K |last17=Magdinier |first17=F |title=Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers. |journal=Neurology |date=19 August 2014 |volume=83 |issue=8 |pages=733–42 |doi=10.1212/WNL.0000000000000708 |pmid=25031281|s2cid=10002229 |url=https://hal.archives-ouvertes.fr/hal-01610019/file/Gaillard%20et%20al.%20-%202014%20-%20Neurology%282%29.pdf }}</ref><ref name="Gould2021Testing" /> Bisulfite sequencing, if validated, would be valuable due to it being able to use lower quality DNA sources, such as those found in saliva.<ref name="Gould2021Testing" />

=== Auxiliary testing ===
[[File:FSHD MRI Asymmetrical Muscle Involvement.tif|thumb|MRI showing asymmetrical involvement of various muscles in FSHD]]
Other tests can support the diagnosis of FSHD, although they are all less sensitive and less specific than genetic testing.<ref name="FSHD Fact Sheet">[http://www.mda.org/publications/fa-fshd.html FSHD Fact Sheet] {{webarchive|url=https://web.archive.org/web/20060306140617/http://www.mda.org/publications/fa-fshd.html |date=2006-03-06 }}, [[Muscular Dystrophy Association|MDA]], 11/1/2001</ref><ref name="Mul2016ClinicalFeatures" /> Nonetheless, they can rule out similar-appearing conditions.<ref name="Tawil2006Review" />
* [[Creatine kinase]] (CK) blood level is often ordered when muscle damage is suspected. CK is an [[enzyme]] found in muscle, leaking into the blood when muscles become damaged. In FSHD, CK level is normal to mildly elevated,<ref name="Wagner2019Review" /> never exceeding five times the upper limit of normal.<ref name="Mul2016ClinicalFeatures" />
* [[Electromyogram]] (EMG) measures the electrical activity in the muscle. EMG can show nonspecific signs of muscle damage or irritability.<ref name="Wagner2019Review" />
* [[Nerve conduction velocity]] (NCV) measures the how fast signals travel along a nerve. The nerve signals are measured with surface electrodes (similar to those used for an electrocardiogram) or needle electrodes.
* [[Muscle biopsy]] is the surgical removal and examination of a small piece of muscle, usually from the arm or leg. [[Microscopy]] and a variety of [[biochemical]] tests are used for examination. Findings in FSHD are nonspecific, such as presence of white blood cells or variation in muscle fiber size. This test is rarely indicated.<ref name="Wagner2019Review" />
* Muscle MRI is sensitive for detecting muscle damage, even in mild cases. [[T1-weighted]] MRI imaging can visualize fatty infiltration of muscles, and [[T2-weighted]] MRI imaging can visualize muscle edema.{{citation needed|date=January 2024}} Because of the particular muscle involvement patterns of FSHD, MRI can help differentiate FSHD from other muscle diseases, directing genetic testing.<ref name="Tasca2014MRIUpperGirdle" /><ref name="Gerevini2016MRIWholeBody" />

===Differential diagnosis===
Included in the [[differential diagnosis]] of FSHD are [[limb-girdle muscular dystrophy]] (especially [[calpainopathy]]),<ref name="Wagner2019Review" /> scapuloperoneal myopathy,<ref name="Preston2020GeneReviews">{{cite journal |last1=Preston |first1=MK |last2=Tawil |first2=R |last3=Wang |first3=LH |last4=Adam |first4=MP |last5=Ardinger |first5=HH |last6=Pagon |first6=RA |last7=Wallace |first7=SE |last8=Bean |first8=LJH |last9=Mirzaa |first9=G |last10=Amemiya |first10=A |title=Facioscapulohumeral Muscular Dystrophy |date=1993 |pmid=20301616 }}</ref> [[mitochondrial myopathy]],<ref name="Wagner2019Review" /> [[Pompe disease]],<ref name="Wagner2019Review" /> and [[polymyositis]].<ref name="Wagner2019Review" /> Calpainopathy and scapuloperoneal myopathy, like FSHD, present with scapular winging.<ref name="Preston2020GeneReviews" /> Features that suggest FSHD are facial weakness, asymmetric weakness, and lack of benefit from immunosuppression medications.<ref name="Wagner2019Review" /> Features the suggest an alternative diagnosis are [[contractures]], respiratory insufficiency, weakness of muscles controlling eye movement, and [[Bulbar palsy|weakness of the tongue or throat]].<ref name="Tawil2006Review" />

== Management ==
No pharmacologic treatment has proven to significantly slow progression of weakness or meaningfully improve strength.<ref name="Tawil2015Guidelines">{{cite journal |last1=Tawil |first1=R |last2=Kissel |first2=JT |last3=Heatwole |first3=C |last4=Pandya |first4=S |last5=Gronseth |first5=G |last6=Benatar |first6=M |last7=Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of |first7=Neurology. |last8=Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic |first8=Medicine. |title=Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. |journal=Neurology |date=28 July 2015 |volume=85 |issue=4 |pages=357–64 |doi=10.1212/WNL.0000000000001783 |pmid=26215877|pmc=4520817 }}</ref><ref name="Wagner2019Review" /><ref name="Mul2022Review" />

===Screening and monitoring of complications===
The [[American Academy of Neurology]] (AAN) recommends several medical tests to detect complications of FSHD.<ref name="Tawil2015Guidelines" /> A dilated [[eye exam]] to look for retinal abnormalities is recommended in those newly diagnosed with FSHD; for those with large D4Z4 deletions, an evaluation by a retinal specialist is recommended yearly.<ref name="Tawil2010CareStandards">{{cite journal |last1=Tawil |first1=R |last2=van der Maarel |first2=S |last3=Padberg |first3=GW |last4=van Engelen |first4=BG |s2cid=18448196 |title=171st ENMC international workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. |journal=Neuromuscular Disorders |date=July 2010 |volume=20 |issue=7 |pages=471–5 |doi=10.1016/j.nmd.2010.04.007 |pmid=20554202}}</ref><ref name="Wagner2019Review" /> A hearing test is recommended for individuals with early-onset FSHD prior to starting school, or for any other FSHD-affected individual with symptoms of hearing loss.<ref name="Tawil2010CareStandards" /><ref name="Wagner2019Review" /> [[Pulmonary function testing]] (PFT) is recommended in those newly diagnosed to establish baseline pulmonary function,<ref name="Wagner2019Review" /> and recurrently for those with pulmonary insufficiency symptoms or risks.<ref name="Tawil2010CareStandards" /><ref name="Wagner2019Review" /> Routine screening for heart conditions, such as through an [[electrocardiogram]] (EKG) or [[echocardiogram]] (echo), is considered unnecessary in those without symptoms of heart disease.<ref name="Tawil2015Guidelines" />

===Physical and occupational therapy===
[[Aerobic exercise]] has been shown to reduce chronic fatigue and decelerate fatty infiltration of muscle in FSHD.<ref name="FSHD CBT & AA on chronic fatigue">{{cite journal |last1=Voet |first1=N |last2=Bleijenberg |first2=G |last3=Hendriks |first3=J |last4=de Groot |first4=I |last5=Padberg |first5=G |last6=van Engelen |first6=B |last7=Geurts |first7=A |s2cid=25382403 |title=Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT. |journal=Neurology |date=18 November 2014 |volume=83 |issue=21 |pages=1914–22 |doi=10.1212/WNL.0000000000001008 |pmid=25339206}}</ref><ref name="FSHD CBT & AA on fatty infiltration">{{cite journal |last1=Janssen |first1=B |last2=Voet |first2=N |last3=Geurts |first3=A |last4=van Engelen |first4=B |last5=Heerschap |first5=A |s2cid=11617226 |title=Quantitative MRI reveals decelerated fatty infiltration in muscles of active FSHD patients. |journal=Neurology |date=3 May 2016 |volume=86 |issue=18 |pages=1700–7 |doi=10.1212/WNL.0000000000002640 |pmid=27037227}}</ref> Physical activity in general might slow disease progression in the legs.<ref name="Mul2022Review" /> The AAN recommends that people with FSHD engage in low-intensity aerobic exercise to promote energy levels, muscle health, and bone health.<ref name="Wagner2019Review" /> Moderate-intensity strength training appears to do no harm, although it has not been shown to be beneficial.<ref>{{Cite journal|last1=Voet|first1=Nicoline Bm|last2=van der Kooi|first2=Elly L.|last3=van Engelen|first3=Baziel Gm|last4=Geurts|first4=Alexander Ch|date=6 December 2019|title=Strength training and aerobic exercise training for muscle disease|journal=The Cochrane Database of Systematic Reviews|volume=2019|issue=12|pages=CD003907|doi=10.1002/14651858.CD003907.pub5|issn=1469-493X|pmc=6953420|pmid=31808555}}</ref> [[Physical therapy]] can address specific symptoms; there is no standardized protocol for FSHD. Anecdotal reports suggest that appropriately applied [[kinesiology tape]] can reduce pain.<ref name="Tawil2016Workshop">{{cite journal |last1=Tawil |first1=R |last2=Mah |first2=JK |last3=Baker |first3=S |last4=Wagner |first4=KR |last5=Ryan |first5=MM |last6=Sydney Workshop |first6=Participants. |title=Clinical practice considerations in facioscapulohumeral muscular dystrophy Sydney, Australia, 21 September 2015. |journal=Neuromuscular Disorders |date=July 2016 |volume=26 |issue=7 |pages=462–71 |doi=10.1016/j.nmd.2016.03.007 |pmid=27185458|doi-access=free }}</ref> [[Occupational therapy]] can be used for training in [[activities of daily living]] (ADLs) and to help adapt to new [[assistive technology|assistive devices]]. [[Cognitive behavioral therapy]] (CBT) has been shown to reduce chronic fatigue in FSHD, and it also decelerates fatty infiltration of muscle when directed towards increasing daily activity.<ref name="FSHD CBT & AA on chronic fatigue" /><ref name="FSHD CBT & AA on fatty infiltration" />

Braces are often used to address muscle weakness. Scapular bracing can improve scapular positioning, which improves shoulder function, although it is often deemed as ineffective or impractical.<ref name="Rochester2019webpageSummary">{{cite web |title=Information for Patients and Families - The Richard Fields Center for FSH Dystrophy (FSHD) & Neuromuscular Research - University of Rochester Medical Center |url=https://www.urmc.rochester.edu/neurology/fields-center/patients.aspx |website=www.urmc.rochester.edu |access-date=14 April 2020 |archive-url=https://web.archive.org/web/20191114090054/https://www.urmc.rochester.edu/neurology/fields-center/patients.aspx |archive-date=14 November 2019}}</ref> [[Orthotics#Ankle–foot orthosis (AFO)|Ankle-foot orthoses]] can improve walking, balance, and quality of life.<ref>{{cite journal |last1=Aprile |first1=I |last2=Bordieri |first2=C |last3=Gilardi |first3=A |last4=Lainieri Milazzo |first4=M |last5=Russo |first5=G |last6=De Santis |first6=F |last7=Frusciante |first7=R |last8=Iannaccone |first8=E |last9=Erra |first9=C |last10=Ricci |first10=E |last11=Padua |first11=L |title=Balance and walking involvement in facioscapulohumeral dystrophy: a pilot study on the effects of custom lower limb orthoses |journal=European Journal of Physical and Rehabilitation Medicine |date=April 2013 |volume=49 |issue=2 |pages=169–78 |pmid=23138679}}</ref>

