Facioscapulohumeral Muscular Dystrophy (FSHD)

D4Z4 array contraction at 4q35 (FSHD1), epigenetic relaxation through SMCHD1, DNMT3B or LRIF1 (FSHD2), and DUX4 expression on a permissive 4qA haplotype.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

FSHD has a distinctive mechanism among muscular dystrophies: rather than loss of a muscle-fibre structural protein, it involves reactivation in adult muscle of a gene normally silenced after the embryo's first divisions. Its name describes the recognisable facial, scapular and upper-arm distribution, but trunk/lower-limb involvement is frequent and progression heterogeneous. One family may contain severe childhood-onset cases and asymptomatic carriers. For clinical genetics, FSHD illustrates repeat disease caused by copy reduction, digenic inheritance, frequent mosaicism and ancestry-dependent interpretation [2, 5].

Louis Landouzy and Jules Dejerine established the modern clinical description in the 1880s, identifying familial “progressive atrophic myopathy” beginning in the face without nervous system abnormalities. Their 1886 Paris Society of Biology communication described the scapulohumeral form underlying the eponym [15, 16]. Landouzy–Dejerine terminology subsequently gave way to FSHD [2]. Diagnosis remained exclusively clinical for a century, accounting for probably underestimated pre-molecular prevalence around 5/100 000 [5].

Genetic discoveries parallel structural genomics. Wijmenga and colleagues demonstrated disease-associated 4q DNA rearrangements in 1992 and de novo mutation transmission that year [17, 18]. In 1993, van Deutekom and colleagues established integer-copy deletion of the approximately 3.3 kb D4Z4 repeat [1, 19]. Lemmers and colleagues showed in 2002 that contraction is pathogenic only on the 4qA subtelomeric variant [20]. Their unifying 2010 model identified a permissive-haplotype polyadenylation signal stabilising DUX4 transcripts [6]. FSHD2 involving SMCHD1 variants with a permissive D4Z4 allele followed in 2012, DNMT3B in 2016 and LRIF1 in 2020 [21–23].

In clinical care, the American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine published the first evidence-based guideline in 2015, reaffirmed in July 2024; the 171st European Neuromuscular Centre (ENMC) workshop had defined standards of care in 2010; the European FSHD trial network updated the genetic diagnostic criteria in 2024; and the 279th ENMC workshop (2024, published 2025) reorganised the terminology of childhood-onset forms [5, 7, 12, 13]. In France, the Haute Autorité de Santé published the French National Diagnosis and Care Protocol (PNDS) for FSHD in January 2022, drafted by a multidisciplinary group from neuromuscular disease reference centres and intended to guide the care pathway, including admission to the long-term condition scheme [9]. During 2024–2026, the field moved from negative trials of indirect modulators to therapies targeting DUX4 RNA with biomarker data in humans, with no marketing authorisation granted by the date of this article [10, 24].

2. Molecular Genetics and Pathophysiology

2.1. D4Z4 array, permissive haplotype and DUX4

Subtelomeric 4q35 contains a tandem D4Z4 macrosatellite array; each approximately 3.3 kb unit contains DUX4, an open reading frame encoding a two-homeodomain protein [2]. European arrays range from 8 to over 100 units. Laboratories conventionally report complete units (U), so “6U” actually measures between 6 and 7 [5]. A nearly identical 10q26 array does not cause FSHD when contracted because its DUX4 polyadenylation-signal variants prevent stable transcription [2].

Distal to the final repeat, 4q has major variants 4qA/4qB, approximately 50% each in European/Asian populations, subdivided into at least nine haplotypes [2, 5, 25]. Permissive 4qA haplotypes contain additional pLAM sequence with a canonical somatic polyadenylation signal. Only DUX4 transcripts processed through this distal exon are sufficiently stable to produce protein [2, 6]. Most common permissive 4A161 is accompanied by rarer 4A159, 4A163, 4A166H and 4A168; 4A166, reported in two Dutch families, and all 4B haplotypes are non-permissive [2]. Approximately 66% of the general population has at least one permissive haplotype, making isolated haplotyping without sizing poorly informative [2].

Approximately 20% have “translocated” alleles: 4q-type arrays on 10q, or hybrid 4q/10q units at 4q35. Arrays translocated to 10q are non-permissive; contracted 4q35 hybrids cause FSHD. Rare translocations transfer the permissive distal 4qA region to chromosome 10 and become pathogenic [2]. These explain some false-negative/false-positive results (section 5).