===Pharmacologic management===
No pharmaceuticals have definitively proven effective for altering the disease course.<ref name="Tawil2015Guidelines" /> Although a few pharmaceuticals have shown improved muscle mass in limited respects, they did not improve quality of life, and the AAN recommends against their use for FSHD.<ref name="Tawil2015Guidelines" />

===Reconstructive surgery===
Scapular winging is amenable to surgical correction, namely operative scapular fixation. Scapular fixation is restriction and stabilization of the position of the scapula, putting it in closer apposition to the rib cage and reducing winging. Absolute restriction of scapular motion by fixation of the scapula to the ribs is most commonly reported.<ref name="Orrell2010FixationReview" /> This procedure often involves inducing bony fusion, called [[arthrodesis]], between the scapula and ribs. Names for this include scapulothoracic fusion, scapular fusion, and scapulodesis. This procedure increases arm active [[range of motion]], improves arm function, decreases pain, and improves cosmetic appearance.<ref>{{cite journal |last1=Demirhan |first1=Mehmet |last2=Uysal |first2=Ozgur |last3=Atalar |first3=Ata Can |last4=Kilicoglu |first4=Onder |last5=Serdaroglu |first5=Piraye |title=Scapulothoracic Arthrodesis in Facioscapulohumeral Dystrophy with Multifilament Cable |journal=Clinical Orthopaedics and Related Research |date=31 March 2009 |volume=467 |issue=8 |pages=2090–2097 |doi=10.1007/s11999-009-0815-9|pmid=19333668 |pmc=2706357 }}</ref><ref name="Romeo">{{cite journal |last1=DeFranco |first1=Michael J. |last2=Nho |first2=Shane |last3=Romeo |first3=Anthony A. |s2cid=27456684 |title=Scapulothoracic Fusion |journal=Journal of the American Academy of Orthopaedic Surgeons |date=April 2010 |volume=18 |issue=4 |pages=236–42 |doi=10.5435/00124635-201004000-00006 |pmid=20357232 }}</ref> Active range of motion of the arm increases most in the setting of severe scapular winging with an unaffected [[deltoid muscle]];<ref name="Eren2020ScapFusionStaging">{{cite journal |last1=Eren |first1=İlker |last2=Birsel |first2=Olgar |last3=Öztop Çakmak |first3=Özgür |last4=Aslanger |first4=Ayça |last5=Gürsoy Özdemir |first5=Yasemin |last6=Eraslan |first6=Serpil |last7=Kayserili |first7=Hülya |last8=Oflazer |first8=Piraye |last9=Demirhan |first9=Mehmet |title=A novel shoulder disability staging system for scapulothoracic arthrodesis in patients with facioscapulohumeral dystrophy |journal=Orthopaedics & Traumatology: Surgery & Research |date=May 2020 |volume=106 |issue=4 |pages=701–707 |doi=10.1016/j.otsr.2020.03.002|pmid=32430271 |doi-access=free }}</ref> however, passive range of motion decreases. In other words, the patient gains the ability to slowly raise their arms to 90+ degrees, but they lose the ability to "throw" their arm up to a full 180 degrees.<ref name="Wagner2019Review" /> The AAN states that scapular fixation can be offered cautiously to select patients after balancing these benefits against the adverse consequences of surgery and prolonged immobilization.<ref name="Tawil2015Guidelines" /><ref name="Mul2022Review" />

Another form of operative scapular fixation is scapulopexy. "Scapulo-" refers to the scapula bone, and "-pexy" is derived from the Greek root "to bind." Some versions of scapulopexy accomplish essentially the same result as scapulothoracic fusion, but instead of inducing bony fusion, the scapula is secured to the ribs with only wire, tendon grafts, or other material. Some versions of scapulopexy do not completely restrict scapular motion, examples including [[tether]]ing the scapula to the ribs, vertebrae, or other scapula.<ref name="Orrell2010FixationReview">{{cite journal |last1=Orrell |first1=Richard W |last2=Copeland |first2=Stephen |last3=Rose |first3=Michael R |title=Scapular fixation in muscular dystrophy |journal=Cochrane Database of Systematic Reviews |date=20 January 2010 |volume=2010 |issue=1 |pages=CD003278 |doi=10.1002/14651858.CD003278.pub2 |pmid=20091543|pmc=7144827 }}</ref><ref name="Heller1996Interscapular_scapulopexy">{{cite journal |last1=Heller |first1=KD |last2=Prescher |first2=A |last3=Forst |first3=J |last4=Stadtmüller |first4=A |last5=Forst |first5=R |title=Anatomo-experimental study for lace fixation of winged scapula in muscular dystrophy. |journal=Surgical and Radiologic Anatomy |date=1996 |volume=18 |issue=2 |pages=75–9 |doi=10.1007/BF01795222 |pmid=8782311|s2cid=20162712 }}</ref> Scapulopexy is considered to be more conservative than scapulothoracic fusion, with reduced recovery time and less effect on breathing.<ref name="Orrell2010FixationReview" /> However, they also seem more susceptible to long-term failure.<ref name="Orrell2010FixationReview" /> Another form of scapular fixation, although not commonly done in FSHD, is [[tendon transfer]], which involves surgically rearranging the attachments of muscles to bone.<ref name="Orrell2010FixationReview" /><ref>{{cite book |last1=Abrams |first1=Jeffrey S. |last2=Bell |first2=Robert H. |last3=Tokish |first3=John M. |title=ADVANCED RECONSTRUCTION OF SHOULDER |year=2018 |publisher=AMER ACAD OF ORTHOPAEDIC |isbn=9781975123475}}</ref><ref name="Intro2004Textbook">{{cite book |last1=Upadhyaya |first1=Meena |last2=Cooper |first2=David N. |editor1-last=Upadhyaya |editor1-first=Meena |editor2-last=Cooper |editor2-first=David N. |title=FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology |date=2004 |publisher=BIOS Scientific Publishers |isbn=1-85996-244-0 |chapter=Introduction and overview of FSHD}}</ref> Examples include pectoralis major transfer and the [[Eden-Lange procedure]].

Various other surgical reconstructions have been described. Upper eyelid gold implants have been used for those unable to close their eyes.<ref name="Sansone1997goldImplants">{{cite journal |last1=Sansone |first1=V |last2=Boynton |first2=J |last3=Palenski |first3=C |title=Use of gold weights to correct lagophthalmos in neuromuscular disease. |journal=Neurology |date=June 1997 |volume=48 |issue=6 |pages=1500–3 |doi=10.1212/wnl.48.6.1500 |pmid=9191754|hdl=2434/210652 |s2cid=16251273 |hdl-access=free }}</ref> Drooping lower lip has been addressed with plastic surgery.<ref name="Matsumoto2016LowerLipSurgery">{{cite journal |last1=Matsumoto |first1=M |last2=Onoda |first2=S |last3=Uehara |first3=H |last4=Miura |first4=Y |last5=Katayama |first5=Y |last6=Kimata |first6=Y |title=Correction of the Lower Lip With a Cartilage Graft and Lip Resection in Patients With Facioscapulohumeral Muscular Dystrophy. |journal=The Journal of Craniofacial Surgery |date=September 2016 |volume=27 |issue=6 |pages=1427–9 |doi=10.1097/SCS.0000000000002720 |pmid=27300465|s2cid=16343571 }}</ref> Select cases of foot drop can be surgically corrected with tendon transfer, in which the [[tibialis posterior muscle]] is repurposed as a [[tibialis anterior muscle]], a version of this being called the Bridle procedure.<ref>{{cite journal |last1=Krishnamurthy |first1=S |last2=Ibrahim |first2=M |title=Tendon Transfers in Foot Drop |journal=Indian Journal of Plastic Surgery |date=January 2019 |volume=52 |issue=1 |pages=100–108 |doi=10.1055/s-0039-1688105 |pmid=31456618|pmc=6664842 }}</ref><ref>{{cite book |last1=Chiodo |first1=Chris |last2=Bluman |first2=Eric M. |title=Tendon transfers in the foot and ankle |publisher=Saunders |isbn=9781455709243 |page=421 |url=https://books.google.com/books?id=tb5IqLsFnJUC&q=bridle%20procedure%20muscular%20dystrophy&pg=PP1 |access-date=1 January 2020|date=2011-10-21 }}</ref><ref name="Tawil2016Workshop" /> Severe scoliosis caused by FSHD can be corrected with [[spinal fusion]]; however, since scoliosis might be a compensatory change in response to muscle weakness, correction of spinal alignment can result in further impaired muscle function.

<gallery mode=packed heights="120px" caption="Scapular winging management">
File:FSHD Kinesiology Tape.png|Kinesiology tape applied across the scapulas.
File:Retraction brace FSHD white.png|A cloth brace to hold the scapulas in retraction to reduce shoulder symptoms, such as collarbone pain.
File:Before and after Scapula-to-scapula scapulopexy FSHD.png|Scapula-to-scapula scapulopexy, pre- and post-operation. The scapulas are tethered together into a retracted position with an [[Achilles tendon]] graft, which, in this case, rendered the rhomboid major muscles distinguishable.
</gallery>

== Prognosis ==
Genetics partially predicts prognosis.<ref name="Tawil2015Guidelines" /> Those with large D4Z4 repeat deletions (with a remaining D4Z4 repeat array size of 10-20 kbp, or 1-4 repeats) are more likely to have severe and early disease, as well as non-muscular symptoms.<ref name="Tawil2015Guidelines" /> Those who have the genetic mutations of both FSHD1 and FSHD2 are more likely to have severe disease.<ref name = "Sacconi2013SMCHD1Modify" /> It has also been observed that D4Z4 shortening is less and disease manifestation is milder when a prominent family history is present, as opposed to a new mutation.<ref name="FSHDTextbook2004_genotypePhenotypeCorrelations">{{cite book |last1=Lunt |first1=Peter |last2=Upadhyaya |first2=Meena |last3=Koch |first3=Manuela C. |editor1-last=Upadhyaya |editor1-first=Meena |editor2-last=Cooper |editor2-first=David N. |title=FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medidne and Molecular Cell Biology |date=2004 |publisher=BIOS Scientific Publishers Limited |page=157 |chapter=Genotype-phenotype relationships in FSHD}}</ref> In some large families, 30% of those with the mutation had no noticeable symptoms, and 30% of those with symptoms did not progress beyond facial and shoulder weakness.<ref name="Padberg2004Textbook" /> Women tend to develop symptoms later in life and have less severe disease courses.<ref name="Intro2004Textbook" />

Remaining variations in disease course are attributed to unknown environmental factors. A single study found that disease course is not worsened by tobacco smoking or alcohol consumption, common risk factors for other diseases.<ref name="Vincenten2021Smoking">{{cite journal |last1=Vincenten |first1=Sanne C.C. |last2=Mul |first2=Karlien |last3=Schreuder |first3=Tim H.A. |last4=Voermans |first4=Nicol C. |last5=Horlings |first5=Corinne G.C. |last6=van Engelen |first6=Baziel G.M. |title=nnExploring the influence of smoking and alcohol consumption on clinical severity in patients with facioscapulohumeral muscular dystrophy |journal=Neuromuscular Disorders |date=July 2021 |volume=31 |issue=9 |pages=824–828 |doi=10.1016/j.nmd.2021.07.005|issn=0960-8966|pmid=34407911 |doi-access=free |hdl=2066/239258 |hdl-access=free }}</ref>

===Pregnancy===
Pregnancy outcomes are overall good in mothers with FSHD; there is no difference in rate of [[preterm labor]], rate of [[miscarriage]], and infant outcomes.<ref name="Massey2022Pregnancy">{{cite journal |last1=Massey |first1=JM |last2=Gable |first2=KL |title=Neuromuscular Disorders and Pregnancy. |journal=Continuum (Minneapolis, Minn.) |date=1 February 2022 |volume=28 |issue=1 |pages=55–71 |doi=10.1212/CON.0000000000001069 |pmid=35133311|s2cid=246651681 }}</ref> However, weakness can increase the need for [[Vaginal delivery#Types of vaginal delivery|assisted delivery]].<ref name="Massey2022Pregnancy" />

A single review found that weakness worsens, without recovery, in 12% of mothers with FSHD during pregnancy, although this might be due to weight gain or [[deconditioning]].<ref name="Massey2022Pregnancy" />

== Epidemiology ==
The [[prevalence]] of FSHD ranges from 1 in 8,333 to 1 in 15,000.<ref name="Wagner2019Review" /> The Netherlands reports a prevalence of 1 in 8,333, after accounting for the undiagnosed.<ref name="Deenen2014Epidemiology">{{cite journal |vauthors=Deenen JC, Arnts H, van der Maarel SM, Padberg GW, Verschuuren JJ, Bakker E, Weinreich SS, Verbeek AL, van Engelen BG | year = 2014 | title = Population-based incidence and prevalence of facioscapulohumeral dystrophy | journal = Neurology | volume = 83 | issue = 12 | pages = 1056–9 | pmid = 25122204 | doi=10.1212/WNL.0000000000000797 | pmc=4166358}}</ref> The prevalence in the United States is commonly quoted as 1 in 15,000.<ref name="Statland and Tawil Review article 2016" />

After genetic testing became possible in 1992, average prevalence was found to be around 1 in 20,000, a large increase compared to before 1992.<ref>{{cite journal |last1=Deenen |first1=JC |last2=Horlings |first2=CG |last3=Verschuuren |first3=JJ |last4=Verbeek |first4=AL |last5=van Engelen |first5=BG |title=The Epidemiology of Neuromuscular Disorders: A Comprehensive Overview of the Literature. |journal=Journal of Neuromuscular Diseases |date=2015 |volume=2 |issue=1 |pages=73–85 |doi=10.3233/JND-140045 |pmid=28198707|doi-access=free }}</ref><ref name="Padberg2004Textbook">{{cite book |last1=Padberg |first1=George W. |editor1-last=Upadhyaya |editor1-first=Meena |editor2-last=Cooper |editor2-first=David N. |title=FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology |date=2004 |publisher=BIOS Scientific Publishers |isbn=1-85996-244-0 |chapter=Facioscapulohumeral muscular dystrophy: a clinician's experience}}</ref><ref name="Deenen2014Epidemiology" /> However, 1 in 20,000 is likely an underestimation, since many with FSHD have mild symptoms and are never diagnosed, or they are siblings of affected individuals and never seek definitive diagnosis.<ref name="Deenen2014Epidemiology" />

Race and ethnicity have not been shown to affect FSHD incidence or severity.<ref name="Statland and Tawil Review article 2016" />

Although the inheritance of FSHD shows no predilection for biological sex, the disease [[penetrance|manifests less often]] in women, and even when it manifests in women, they on average are less severely affected than affected males.<ref name="Statland and Tawil Review article 2016" /> [[Estrogen]] has been suspected to be a protective factor that accounts for this discrepancy. One study found that estrogen reduced ''DUX4'' activity.<ref>{{cite journal |last1=Teveroni |first1=E |last2=Pellegrino |first2=M |last3=Sacconi |first3=S |last4=Calandra |first4=P |last5=Cascino |first5=I |last6=Farioli-Vecchioli |first6=S |last7=Puma |first7=A |last8=Garibaldi |first8=M |last9=Morosetti |first9=R |last10=Tasca |first10=G |last11=Ricci |first11=E |last12=Trevisan |first12=CP |last13=Galluzzi |first13=G |last14=Pontecorvi |first14=A |last15=Crescenzi |first15=M |last16=Deidda |first16=G |last17=Moretti |first17=F |title=Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity. |journal=The Journal of Clinical Investigation |date=3 April 2017 |volume=127 |issue=4 |pages=1531–1545 |doi=10.1172/JCI89401 |pmid=28263188|pmc=5373881 }}</ref> However, another study found no association between disease severity and lifetime estrogen exposure in females. The same study found that disease progression was not different through periods of hormonal changes, such as [[menarche]], pregnancy, and [[menopause]].<ref>{{cite journal |last1=Mul |first1=K |last2=Horlings |first2=CGC |last3=Voermans |first3=NC |last4=Schreuder |first4=THA |last5=van Engelen |first5=BGM |title=Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy. |journal=Neuromuscular Disorders |date=June 2018 |volume=28 |issue=6 |pages=508–511 |doi=10.1016/j.nmd.2018.02.012 |pmid=29655530|doi-access=free |hdl=2066/194350 |hdl-access=free }}</ref>

==History==
The first description of a person with FSHD in medical literature appears in an autopsy report by [[Jean Cruveilhier]] in 1852.<ref name="Cruveilhier1852Firstdescription">{{cite journal |last1=Cruveilhiers |first1=J. |title=Mémoire sur la paralysie musculaire atrophique |journal=Bulletins de l'Académie de Médecine |date=1852–1853 |volume=18 |pages=490–502, 546–583}}</ref><ref name="Rogers2004TextbookHistory">{{cite book |last1=Rogers |first1=Mark T. |editor1-last=Upadhyaya |editor1-first=Meena |editor2-last=Cooper |editor2-first=David N. |title=FSHD facioscapulohumeral muscular dystrophy : clinical medicine and molecular cell biology |date=2004 |publisher=BIOS Scientific Publishers |isbn=1-85996-244-0 |chapter=Facioscapulohumeral muscular dystrophy: historical background and literature review}}</ref> In 1868, Duchenne published his seminal work on [[Duchenne muscular dystrophy]], and as part of its [[differential diagnosis|differential]] was a description of FSHD.<ref name="Duchenne1868Seminal">{{cite journal |last1=Duchenne |first1=Guillaume-Benjamin |title=De la paralysie musculaire pseudo-hypertrophique, ou paralysie myo-sclérosique |journal=Arch. Gen. Med. |volume=11
|pages=5–25, 179–209, 305–321, 421–443, 552–588|date=1868 |url=https://gallica.bnf.fr/ark:/12148/bpt6k851346p.image |access-date=18 May 2020 |location=Bibliothèque nationale de France |language=fr}}</ref><ref name="Rogers2004TextbookHistory"/> First in 1874, then with a more commonly cited publication in 1884, and again with pictures in 1885, the French physicians [[Louis Landouzy]] and [[Joseph Dejerine]] published details of the disease, recognizing it as a distinct clinical entity, and thus FSHD is sometimes referred to as '''Landouzy Dejerine disease.'''<ref name="Landouzy1885Review">{{cite journal |last1=Landouzy |first1=L. |last2=Dejerine |first2=J. |editor1-last=Landouzy |editor1-first=L. |editor2-last=Lépine |editor2-first=R. |title=De la myopathie atrophique progressive (myopathie sans neuropathie débutant d'ordinaire dans l'enfance par la face) |journal=Revue de Médecine |date=1885 |volume=5 |pages=253–366 |url=https://books.google.com/books?id=2fdXAAAAMAAJ&q=De%20la%20myopathie%20atrophique%20progressive%20Revue%20de%20medecine&pg=PA253 |access-date=19 May 2020 |publisher=Felix Alcan |language=fr}}</ref><ref name="Rogers2004TextbookHistory"/> In their paper of 1886, Landouzy and Dejerine drew attention to the familial nature of the disorder and mentioned that four generations were affected in the kindred that they had investigated.<ref name="whonamedit">[http://www.whonamedit.com/synd.cfm/1900.html Landouzy-Dejerine syndrome], whonamedit.com, date accessed March 11, 2007</ref> Formal definition of FSHD's clinical features did not occur until 1952 when a large Utah family with FSHD was studied. Beginning about 1980 an increasing interest in FSHD led to increased 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.<ref name="Quest March–April 2007">[https://web.archive.org/web/20070919140717/http://www.mdaquest-digital.com/mdaquest/20070304/?pg=28 Impossible Things: Through the looking glass with FSH Dystrophy Researchers], Margaret Wahl, [[Muscular Dystrophy Association|MDA]], Quest magazine, Vol 14, No 2, March–April 2007</ref>

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.<ref name="Tawil2014PathophysConsensus">{{Cite journal|title = Facioscapulohumeral dystrophy: the path to consensus on pathophysiology|last1 = Tawil|first1 = Rabi|date = 10 June 2014|journal = Skeletal Muscle|doi = 10.1186/2044-5040-4-12|pmid = 24940479|pmc = 4060068|last2 = van der Maarel|first2 = SM|last3 = Tapscott|first3 = SJ|volume = 4|page = 12|issue=1 | doi-access=free }}
</ref>

Alternate and historical names for FSHD include the following:
* facioscapulohumeral disease<ref name="Padberg1982thesis" />
* faciohumeroscapular {{citation needed|date=October 2020}}
* Landouzy-Dejerine disease<ref name="Padberg1982thesis" /> (or 'syndrome'<ref name="whonamedit" /> or 'type of muscular dystrophy'<ref name="Padberg1982thesis" />)
* Erb-Landouzy-Dejerine syndrome{{citation needed|date=October 2020}}