2.2. FSHD1: array contraction

Approximately 95% have DUX4 derepression through D4Z4 contraction to 1–10 units on permissive 4qA [2, 5]. GeneReviews defines normal alleles as ≥11 units, EcoRI/p13E-11 fragments ≥43 kb, or any size on non-permissive haplotypes; reduced-penetrance contractions as 8–10 permissive units; and fully penetrant contractions as ≤7 permissive units [2]. The 2024 guidance calls 8–10U a “grey zone”, present in approximately 1–2% of European controls without signs/family history [5]. Contraction produces local chromatin relaxation, with CpG methylation loss proportional to size [5].

Oxford Desk Reference gives corresponding restriction-fragment thresholds: disease usually ≤34 kb, normal usually >42 kb, with 34–42 kb overlap usually associated with mild scapulohumeral weakness [1]. ENMC 279 states most FSHD1 EcoRI fragments correspond to 4–10 units (15–38 kb), with large contractions of 1–3 units (10–14 kb) associated with greater severity [13].

2.3. FSHD2: epigenetic relaxation without classic contraction

Approximately 5% have FSHD2 through a pathogenic epigenetic modifier variant relaxing D4Z4 chromatin. Hypomethylation affects both 4q/10q arrays but produces disease only with permissive 4qA, usually 8–20 units [2, 5]. A SMCHD1 carrier with two 4qB alleles neither expresses DUX4 nor develops FSHD [5]. FSHD1/FSHD2 are clinically indistinguishable; both show an approximate inverse relationship between shortest permissive 4qA size and severity [5].

GeneReviews groups all three under “FSHD2”; OMIM separates LRIF1 FSHD3 and DNMT3B FSHD4, reflecting the same permissive-allele hypomethylation mechanism [2, 3]. D4Z4 methylation below 25% indicates FSHD2: control mean 45%, FSHD2 mean 11%. Interpretation nevertheless requires chromosome 4/10 array sizes because short arrays inherently have lower methylation [2]. Rare control cis array duplications occur in approximately 8% of FSHD2 [5]. Only approximately 20% of pathogenic SMCHD1 carriers develop FSHD, those with permissive 4qA particularly 8–20 units [5].

2.4. Cellular and tissue mechanism

Both pathways converge on inappropriate skeletal muscle nuclear DUX4 expression, a gain-of-function mechanism [2, 6]. DUX4 is a germline/embryonic transcription factor whose sporadic adult-muscle expression is considered toxic, causing cell death [1, 5, 13]. Expression “bursts” help explain asymmetry, stepwise progression and difficulty measuring DUX4 directly in biopsies. Target-gene panels and more recently plasma KHDC1L provide pharmacodynamic biomarkers [2, 13, 28]. MRI shows greater DUX4 expression in T2-STIR-hyperintense muscles, which more often progress to fatty replacement [13].

Pre-DUX4 hypotheses such as 4q35 neighbouring-gene derepression after D4Z4 repressor-complex loss, including FRG1 approximately 100 kb centromeric, were historically relevant; current consensus attributes disease to DUX4 [1, 2]. Biopsies show non-specific chronic myopathic changes with small angular fibres and, in up to 40%, usually perivascular mononuclear infiltration sometimes sufficient to suggest inflammatory myopathy [1, 2].

2.5. Modifiers, mosaicism and allelic dosage

Allele size explains only approximately 10% of phenotypic variation [2, 29]. Size-independent methylation differences correlate with variation among 7–10U carriers even without SMCHD1 variants, while FSHD2 genes worsen FSHD1 in grey-zone families [5, 26]. A borderline FSHD1 allele with another muscle disease, “dual pathology”, can explain atypical phenotypes. Saudubray gives AMP deaminase 1 deficiency, requiring cautious interpretation when coexisting [5, 30].

De novo rearrangements account for 10–30% of FSHD1 [2, 5]. Approximately half contract in early postzygotic divisions, producing gonadosomatic mosaicism; half arise in parental germ cells [2, 5]. Oxford estimates at least 40% of new mutations occur mitotically in the early blastocyst [1]. Mosaic severity depends on affected-cell proportion and allele size. Offspring inheriting the allele have it throughout their cells and tend to be more severely affected [2, 5]. Köhler and colleagues described predominantly oogenesis-associated FSHD1 germline mosaicism [31].

Compound heterozygotes with two FSHD1 alleles have been described with dosage effects, along with a Brazilian contracted-4A homozygote no more severe than some heterozygous relatives in a family containing many asymptomatic heterozygotes [2, 32]. Anticipation has not been described; repeat size remains stable between generations [2].