=== Chronology of important FSHD-related genetic research ===
<!-- To edit this table with visual editor, comment out the div col templates at the beginning and end of table -->
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{| class="wikitable"
|-
|valign="top"|'''1861'''
|Person with muscular dystrophy depicted by Duchenne. Based on the muscles involved, this person could have had FSHD.[[File:Possible_FSHD_described_by_Duchenne.png|237x237px|center|frameless]]
|-
|valign="top"|'''1884'''
| Landouzy 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.<ref>{{Cite journal|title = De la myopathie atrophique progressive (myopathie héréditaire, débutant dans l'enfance par la face, sans altération du système nerveux)|last1 = Landouzy|date = 1884|journal = Comptes Rendus de l'Académie des Sciences|last2 = Dejerine|volume = 98|pages = 53–55}}</ref>
{{multiple image
 | align = center
 | direction = horizontal
 | total_width = 400
 | header = Two brothers with FSHD followed by Landouzy and Dejerine
 | image1 = Landouzy-Dejerine FSHD Georges Profile and Back.png
 | alt1 = 
 | caption1 = Photograph of one brother at age 21. The right scapula is protracted, downwardly rotated, and laterally displaced.
 | image2 = Landouzy-Dejerine FSHD Léon.png
 | caption2 = Drawing of another brother at age 17. Visible is lumbar hyperlordosis. The upper arm and pectoral muscles appear atrophied.}}
|-
|valign="top"|'''1886'''
|Landouzy and Dejerine describe progressive muscular atrophy of the scapulo-humeral type.<ref>{{Cite journal|title = Contribution à l'étude de la myopathie atrophique progressive (myopathie atrophique progressive, à type scapulo-huméral)|last1 = Landouzy|date = 1886|journal = Comptes Rendus des Séances de la Société de Biologie|volume = 38|pages = 478–481|last2 = Dejerine}}</ref>
|-
|valign="top"|'''1950'''
|Tyler 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''.''<ref>{{Cite journal|title = Studies in disorders of muscle. II Clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family|last1 = Tyler|first1 = Frank|date = April 1950|journal = Annals of Internal Medicine|doi = 10.7326/0003-4819-32-4-640|pmid = 15411118|last2 = Stephens|volume = 32|issue = 4|pages = 640–660|first2 = FE}}</ref>
|-
|valign="top"|'''1982'''
|Padberg provides the first linkage studies to determine the [[Locus (genetics)|genetic locus]] for FSHD in his seminal thesis "Facioscapulohumeral disease."<ref name="Padberg1982thesis">{{Cite thesis|url =https://openaccess.leidenuniv.nl/handle/1887/25818 |title = Facioscapulohumeral disease |last = Padberg|first = GW|date = 1982-10-13|publisher= Leiden University}}</ref>
|-
|valign="top"|'''1987'''
|The complete sequence of the [[Dystrophin]] gene ([[Duchenne muscular dystrophy|Duchenne's MD]]) is determined.<ref>{{Cite journal|url = http://www.cell.com/cell/abstract/0092-8674(87)90504-6?cc=y=?cc=y=|title = Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals|last1 = Koenig|first1 = M|date = Jul 31, 1987|journal = Cell|doi = 10.1016/0092-8674(87)90504-6|pmid = 3607877|last2 = Hoffman|volume = 50|issue = 3|pages = 509–517|first2 = EP|last3 = Bertelson|first3 = CJ|last4 = Monaco|first4 = AP|last5 = Feener|first5 = C|last6 = Kunkel|first6 = LM|s2cid = 35668717}}</ref>
|-
|valign="top"|'''1991'''
|The genetic defect in FSHD is linked to a region (4q35) near the tip of the long arm of [[Chromosome 4 (human)|chromosome 4]].<ref>{{Cite journal|title = Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization|last1 = Wijmenga|first1 = C|date = April 1991|journal = Genomics|doi = 10.1016/0888-7543(91)90348-I|pmid = 2037288|volume = 9|issue = 4|pages = 570–575|last2 = Padberg|first2 = GW|last3 = Moerer|first3 = P|display-authors=etal}}</ref>
|-
|valign="top"|'''1992'''
|FSHD, in both familial and [[De novo mutation|de novo cases]], is found to be linked to a recombination event that reduces the size of 4q ''[[EcoR1|Eco]]''[[EcoR1|R1]] fragment to < 28 kb (50–300 kb normally).<ref name="Wijmenga1992p13E-11">{{Cite journal|title = Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy|last1 = Wijmenga|first1 = C|date = Sep 1992|journal = Nature Genetics|doi = 10.1038/ng0992-26|pmid = 1363881|volume = 2|pages = 26–30|last2 = Hewitt|first2 = JE|last3 = Sandkuijl|first3 = LA|s2cid = 21940164|issue=1|display-authors=etal}}</ref>
|-
|valign="top"|'''1993'''
|4q ''Eco''R1 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.<ref name="vanDeutekom1993D4Z4">{{Cite journal|title = FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit|last1 = van Deutekom|first1 = JC|date = Dec 1993|journal = Human Molecular Genetics|doi = 10.1093/hmg/2.12.2037|pmid = 8111371|volume = 2|pages = 2037–2042|last2 = Wijmenga|first2 = C|last3 = van Tienhoven|first3 = EA|issue=12|display-authors=etal}}</ref>
A study of seven families with FSHD reveals evidence of [[genetic heterogeneity]] in FSHD.<ref>{{Cite journal|title = Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)|last1 = Gilbert|first1 = JR|date = Aug 1993|journal = American Journal of Human Genetics|volume = 53|pages = 401–408|last2 = Stajich|first2 = JM|last3 = Wall|first3 = S|pmc=1682358|pmid=8328457|issue=2|display-authors=etal}}</ref>
|-
|valign="top"|'''1994'''
|The [[Heterochromatin|heterochromatic]] structure of 4q35 is recognized as a factor that may affect the expression of FSHD, possibly via [[position-effect variegation]]''.''<ref name="Winokur1994chromatin">{{Cite journal|title = The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: implications for a role of chromatin structure in the pathogenesis of the disease|last1 = Winokur|first1 = ST|date = May 1994|journal = Chromosome Research|doi = 10.1007/bf01553323|pmid = 8069466|last2 = Bengtsson|volume = 2|issue = 3|pages = 225–234|first2 = U|last3 = Feddersen|first3 = J|s2cid = 6933736|display-authors=etal}}</ref>

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.<ref name="Winokur1994chromatin" /><ref>{{Cite journal|title = Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy|last1 = Hewitt|first1 = JE|date = Aug 1994|journal = Human Molecular Genetics|doi = 10.1093/hmg/3.8.1287|pmid = 7987304|last2 = Lyle|volume = 3|pages = 1287–1295|first2 = R|last3 = Clark|first3 = LN|issue=8|display-authors=etal}}</ref>
|-
|valign="top"|'''1995'''
|The terms FSHD1A and FSHD1B are introduced to describe 4q-linked and non-4q-linked forms of the disease.<ref>{{Cite journal|title = Exclusion mapping of chromosomal regions which cross hybridise to FSHD1A associated markers in FSHD1B|last1 = Gilbert|first1 = JR|date = Oct 1995|journal = Journal of Medical Genetics|doi = 10.1136/jmg.32.10.770|pmid = 8558552|volume = 32|pages = 770–773|last2 = Speer|first2 = MC|last3 = Stajich|first3 = J|issue=10|display-authors=etal|pmc = 1051697}}</ref>
|-
|valign="top"|'''1996'''
|FSHD Region Gene1 ([[FRG1]]) is discovered 100 kb proximal to D4Z4.<ref>{{Cite journal|title = Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35|last1 = van Deutekom|first1 = JC|date = May 1996|journal = Human Molecular Genetics|doi = 10.1093/hmg/5.5.581|last2 = Lemmers|first2 = RJ|volume = 5|pages = 581–590|last3 = Grewal|first3 = PK|issue=5|pmid=8733123|display-authors=etal|doi-access = free}}</ref>
|-
|valign="top"|'''1998'''
|Mono[[zygote|zygotic]] twins with vastly different clinical expression of FSHD are described.<ref name="Tupler1998Twins">{{Cite journal|title = Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression|last1 = Tupler|first1 = R|date = Sep 1998|journal = Journal of Medical Genetics|doi = 10.1136/jmg.35.9.778|pmid = 9733041|volume = 35|pages = 778–783|last2 = Barbierato|first2 = L|issue=9|display-authors=etal|pmc = 1051435}}</ref>
|-
|valign="top"|'''1999'''
|Complete 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<ref name="Kowaljow2007DUX4Apoptosis">{{Cite journal|url = http://www.nmd-journal.com/article/S0960-8966(07)00121-6/abstract|title = The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein|last1 = Kowaljow|first1 = V|date = Aug 2007|journal = Neuromuscular Disorders|doi = 10.1016/j.nmd.2007.04.002|pmid = 17588759|last2 = Marcowycz|first2 = A|volume = 17|issue = 8|pages = 611–623|last3 = Ansseau|first3 = E|s2cid = 25926418|display-authors=etal}}</ref>), given the name ''[[DUX4]]''.<ref>{{Cite journal|title = Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element|last1 = Gabriels|first1 = J|date = Aug 5, 1999|journal = Gene|doi = 10.1016/S0378-1119(99)00267-X|last2 = Beckers|first2 = MC|volume = 236|pages = 25–32|last3 = Ding|first3 = H|pmid=10433963|issue=1|display-authors=etal}}</ref>
|-
|valign="top"|'''2001'''
|Investigators assessed the [[methylation]] state ([[heterochromatin]] is more highly methylated than [[euchromatin]]) of DNA in 4q35 D4Z4. An examination of ''Sma''I, ''Mlu''I, ''Sac''II, and ''Eag''I [[restriction fragment]]s 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 (human)|chromosome 10]]. However, in all instances, D4Z4 from sperm was hypomethylated relative to D4Z4 from [[Somatic (biology)|somatic]] tissues.<ref>{{Cite journal|title = Methylation of the FSHD syndrome-linked subtelomeric repeat in normal and FSHD cell cultures and tissues|last1 = Tsien|first1 = F|date = Nov 2001|journal = Molecular Genetics and Metabolism|doi = 10.1006/mgme.2001.3219|last2 = Sun|first2 = B|volume = 74|issue = 3|pages = 322–331|last3 = Hopkins|first3 = NE|display-authors=etal|pmid=11708861}}</ref>
|-
|valign="top"|'''2002'''
|A polymorphic segment of 10 kb directly distal to D4Z4 is found to exist in two [[allele|allelic]] forms, designated 4qA and 4qB. FSHD1 is associated solely with the 4qA allele.<ref>{{Cite journal|title = Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere|last1 = Lemmers|first1 = RJ|date = Oct 2002|journal = Nature Genetics|doi = 10.1038/ng999|last2 = de Kievit|first2 = P|volume = 32|pages = 235–236|last3 = Sandkuijl|first3 = L|s2cid = 28107557|issue=2|display-authors=etal|pmid=12355084}}</ref>

Three genes (FRG1, [[FRG2]], [[ANT1 gene|ANT1]]) located in the region just [[Centromere|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.<ref>{{Cite journal|title = Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle|last1 = Gabellini|first1 = D|date = Aug 9, 2002|journal = Cell|doi = 10.1016/S0092-8674(02)00826-7|pmid = 12176321|volume = 110|issue = 3|pages = 339–348|last2 = Green|first2 = MR|last3 = Tupler|first3 = R|s2cid = 16396883|doi-access = free|hdl = 11380/459475|hdl-access = free}}</ref>
|-
|valign="top"|'''2003'''
|A further examination of DNA methylation in different 4q35 D4Z4 restriction fragments (''BsaA''I and ''Fse''I) showed significant hypomethylation at both sites for individuals with FSHD1, non-FSHD-expressing gene carriers, and individuals with [[Phenotype|phenotypic]] FSHD relative to unaffected controls.<ref>{{Cite journal|title = Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy|last1 = van Overveld|first1 = PG|date = Dec 2003|journal = Nature Genetics|doi = 10.1038/ng1262|volume = 35|pages = 315–317|last2 = Lemmers|first2 = RJ|last3 = Sandkuijl|first3 = LA|s2cid = 28696708|issue=4|display-authors=etal|pmid=14634647}}</ref>
|-
|valign="top"|'''2004'''
|Contraction of the D4Z4 region on the 4qB allele to < 38 kb does not cause FSHD.<ref>{{Cite journal|url= |title = Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy|last1 = Lemmers|first1 = RJ|date = Dec 2004|journal = The American Journal of Human Genetics|doi = 10.1086/426035|volume = 75|issue = 6|pages = 1124–1130|last2 = Wohlgemuth|first2 = M|last3 = Frants|first3 = RR|last4 = Padberg|first4 = GW|last5 = Morava|first5 = E|last6 = van der Maarel|first6 = SM|pmid=15467981|pmc=1182148}}</ref>
|-
|valign="top"|'''2006'''
|Transgenic mice overexpressing FRG1 are shown to develop severe myopathy.<ref>{{Cite journal|title = Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1|last1 = Gabellini|first1 = D|date = Feb 23, 2006|journal = Nature|doi = 10.1038/nature04422|volume = 439|pages = 973–977|last2 = D'Antona|first2 = G|last3 = Moggio|first3 = M|s2cid = 4427465|issue=7079|pmid=16341202|display-authors=etal|bibcode = 2006Natur.439..973G}}</ref>
|-
|valign="top"|'''2007'''
|The 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.<ref>{{Cite journal|url= |title = Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy|last1 = Clapp|first1 = J|date = Aug 2007|journal = The American Journal of Human Genetics|doi = 10.1086/519311|pmid = 17668377|pmc = 1950813|volume = 81|issue = 2|pages = 264–279|last2 = Mitchell|first2 = LM|last3 = Bolland|first3 = DJ|display-authors=etal}}</ref>

Researchers identify DUX4 mRNA in primary FSHD [[myoblasts]] and identify in D4Z4-transfected cells a DUX4 protein, the overexpression of which induces cell death.<ref name="Kowaljow2007DUX4Apoptosis"/>

DUX4 [[Messenger RNA|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]]).''<ref>{{Cite journal|title = DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1|last1 = Dixit|first1 = M|date = Nov 13, 2007|journal = Proceedings of the National Academy of Sciences of the USA|doi = 10.1073/pnas.0708659104|last2 = Ansseau|first2 = E|volume = 104|pages = 18157–18162|last3 = Tassin|first3 = A|issue=46|pmid=17984056|pmc=2084313|display-authors=etal|bibcode = 2007PNAS..10418157D|doi-access = free}}</ref>
|-
|valign="top"|'''2009'''
|The 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.<ref>{{Cite journal|title = Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD|last1 = de Greef|first1 = JC|date = Oct 2009|journal = Human Mutation|doi = 10.1002/humu.21091|last2 = Lemmers|first2 = RJ|volume = 30|issue = 10|pages = 1449–1459|last3 = van Engelen|first3 = BG|display-authors=etal|pmid=19728363|citeseerx = 10.1.1.325.8388|s2cid = 14517505}}</ref>

Splicing and cleavage of the terminal (most [[Telomere|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 RNA]]s, [[antisense RNA]]s and capped mRNAs as new candidates for the [[pathophysiology]] of FSHD.<ref>{{Cite journal|url= |title = RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy|last1 = Snider|first1 = L|date = Jul 1, 2009|journal = Human Molecular Genetics|doi = 10.1093/hmg/ddp180|last2 = Asawachaicharn|first2 = A|volume = 18|pages = 2414–2430|last3 = Tyler|first3 = AE|issue=13|display-authors=etal|pmid=19359275|pmc=2694690}}</ref>

Mechanism proposed of DBE-T (D4Z4 Regulatory Element transcript) leading to de-repression of 4q35 genes.<ref name = Cabianca2012DBE-T />
|-
|valign="top"|'''2010'''
|A 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.<ref name="Unifying" /> Several organizations including ''The New York Times'' highlighted this research<ref name="NYTJunkDNA">{{cite news|last=Kolata|first=Gina|title=Reanimated 'Junk' DNA Is Found to Cause Disease|url=https://www.nytimes.com/2010/08/20/science/20gene.html|access-date=29 August 2010|newspaper=[[The New York Times]]|date=19 August 2010}}</ref> (See [https://web.archive.org/web/20100823233602/http://www.fshsociety.org/pages/resMilestones.html FSHD Society]).
Dr. [[Francis Collins (geneticist)|Francis Collins]], who oversaw the first sequencing of the [[Human Genome]] with the [[National Institutes of Health]] stated:<ref name="NYTJunkDNA" />
{{blockquote|"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:<ref>{{Cite web |date=2010-08-23 |title=FSH Society |url=http://www.fshsociety.org/pages/resMilestones.html |access-date=2024-02-21 |archive-url=https://web.archive.org/web/20100823233602/http://www.fshsociety.org/pages/resMilestones.html |archive-date=2010-08-23 }}</ref>
{{blockquote|"This is a long-sought explanation of the exact biological workings of [FSHD]" }}
The MDA stated that:{{Citation needed|date=October 2020}}
{{blockquote|"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{{Citation needed|date=October 2020}}
{{blockquote|"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.<ref name="Snider2010retrotransposed"/>
|-
|valign="top"|'''2012'''
|Some 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.<ref name="Lemmers 1370–1374"/>

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.<ref>{{Cite journal|url= |title = Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy|last1 = Scionti|first1 = I|date = Apr 6, 2012|journal = The American Journal of Human Genetics|doi = 10.1016/j.ajhg.2012.02.019|volume = 90|issue = 4|pages = 628–635|last2 = Greco|first2 = F|last3 = Ricci|first3 = G|display-authors=etal|pmid=22482803|pmc=3322229}}</ref>

When expressed in primary myoblasts, DUX4-fl acted as a transcriptional activator, producing a > 3-fold change in the expression of 710 genes.<ref>{{Cite journal|url= |title = DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy|last1 = Geng|first1 = LN|date = Jan 17, 2012|journal = Developmental Cell|doi = 10.1016/j.devcel.2011.11.013|volume = 22|issue = 1|pages = 38–51|last2 = Yao|first2 = Z|last3 = Snider|first3 = L|display-authors=etal|pmid=22209328|pmc=3264808}}</ref> 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, ''pe''r se, is not sufficient to cause pathology, and that additional modifiers are determinants of disease progression.<ref>{{Cite journal|url= |title = Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis|last1 = Jones|first1 = TI|date = Oct 15, 2012|journal = Human Molecular Genetics|doi = 10.1093/hmg/dds284|volume = 21|pages = 4419–4430|last2 = Chen|first2 = JC|last3 = Rahimov|first3 = F|issue=20|pmid=22798623|display-authors=etal|pmc = 3459465}}</ref>
|-
|-
|valign="top"|'''2013'''
|Mutations in SMCHD1 are shown to increase the severity of FSHD1.<ref name = "Sacconi2013SMCHD1Modify" />

[[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.<ref>{{Cite journal|title = Intrinsic Epigenetic Regulation of the D4Z4 Macrosatellite Repeat in a Transgenic Mouse Model for FSHD|last1 = Krom|first1 = YD|date = Apr 2013|journal = PLOS Genetics|doi = 10.1371/journal.pgen.1003415|volume = 9|issue = 4|page = e1003415|last2 = Thijssen|first2 = PE|last3 = Young|first3 = JM|display-authors=etal|pmid=23593020|pmc=3616921 | doi-access=free }}</ref>
|-
|valign="top"|'''2014'''
|DUX4-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.<ref>{{Cite journal|url = https://www.researchgate.net/publication/256072749|title = DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles|last1 = Ferreboeuf|first1 = M|date = Jan 1, 2014|journal = Human Molecular Genetics|doi = 10.1093/hmg/ddt409|volume = 23|issue = 1|pages = 171–181|last2 = Mariot|first2 = V|last3 = Bessieres|first3 = B|display-authors=etal|pmid=23966205|doi-access = free}}</ref>

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."<ref name="Tawil2014PathophysConsensus" />
|-
|valign="top"|'''2020'''
|[https://www.fshdsociety.org/wp-content/uploads/2020/11/Voice-of-the-Patient-Report-FINAL.pdf Voice of the Patient Report] released documenting FSHD's impacts on daily life as conveyed by about 400 patients during an FDA externally led Patient-Focused Drug Development meeting, which was held on June 29, 2020.<ref name=":1" /><ref name=":3" /><ref name=":0" /><ref name=":2" />
|}