The French PNDS (French National Diagnosis and Care Protocol) adds some background data. The D4Z4 units of 4q and 10q are approximately 98% identical in sequence; contractions of the 10q26 array, present in 10–20% of the general population, are associated neither with FSHD nor with any other disease, and FSHD has never been observed with complete loss of the array (zero units), as in 4qter monosomy [9]. In the general population, the distal 4qA and 4qB variants have frequencies of approximately 42% and 52%, and FSHD1 has never been associated with 4qB [9]. The inverse correlation between unit number and severity is presented in three bands — 1–3 units with severe, early forms; 4–7 with classic forms of highly variable age at onset and severity; and 8–10 (the “grey zone”) with milder, later forms — with the caveat that severe phenotypes occur with 8 or more units and that carriers of 2–3 units may be asymptomatic or mildly affected [9]. Overall penetrance lies between 79% and 97% depending on the study, falls to approximately 50% with 9–10 units and is higher in males; de novo cases have shorter alleles (1–4 units) than familial cases (5–10 units) and a usually more severe phenotype; in de novo mosaics, the difference in severity between men and women is more marked than in constitutional contractions [9]. The PNDS estimates the proportion of FSHD2 with a SMCHD1 variant at 80%, against approximately 85% in GeneReviews, and mentions FAT1 as a gene implicated in a small number of patients with neither a contraction nor a SMCHD1 variant [2, 9].

2.6. Allelic disorders and related entities

Heterozygous missense variants in the extended SMCHD1 ATPase domain cause usually de novo Bosma arhinia–microphthalmia–hypogonadotropic hypogonadism syndrome, with normal intelligence [33–36]. Both FSHD2/Bosma variants reduce DUX4 methylation; FSHD2 variants span the gene, while Bosma variants cluster in ATPase with largely disease-specific residues [37]. Among 14 FSHD2 patients and 4 relatives carrying N-terminal missense variants, none had Bosma congenital abnormalities/dysmorphism. The authors concluded these are not one phenotypic spectrum and SMCHD1 variants alone cannot cause either disorder [38]. Smith identifies FSHD2 as a clear digenic example [33].

18p deletion including SMCHD1 produces hemizygosity; approximately one in eight 18p-deletion individuals may risk FSHD2 with appropriately sized permissive alleles [39, 40]. Biallelic DNMT3B causes autosomal recessive immunodeficiency, centromeric instability and facial anomalies type 1 (ICF1; OMIM 242860), clinically unrelated to dystrophy [2, 3]. No other phenotypes associate with D4Z4 contraction or germline LRIF1 variants [2].

2.7. Variant nomenclature and reference transcripts

Report FSHD2 genes on versioned MANE Select transcripts: SMCHD1 NM_015295.3 (NP_056110.2), DNMT3B NM_006892.4 (NP_008823.1) and LRIF1 NM_018372.4 (NP_060842.3) [41]. The following examples were checked in ClinVar on 6 October 2026 to illustrate nomenclature/associations rather than frequency.

“No assertion criteria” denotes research submissions rather than peer-reviewed clinical classification. SMCHD1 interpretation requires functional D4Z4 hypomethylation evidence under 2024 guidance [5, 41]. Five-class classification follows American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards [42].

3. Clinical Spectrum and Manifestations by System

3.1. Classic form

FSHD is characterised by progressive weakness of the facial, shoulder-girdle, upper-arm and lower-leg (peroneal) muscles and, in later stages, of the pelvic girdle, with frequent asymmetry of the face, limbs and shoulders [2]. The classic presentation appears between 15 and 30 years of age; in GeneReviews, patients typically become symptomatic in adolescence, with variable age at onset [2, 43]. The Oxford Desk Reference describes usual onset before 20 years, lower-limb involvement in approximately half of patients and foot-dorsiflexor weakness as an early sign [1]. Progression is generally slow, but many patients describe a stepwise course, with periods of stability interspersed with rapid deterioration; approximately 20% eventually require a wheelchair, and life expectancy is not reduced [1, 2]. The European patient organisation argues that the disease should be described as progressive with a highly variable course, rather than merely as “slowly progressive”, to reflect the real burden of the disease [44]. The French PNDS (French National Diagnosis and Care Protocol) lists as the most frequent reasons for consultation difficulty raising the arms, unilateral or bilateral scapular winging, gait difficulty with steppage, falls and musculoskeletal pain; camptocormia may be the presenting feature, onset may be acute or subacute in one limb or limb segment, and facial weakness, although present for years, rarely prompts consultation [9]. On examination, it describes a horizontal anterior axillary fold over the atrophied pectoral muscles, the “transverse” smile without elevation of the mouth corners, sparing of eye, tongue and jaw movements, secondary involvement of brachioradialis and, late and infrequently, distal finger weakness up to a dropped hand with a pseudo-radial appearance; Beevor's sign is present in approximately 90% of patients, dysphagia in fewer than 2%, and the combination of steppage with proximal weakness produces a waddling gait [9]. The muscle phenotype of FSHD2 does not differ significantly from that of FSHD1, with comparable lower-limb MRI patterns [9].