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=== Past pharmaceutical development ===
Early drug trials, before the pathogenesis involving ''DUX4'' was discovered, were untargeted and largely unsuccessful.<ref name="Cohen2020Therapeutics">{{cite journal |last1=Cohen |first1=Justin |last2=DeSimone |first2=Alec |last3=Lek |first3=Monkol |last4=Lek |first4=Angela |title=Therapeutic Approaches in Facioscapulohumeral Muscular Dystrophy |journal=Trends in Molecular Medicine |date=October 2020 |volume=27 |issue=2 |pages=123–137 |doi=10.1016/j.molmed.2020.09.008|pmid=33092966 |pmc=8048701 |doi-access=free }}</ref> Compounds were trialed with goals of increasing muscle mass, decreasing inflammation, or addressing provisional theories of disease mechanism.<ref name="Cohen2020Therapeutics" /> The following drugs failed to show efficacy:
* [[Prednisone]], a steroid, based on its antiinflammatory properties and therapeutic effect in Duchenne muscular dystrophy.<ref>{{cite journal |last1=Tawil |first1=R |last2=McDermott |first2=MP |last3=Pandya |first3=S |last4=King |first4=W |last5=Kissel |first5=J |last6=Mendell |first6=JR |last7=Griggs |first7=RC |s2cid=729275 |title=A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY Group |journal=Neurology |date=January 1997 |volume=48 |issue=1 |pages=46–9 |doi=10.1212/wnl.48.1.46 |pmid=9008492}}</ref>
* Oral [[salbutamol|albuterol]], a [[Beta2-adrenergic agonist|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.<ref>{{cite journal |last1=Kissel |first1=JT |last2=McDermott |first2=MP |last3=Natarajan |first3=R |last4=Mendell |first4=JR |last5=Pandya |first5=S |last6=King |first6=WM |last7=Griggs |first7=RC |last8=Tawil |first8=R |s2cid=24848310 |title=Pilot trial of albuterol in facioscapulohumeral muscular dystrophy. FSH-DY Group. |journal=Neurology |date=May 1998 |volume=50 |issue=5 |pages=1402–6 |doi=10.1212/wnl.50.5.1402 |pmid=9595995}}</ref><ref>{{cite journal |last1=Kissel |first1=JT |last2=McDermott |first2=MP |last3=Mendell |first3=JR |last4=King |first4=WM |last5=Pandya |first5=S |last6=Griggs |first6=RC |last7=Tawil |first7=R |last8=FSH-DY |first8=Group. |s2cid=28093111 |title=Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. |journal=Neurology |date=23 October 2001 |volume=57 |issue=8 |pages=1434–40 |doi=10.1212/wnl.57.8.1434 |pmid=11673585}}</ref><ref>{{cite journal |last1=van der Kooi |first1=EL |last2=Vogels |first2=OJ |last3=van Asseldonk |first3=RJ |last4=Lindeman |first4=E |last5=Hendriks |first5=JC |last6=Wohlgemuth |first6=M |last7=van der Maarel |first7=SM |last8=Padberg |first8=GW |s2cid=22778327 |title=Strength training and albuterol in facioscapulohumeral muscular dystrophy |journal=Neurology |date=24 August 2004 |volume=63 |issue=4 |pages=702–8 |doi=10.1212/01.wnl.0000134660.30793.1f |pmid=15326246}}</ref> Interestingly, β2 agonists were later shown to reduce DUX4 expression.<ref name="BET B2 Sverdrup" />
* [[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.<ref>{{cite journal |last1=Elsheikh |first1=BH |last2=Bollman |first2=E |last3=Peruggia |first3=M |last4=King |first4=W |last5=Galloway |first5=G |last6=Kissel |first6=JT |s2cid=361422 |title=Pilot trial of diltiazem in facioscapulohumeral muscular dystrophy |journal=Neurology |date=24 April 2007 |volume=68 |issue=17 |pages=1428–9 |doi=10.1212/01.wnl.0000264017.08217.39 |pmid=17452589}}</ref>
* [[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.<ref>[http://www.medicalnewstoday.com/medicalnews.php?newsid=20441 Wyeth Initiates Clinical Trial with Investigational Muscular Dystrophy Therapy MYO-029<!-- Bot generated title -->]</ref>
* ACE-083, a TGF-β inhibitor, was developed to promote muscle growth.<ref>{{cite news |last1=Malcolm |first1=Emily |title=ACE-083 |url=https://musculardystrophynews.com/ace-083/ |access-date=19 December 2019 |work=Muscular Dystrophy News |date=18 June 2019}}</ref>

== Society and culture ==
===Media===
* In the [[Amazon Video]] series [[The Man in the High Castle (TV series)|''The Man in the High Castle'']], [[Obergruppenführer]] John Smith's son, Thomas, is diagnosed with Landouzy-Dejerine syndrome.<ref name="Vultaggio2018ManHighCastle">{{cite news |last1=Vultaggio |first1=Maria |title=Why Rufus Sewell wanted to play 'Man in the High Castle' villain John Smith |url=https://www.newsweek.com/man-high-castle-season-3-smith-rufus-sewelll-1154783 |access-date=12 April 2022 |work=Newsweek |date=5 October 2018 |archive-url=https://web.archive.org/web/20181106172126/https://www.newsweek.com/man-high-castle-season-3-smith-rufus-sewelll-1154783 |archive-date=6 November 2018 |language=en}}</ref>
* In the biography ''[[Stuart: A Life Backwards]]'', the protagonist was affected by muscular dystrophy,<ref>{{cite news |last1=Kakutani |first1=Michiko |title='Stuart: A Life Backwards,' by Alexander Masters, a Portrait of a Homeless Man |url=https://www.nytimes.com/2006/06/09/books/09book.html |work=The New York Times |date=9 June 2006 |archive-url=https://web.archive.org/web/20180116080336/http://www.nytimes.com/2006/06/09/books/09book.html |archive-date=16 January 2018}}</ref> presumably FSHD.{{Citation needed|date=April 2022}}
* [[Good Bad Things]], a independent film about an entrepreneur afflicted with FSHD and his journey of transformation, self-acceptance and discovery. The movie premiered at the 2024 [[Slamdance Film Festival]]<ref>{{Cite web |last=White |first=Abbey |date=2023-12-19 |title='Ramy' Star Steve Way Boards Indie Drama 'Good Bad Things' as Executive Producer (Exclusive) |url=https://www.hollywoodreporter.com/movies/movie-news/steve-way-ramy-star-executive-producer-good-bad-things-1235765618/ |access-date=2024-01-31 |website=The Hollywood Reporter |language=en-US}}</ref><ref>{{Cite web |last=jkinoshita |date=2022-08-25 |title=New movie will feature man with FSHD |url=https://www.fshdsociety.org/2022/08/25/new-movie-will-feature-man-with-fshd/ |access-date=2024-01-31 |website=FSHD Society |language=en-US}}</ref>
* [[The Lost Voice]], a short film featuring Dr. Tristram Ingham who lives with FSHD. Dr. Ingham used Apple's [[Personal Voice for Apple|Personal Voice]] feature to recreate his voice and use it to read a children's book titled "The Lost Voice"  for [[International Day of Persons with Disabilities]] in 2023.<ref>{{Cite web |title=A disability advocate preserves his voice with iPhone |url=https://www.apple.com/newsroom/2023/11/a-disability-advocate-preserves-his-voice-with-iphone/ |access-date=2024-02-21 |website=Apple Newsroom |language=en-US}}</ref>

===Patient and research organizations===
* The '''FSHD Society''' (named "FSH Society" until 2019)<ref name="FSHDSociety_name">{{cite web |last1=Kinoshita |first1=June |title=What's in a name? – FSHD Society |url=https://www.fshdsociety.org/2019/08/16/whats-in-a-name/ |website=FSHD Society |date=16 August 2019 |access-date=18 August 2019 |archive-url=https://web.archive.org/web/20220412190402/https://www.fshdsociety.org/2019/08/16/whats-in-a-name/ |archive-date=12 April 2022}}</ref> was founded in 1991 on the East Coast by two individuals with FSHD, Daniel Perez and Stephen Jacobsen.<ref name="FSHDSociety_History">{{cite web |title=Our History |url=https://www.fshdsociety.org/about-us/our-history/ |website=FSHD Society |archive-url=https://web.archive.org/web/20220227105231/https://www.fshdsociety.org/about-us/our-history/ |archive-date=27 February 2022}}</ref><ref name="Bartlett2014PerezInterview">{{cite news |last1=Bartlett |first1=Jessica |url=https://www.bizjournals.com/boston/blog/health-care/2014/08/dan-perez-living-with-and-fighting-against-a.html |access-date=12 April 2022 |work=Boston Business Journal |date=19 August 2014 |archive-url=https://web.archive.org/web/20220412220102/https://www.bizjournals.com/boston/blog/health-care/2014/08/dan-perez-living-with-and-fighting-against-a.html |archive-date=12 April 2022}}</ref> The FSHD Society claims to have advocated for the standardization of the disease name ''facioscapulohumeral muscular dystrophy'' and its abbreviation ''FSHD''.<ref name="FSHDSociety_name" /> The FSHD Society claims to have raised funding for seed grants for FSHD research and co-wrote the [[MD CARE Act|MD-CARE Act]] of 2001, which provided federal funding for all muscular dystrophies.<ref name="FSHDSociety_History" /><ref name="Bartlett2014PerezInterview" /> The FSHD Society has grown into the world's largest [[grassroots]] organization advocating for patient education and scientific and medical research for FSHD.<ref name="NORD-FSHD-Society">{{cite journal |title=FSHD Society |journal=NORD (National Organization for Rare Disorders) |url=https://rarediseases.org/organizations/fshd-society/ |access-date=2022-04-12 |archive-date=2022-05-13 |archive-url=https://web.archive.org/web/20220513135615/https://rarediseases.org/organizations/fshd-society/ |url-status=dead }}</ref><ref name="CisionPRWeb2022FSHDSociety">{{cite news |title=FSHD Society Achieves Accreditation from BBB Wise Giving Alliance |url=https://www.prweb.com/releases/fshd_society_achieves_accreditation_from_bbb_wise_giving_alliance/prweb18640312.htm |newspaper=Prweb |access-date=29 April 2022 |archive-url=https://web.archive.org/web/20220429025115/https://www.prweb.com/releases/fshd_society_achieves_accreditation_from_bbb_wise_giving_alliance/prweb18640312.htm |archive-date=29 April 2022 |date=26 April 2022}}</ref> One notable spokesperson for FSHD Society has been [[Max Adler (actor)|Max Adler]], an actor on the TV series [[Glee (TV series)|Glee]].<ref>{{cite news |title=This Is FSHD |url=https://www.huffpost.com/entry/fsh-muscular-dystrophy_b_5588661 |access-date=12 April 2022 |work=HuffPost |date=16 July 2014 |archive-url=https://web.archive.org/web/20190802113333/https://www.huffpost.com/entry/fsh-muscular-dystrophy_b_5588661 |archive-date=2 August 2019 |language=en}}</ref>
* '''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.<ref name="FSHFriends">{{cite news |last1=Krummey |first1=Catherine |title=Kirkland couple raises $3.2 million for FSH muscular dystrophy research |url=https://www.kirklandreporter.com/life/kirkland-couple-raises-3-2-million-for-fsh-muscular-dystrophy-research/ |access-date=9 April 2022 |work=Kirkland Reporter |date=30 March 2017 |archive-url=https://web.archive.org/web/20170616040245/https://www.kirklandreporter.com/life/kirkland-couple-raises-3-2-million-for-fsh-muscular-dystrophy-research/ |archive-date=16 June 2017}}</ref><ref name="FSHFriends_About">{{cite web |title=About Us :: Friends of FSH Research |url=https://fshfriends.org/about |website=Friends of FSH Research |access-date=9 April 2022 |archive-url=https://web.archive.org/web/20200217233146/http://fshfriends.org/about |archive-date=17 February 2020}}</ref><ref name="AMRA_FSHFriends">{{cite news |last1=AMRA Medical |title=AMRA Medical's Whole-body MRI Analysis Used in FSHD Clinical Trial Research Network Study for Biomarker Development |url=https://www.prnewswire.com/news-releases/amra-medicals-whole-body-mri-analysis-used-in-fshd-clinical-trial-research-network-study-for-biomarker-development-301399360.html |access-date=9 April 2022 |work=Cision PR Newswire |date=13 Oct 2021|archive-url=https://web.archive.org/web/20211101093610/https://www.prnewswire.com/news-releases/amra-medicals-whole-body-mri-analysis-used-in-fshd-clinical-trial-research-network-study-for-biomarker-development-301399360.html |archive-date=1 November 2021|language=en}}</ref><ref name="Avidity_FSHFriends">{{cite news |last1=Avidity Biosciences, Inc. |title=Avidity Biosciences Enters Into Collaboration with FSHD Clinical Trial Network to Support Development of Biomarkers for Future Clinical Trial Use |url=https://www.prnewswire.com/news-releases/avidity-biosciences-enters-into-collaboration-with-fshd-clinical-trial-network-to-support-development-of-biomarkers-for-future-clinical-trial-use-301355221.html |work=Cision PR Newswire |date=16 August 2021 |archive-url=https://web.archive.org/web/20210816133730/https://www.prnewswire.com/news-releases/avidity-biosciences-enters-into-collaboration-with-fshd-clinical-trial-network-to-support-development-of-biomarkers-for-future-clinical-trial-use-301355221.html |archive-date=16 August 2021 |language=en}}</ref>
* The '''FSHD Global Research Foundation''' was founded in 2007 by Bill Moss in Australia, a former [[Macquarie Bank]] executive affected by FSHD.<ref name="Overington2016Australian">{{cite news |last1=Overington |first1=Caroline |title=He's physically wasting but his brain is sharp. Former Macquarie banker Bill Moss is back in business. |work=The Australian |date=24 September 2016}}</ref><ref name="Chancellor2020TheAustralian">{{cite news |last1=Chancellor |first1=Jonathan |title=Buyer swoops on Brett Whiteley's corella |url=https://www.theaustralian.com.au/business/margin-call/buyer-swoops-on-whiteleys-corella/news-story/9abe28a602a02399718bf750991d8f51 |access-date=9 April 2022 |work=The Australian |date=7 September 2020 }}</ref><ref name="2018Tasker_TheAustralian">{{cite news |last1=Tasker |first1=Sarah-Jane |title=Bill Moss, the single-minded biotech and a search for a cure |url=https://www.theaustralian.com.au/business/bill-moss-the-singleminde...nd-a-search-for-a-cure/news-story/746916e017a29e356a16281bf27a77bd |access-date=9 April 2022 |work=The Australian |date=26 May 2018}}</ref> It is currently directed by Moss's daughter.<ref name="Chancellor2020TheAustralian" /> It was named Australian charity of the year for 2017.<ref name="Chancellor2020TheAustralian" /> It is the largest funder of FSHD medical research outside of the United States as of 2018.<ref name="2018Tasker_TheAustralian" />
* '''FSHD EUROPE''' was founded in 2010.<ref name="Voermans2021FSHD-Europe">{{cite journal |last1=Voermans |first1=NC |last2=Vriens-Munoz Bravo |first2=M |last3=Padberg |first3=GW |last4=Laforêt |first4=P |last5=FSHD European Trial Network workshop study |first5=group. |title=1st FSHD European Trial Network workshop:Working towards trial readiness across Europe. |journal=Neuromuscular Disorders |date=September 2021 |volume=31 |issue=9 |pages=907–918 |doi=10.1016/j.nmd.2021.07.013 |pmid=34404575|s2cid=236217036 |hdl=1887/3505452 |hdl-access=free }}</ref> Spanning multiple countries in Europe, it has launched the European Trial Network.<ref name="Voermans2021FSHD-Europe" />

===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'.<ref name="Judd2022ChipWilson">{{cite news |last1=Judd |first1=Amy |title=Lululemon founder Chip Wilson donates $100M to find cure for his illness, 30 years after diagnosis {{!}} Globalnews.ca |url=https://globalnews.ca/news/8667229/chip-wilson-100-million-donation-facioscapulohumeral-muscular-dystrophy/ |access-date=9 April 2022 |work=Global News |date=8 March 2022}}</ref>
* [[Chris Carrino]] is the radio voice of the [[Brooklyn Nets]]. He founded the 'Chris Carrino Foundation for FSHD', oriented towards research funding.<ref name="Isola2019Carrino">{{cite news |last1=Isola |first1=Frank |title='You're not going to quit': One step at a time, Nets radio voice Chris Carrino continues to walk tall |url=https://theathletic.com/939415/2019/04/23/youre-not-going-to-quit-one-step-at-a-time-nets-radio-voice-chris-carrino-continues-to-walk-tall/ |access-date=9 April 2022 |work=The Athletic |date=23 April 2019}}</ref>
* [[Madison Ferris]] is an American actress with FSHD who was the first wheelchair user to play a lead on [[Broadway theatre|Broadway]].<ref>{{Cite web |title=Actress Breaking Barriers as Broadway's First Lead Actor in Wheelchair |url=https://www.nbcnews.com/nightly-news/video/actress-breaking-barriers-as-broadway-s-first-lead-actor-in-wheelchair-949892675524 |access-date=2024-02-21 |website=NBC News |language=en}}</ref><ref>{{Cite web |title=Community Profiles: Actress Madison Ferris |url=https://audioboom.com/posts/8156539-community-profiles-actress-madison-ferris |access-date=2024-02-21 |website=Audioboom |language=en}}</ref>
* [[Morgan Hoffman]] is an American professional golfer. He started the Morgan Hoffman Foundation, oriented towards research funding.<ref name="Shedloski2020Hoffman">{{cite news |last1=Shedloski |first1=Dave |title=There's no stopping Morgan Hoffmann in his fight against muscular dystrophy |url=https://www.golfdigest.com/story/there-is-no-stopping-morgan-hoffmann-in-his-fight-against-muscular-dystrophy |access-date=12 April 2022 |work=Golf Digest |date=24 February 2020 |archive-url=https://web.archive.org/web/20220305063841/https://www.golfdigest.com/story/there-is-no-stopping-morgan-hoffmann-in-his-fight-against-muscular-dystrophy |archive-date=5 March 2022 |language=en}}</ref>
* Dr. [[Arnold Gold]] (1925-2024) was a pediatric neurologist, founder of the Arnold P. Gold Foundation, and creator of [[White coat ceremony|white coat ceremonies]]. Dr. Gold focused on patient-centered care and [[humanism]].<ref>{{Cite news |last=Sandomir |first=Richard |date=2018-02-03 |title=Dr. Arnold Gold, 92, Dies; Made Compassionate Care a Cause |url=https://www.nytimes.com/2018/02/02/obituaries/dr-arnold-gold-92-dies-made-compassionate-care-a-cause.html |access-date=2024-02-21 |work=The New York Times |language=en-US |issn=0362-4331}}</ref>

==Research directions==
=== Pharmaceutical development ===
[[File:Timelapse Expression of DUX4 Protein in FSHD Cells.ogv|thumb|thumbtime=34|250px|Timelapse of DUX4 expression in FSHD muscle cells<ref name=DUX4expression>{{cite journal|last1=Rickard|first1=Amanda|last2=Petek|first2=Lisa|last3=Miller|first3=Daniel|title=Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways|journal=Hum. Mol. Genet.|date=August 5, 2015|doi=10.1093/hmg/ddv315|url= |pmid=26246499|pmc=4581613|volume=24|issue=20|pages=5901–14}}</ref>]]
After achieving consensus on FSHD pathophysiology in 2014, researchers proposed four approaches for therapeutic intervention:<ref name="Tawil2014PathophysConsensus" />
# enhance the epigenetic repression of the D4Z4
# target the DUX4 mRNA, including altering splicing or polyadenylation;
# block the activity of the DUX4 protein
# inhibit the DUX4-induced process, or processes, that leads to pathology.

'''Small molecule drugs'''

Most drugs used in medicine are "[[Small molecule#Drugs|small molecule drugs]]," as opposed to biologic medical products that include proteins, vaccines, and nucleic acids. Small molecule drugs can typically be taken by ingestion, rather than injection.
* [[Losmapimod]], a selective inhibitor of [[p38 mitogen-activated protein kinases|p38α/β mitogen-activated protein kinases]], was identified by Fulcrum Therapeutics as a potent suppressor of DUX4 in vitro.<ref>{{cite news |title=Fulcrum Therapeutics Acquires Global Rights to Losmapimod, a Potential Disease-Modifying Therapy for Facioscapulohumeral Muscular Dystrophy |url=https://www.biospace.com/article/releases/fulcrum-therapeutics-acquires-global-rights-to-losmapimod-a-potential-disease-modifying-therapy-for-facioscapulohumeral-muscular-dystrophy/ |access-date=12 August 2019 |work=BioSpace}}</ref> Results of a phase IIb clinical trial, revealed in June 2021, showed statistically significant slowing of muscle function deterioration. Further trials are pending.<ref>{{cite web |title=ReDUX4 trial result exceeds expectations |url=https://www.fshdsociety.org/2021/06/24/redux4-trial-result-exceeds-expectations/ |website=FSHD Society |access-date=26 June 2021 |archive-url=https://web.archive.org/web/20210626171442/https://www.fshdsociety.org/2021/06/24/redux4-trial-result-exceeds-expectations/ |archive-date=26 June 2021 |location=Wayback Machine |date=2021-06-24}}</ref><ref>{{cite web |title=Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) |url=https://clinicaltrials.gov/ct2/show/NCT04003974?term=losmapimod&rank=3 |website=ClinicalTrials.gov |publisher=United States National Library of Medicine |access-date=12 August 2019 |language=en}}</ref>
* [[Casein kinase 1]] (CK1) inhibition has been identified by Facio Therapies, a Dutch pharmaceutical company, to repress ''DUX4'' expression and is in preclinical development. Facio Therapies claims that CK1 inhibition leaves myotube fusion intact, unlike BET inhibitors, [[P38 mitogen-activated protein kinases|p38 MAPK]] inhibitors, and [[Beta2-adrenergic agonist|β2 agonists]].<ref>{{cite news |title=Facio to present at the World Muscle Society Congress |url=https://www.facio-therapies.com/news/facio-to-present-at-the-world-muscle-society-congress/ |access-date=9 November 2019 |work=Facio Therapies |date=30 September 2019}}</ref><ref>{{cite news |title=Facio reveals novel mechanism targeting the cause of FSHD |url=https://www.facio-therapies.com/news/facio-reveals-novel-mechanism-targeting-the-cause-of-fshd/ |access-date=9 November 2019 |work=Facio Therapies |date=24 June 2019}}</ref>
'''Gene therapy'''

[[Gene therapy]] is the administration of [[nucleotide]]s to treat disease. Multiple types of gene therapy are in the preclinical stage of development for the treatment of FSHD.
* [[Antisense therapy]] utilizes [[Oligonucleotide#Antisense oligonucleotides|antisense oligonucleotides]] that bind to DUX4 messenger RNA, inducing its degradation and preventing DUX4 protein production. [[morpholino|Phosphorodiamidate morpholinos]], an oligonucleotide modified to increase its [[Half-life#In biology and pharmacology|stability]], have been shown to selectively reduce DUX4 and its effects; however, these antisense nucleotides have poor ability to penetrate muscle.<ref name="Wagner2019Review" />
* [[MicroRNAs]] (miRNAs) directed against DUX4, delivered by [[viral vectors]], have shown to reduce DUX4, protect against muscle pathology, and prevent loss of grip strength in mouse FSHD models.<ref name="Wagner2019Review" /> Arrowhead pharmaceuticals is developing an [[RNA interference]] therapeutic against DUX4, named ARO-DUX4, and intends to file for regulatory clearance in third quarter of 2021 to begin clinical trials.<ref name="2021FSHDSociety_ARO_DUX4">{{cite news |title=Arrowhead Pharmaceuticals announces FSHD drug candidate |url=https://www.fshdsociety.org/2021/04/15/arrowhead-pharmaceuticals-announces-fshd-drug-candidate/ |access-date=15 April 2021 |work=FSHD Society |date=15 April 2021}}</ref><ref name="2021PressRelease_ARO-DUX4">{{cite news |title=Arrowhead Announces ARO-DUX4 as First Muscle Targeted RNAi Candidate Using TRiMTM Platform |url=https://www.businesswire.com/news/home/20210415005323/en/Arrowhead-Announces-ARO-DUX4-as-First-Muscle-Targeted-RNAi-Candidate-Using-TRiMTM-Platform |access-date=15 April 2021 |work=Businesswire |date=15 April 2021 |language=en}}</ref><ref name="Saad2021miRNA">{{cite journal |last1=Saad |first1=Nizar Y. |last2=Al-Kharsan |first2=Mustafa |last3=Garwick-Coppens |first3=Sara E. |last4=Chermahini |first4=Gholamhossein Amini |last5=Harper |first5=Madison A. |last6=Palo |first6=Andrew |last7=Boudreau |first7=Ryan L. |last8=Harper |first8=Scott Q. |title=Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy |journal=Nature Communications |date=December 2021 |volume=12 |issue=1 |pages=7128 |doi=10.1038/s41467-021-27430-1|pmid=34880230 |pmc=8654987 |bibcode=2021NatCo..12.7128S }}</ref>
* [[Genome editing]], the permanent alteration of genetic code, is being researched. One study tried to use [[CRISPR gene editing|CRISPR-Cas9]] to [[gene knockout|knockout]] the polyadenylation signal in lab dish models, but was unable to show therapeutic results.<ref>{{cite journal |last1=Joubert |first1=R |last2=Mariot |first2=V |last3=Charpentier |first3=M |last4=Concordet |first4=JP |last5=Dumonceaux |first5=J |title=Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD? |journal=Journal of Personalized Medicine |date=23 December 2020 |volume=11 |issue=1 |page=7 |doi=10.3390/jpm11010007 |pmid=33374516|pmc=7822190 |doi-access=free }}</ref>

'''Potential drug targets'''
* Inhibition of the [[hyaluronic acid]] (HA) pathway is a potential therapy. One study found that many ''DUX4''-induced molecular pathologies are mediated by HA signaling, and inhibition of HA biosynthesis with 4-methylumbelliferone prevented these molecular pathologies.<ref>{{cite journal |last1=DeSimone |first1=Alec M. |last2=Leszyk |first2=John |last3=Wagner |first3=Kathryn |last4=Emerson |first4=Charles P. |title=Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy |journal=Science Advances |date=11 December 2019 |volume=5 |issue=12 |pages=eaaw7099 |doi=10.1126/sciadv.aaw7099|pmid=31844661 |pmc=6905861 |bibcode=2019SciA....5.7099D }}</ref>
* P300 inhibition has shown to inhibit the deleterious effects of ''DUX4''<ref>{{cite journal |last1=Bosnakovski |first1=D |last2=da Silva |first2=MT |last3=Sunny |first3=ST |last4=Ener |first4=ET |last5=Toso |first5=EA |last6=Yuan |first6=C |last7=Cui |first7=Z |last8=Walters |first8=MA |last9=Jadhav |first9=A |last10=Kyba |first10=M |title=A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death |journal=Science Advances |date=September 2019 |volume=5 |issue=9 |pages=eaaw7781 |doi=10.1126/sciadv.aaw7781 |pmid=31535023|pmc=6739093 |bibcode=2019SciA....5.7781B }}</ref>
* [[BET inhibitors]] have been shown to reduce DUX4 expression.<ref name="BET B2 Sverdrup">{{cite journal |last1=Campbell |first1=AE |last2=Oliva |first2=J |last3=Yates |first3=MP |last4=Zhong |first4=JW |last5=Shadle |first5=SC |last6=Snider |first6=L |last7=Singh |first7=N |last8=Tai |first8=S |last9=Hiramuki |first9=Y |last10=Tawil |first10=R |last11=van der Maarel |first11=SM |last12=Tapscott |first12=SJ |last13=Sverdrup |first13=FM |title=BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells |journal=Skeletal Muscle |date=4 September 2017 |volume=7 |issue=1 |pages=16 |doi=10.1186/s13395-017-0134-x |pmid=28870238|pmc=5584331 |doi-access=free }}</ref>
* Antioxidants could potentially reduce the effects of FSHD. One study found that [[vitamin C]], [[vitamin E]], [[zinc gluconate]], and [[selenomethionine]] supplementation increased endurance and strength of the quadriceps, but had no significant benefit on walking performance.<ref>{{cite journal |last1=Passerieux |first1=E |last2=Hayot |first2=M |last3=Jaussent |first3=A |last4=Carnac |first4=G |last5=Gouzi |first5=F |last6=Pillard |first6=F |last7=Picot |first7=MC |last8=Böcker |first8=K |last9=Hugon |first9=G |last10=Pincemail |first10=J |last11=Defraigne |first11=JO |last12=Verrips |first12=T |last13=Mercier |first13=J |last14=Laoudj-Chenivesse |first14=D |title=Effects of vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation on muscle function and oxidative stress biomarkers in patients with facioscapulohumeral dystrophy: a double-blind randomized controlled clinical trial. |journal=Free Radical Biology & Medicine |date=April 2015 |volume=81 |pages=158–69 |doi=10.1016/j.freeradbiomed.2014.09.014 |pmid=25246239|s2cid=10971952 |url=https://hal.archives-ouvertes.fr/hal-01679192/file/Passerieux%20et%20al%20FRBM%202015.pdf }}</ref> Further study is warranted.<ref name="Wagner2019Review" />

=== Outcome measures ===
Ways of measuring the disease are important for studying disease progression and assessing the efficacy of drugs in clinical trials.
* [[Reachable workspace]] uses the [[Kinect]] motion sensing system to compare range of reach before and after a therapeutic clinical trial.<ref>{{Cite journal |last1=Han |first1=Jay J. |last2=Kurillo |first2=Gregorij |last3=Abresch |first3=Richard T. |last4=de Bie |first4=Evan |last5=Nicorici |first5=Alina |last6=Bajcsy |first6=Ruzena |date=February 2015 |title=Reachable Workspace in Facioscapulohumeral muscular dystrophy (FSHD) by Kinect |journal=Muscle & Nerve |volume=51 |issue=2 |pages=168–175 |doi=10.1002/mus.24287 |issn=0148-639X |pmc=4233016 |pmid=24828906}}</ref>
* [[Quality of life]] can be measured with questionnaires, such as the FSHD Health Index.<ref name="Dany2015" /><ref name="Wagner2019Review" />
* How the disease affects daily activities can measured with questionnaires, such as the FSHD‐[[Rasch model|Rasch‐built]] overall disability scale (FSHD-RODS)<ref name="Mul2021Rasch-built">{{cite journal |last1=Mul |first1=K |last2=Hamadeh |first2=T |last3=Horlings |first3=CGC |last4=Tawil |first4=R |last5=Statland |first5=JM |last6=Sacconi |first6=S |last7=Corbett |first7=AJ |last8=Voermans |first8=NC |last9=Faber |first9=CG |last10=van Engelen |first10=BGM |last11=Merkies |first11=ISJ |title=The FacioScapuloHumeral muscular Dystrophy Rasch-built Overall Disability Scale (FSHD-RODS). |journal=European Journal of Neurology |date=10 April 2021 |volume=28 |issue=7 |pages=2339–2348 |doi=10.1111/ene.14863 |pmid=33838063|pmc=8251612 |doi-access=free }}</ref> or FSHD composite outcome measure (FSHD-COM).<ref name="FSHD-COM">{{cite journal |last1=Eichinger |first1=K |last2=Heatwole |first2=C |last3=Iyadurai |first3=S |last4=King |first4=W |last5=Baker |first5=L |last6=Heininger |first6=S |last7=Bartlett |first7=A |last8=Dilek |first8=N |last9=Martens |first9=WB |last10=Mcdermott |first10=M |last11=Kissel |first11=JT |last12=Tawil |first12=R |last13=Statland |first13=JM |title=Facioscapulohumeral muscular dystrophy functional composite outcome measure. |journal=Muscle & Nerve |date=2018-01-30 |volume=58 |pages=72–78 |doi=10.1002/mus.26088 |pmid=29381807|pmc=6066464 }}</ref>
* [[Electrical impedance myography]] is being studied as a way to measure muscle damage.<ref name="Wagner2019Review" />
* Muscle MRI is useful for assessment of all the muscles in the body. Muscles can be scored based on the degree of fat infiltration.<ref name="Wagner2019Review" />

==References==
{{Reflist|3|refs=
<ref name="Dany2015">{{cite journal|last1=Dany|first1=Antoine|last2=Barbe|first2=Coralie|last3=Rapin|first3=Amandine|last4=Réveillère|first4=Christian|last5=Hardouin|first5=Jean-Benoit|last6=Morrone|first6=Isabella|last7=Wolak-Thierry|first7=Aurore|last8=Dramé|first8=Moustapha|last9=Calmus|first9=Arnaud|last10=Sacconi|first10=Sabrina|last11=Bassez|first11=Guillaume|last12=Tiffreau|first12=Vincent|last13=Richard|first13=Isabelle|last14=Gallais|first14=Benjamin|last15=Prigent|first15=Hélène|last16=Taiar|first16=Redha|last17=Jolly|first17=Damien|last18=Novella|first18=Jean-Luc|last19=Boyer|first19=François Constant|s2cid=25834947|title=Construction of a Quality of Life Questionnaire for slowly progressive neuromuscular disease|journal=Quality of Life Research|volume=24|issue=11|year=2015|pages=2615–2623|issn=0962-9343|doi=10.1007/s11136-015-1013-8|pmid=26141500}}</ref>
}}

== External links ==
* [https://www.fshdsociety.org/connect/worldfshdalliance/ World FSHD Alliance: FSHD patient advocacy organizations across the world]
* [http://clinicaltrials.gov/ct2/results?term=fshd&cond=%22Muscular+Dystrophy%2C+Facioscapulohumeral%22 list of clinical trials for FSHD], [[Clinicaltrials.gov]].
* {{GeneTests|fsh}}
{{Medical resources
| DiseasesDB      = 7247
| ICD10           = {{ICD10|G|71|0|g|70}}
| ICD9            = {{ICD9|359.1}}
| ICDO            =
| OMIM            = 158900
| OMIM_mult       = {{OMIM|158901||none}}
| MedlinePlus     = 000707
| eMedicineSubj   = neuro
| eMedicineTopic  = 133
| MeshID          = D020391
| GeneReviewsName = Facioscapulohumeral muscular dystrophy
| GeneReviewsNBK  = NBK1443
| Orphanet        = 269
| ICD10CM         = {{ICD10CM|G71.02}}
}}
{{Commons|FSHD}}

{{Muscular Dystrophy}}
{{Diseases of myoneural junction and muscle}}

[[Category:Muscular dystrophy]]
[[Category:Rare diseases]]
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