3.2. Pain, fatigue and psychosocial effects

Chronic pain is frequent: in the PRISM-FSHD study, 82% of patients reported pain, with a negative impact on quality of life irrespective of disease duration or age [2]. The AAN guideline recorded pain in up to 79% of patients, with the lumbar region as the commonest site [7]. Chronic fatigue is the most prominent symptom after weakness in the Dutch registry and affects social participation and employment [2]. In the ENMC 279 report, fatigue (83%), pain (63%) and reduced quality of life (70%) were described across patients with FSHD; children report more pain and fatigue and poorer quality of life than healthy peers, and adolescents with neuromuscular diseases show greater illness “engulfment” of identity [13]. The French PNDS estimates the proportion of patients with chronic muscle, joint or ligament pain at approximately 50%, lower than the 79–82% above, reflecting differences in definition and population; it recommends systematic pain assessment and systematic screening for depression, which amplifies pain perception [9].

3.3. Respiratory system

The prevalence of respiratory dysfunction is uncertain because most patients have never undergone pulmonary function testing: in a referral cohort, up to 50% of those tested had abnormalities, with a restrictive pattern and reduced forced vital capacity (FVC), usually mild or subclinical [2]. A 2026 review estimates restrictive patterns in approximately 10–45% of patients, associated with early onset, greater severity, spinal deformity and loss of ambulation, and stresses that sleep-disordered breathing may develop independently of overall motor disability and be the first clinically relevant manifestation [45]. In ENMC 279, up to 11% of early-onset children required respiratory intervention, against 1% in an adult study [13]. The AAN guideline considers respiratory failure rare but recommends baseline pulmonary function testing in all patients and regular monitoring when results are abnormal or there is severe proximal weakness, kyphoscoliosis, wheelchair dependence or ventilatory comorbidity (level B) [7]. The French PNDS cites most series as showing respiratory involvement in fewer than 20%, but a study of 94 ambulatory and non-ambulatory patients found a restrictive syndrome in 38.3% and need for assisted ventilation in 14%, against 1–3% in earlier studies; the probability increases with early onset, a moderate to severe phenotype and a contraction of <3 units, and appears higher in FSHD2 [9]. Sleep-related breathing disorders (apnoeas, nocturnal alveolar hypoventilation) are reportedly frequent and early, with no clear relationship to motor severity; facial weakness hampers lip seal around the mouthpiece and may lead to underestimation in pulmonary function tests [9].

3.4. Eyes

Retinal vasculopathy — telangiectasia, microaneurysms and arterial tortuosity, visible on fluorescein angiography or optical coherence tomography angiography — is frequent and usually asymptomatic [1, 2]. The AAN reports retinal changes in up to 25% of patients and symptomatic retinal disease in 0.6% [7]. An exudative retinopathy indistinguishable from Coats disease may cause retinal detachment and visual loss, and is potentially preventable by early photocoagulation [2, 7]. In ENMC 279, vasculopathy was described in 37% of early-onset children, with visual loss in 6%, against 0.8–1.7% in classic FSHD [13]. In Portugal, a case was published of a 62-year-old man with genetically confirmed FSHD and exudative maculopathy due to macular telangiectasia, treated with intravitreal bevacizumab and focal photocoagulation, with visual acuity of 20/20 at 12 months [46]. Orbicularis oculi weakness may cause exposure keratitis [2]. The French PNDS gives a frequency of retinal vascular abnormalities of 21–75% depending on the study, almost exclusively with large contractions (1–4 units), sometimes bilateral and at any age, unlike Coats disease, exceptionally preceding the muscle manifestations and never described in FSHD2; it identifies new-generation optical coherence tomography as a useful alternative in patients whose pupils dilate poorly, and slit-lamp examination with fluorescein testing for nocturnal lagophthalmos [9].

3.5. Hearing

High-frequency sensorineural hearing loss is the commonest extramuscular manifestation. Approximately 15% of patients have an abnormal audiogram, a figure that reaches 32% in carriers of large contractions (fragments <20 kb) [2, 7]. In the US population-based MD STARnet network, among 548 people with FSHD followed between 2008 and 2019, 13% had recorded hearing loss, with a median age at diagnosis of 46.5 years [47]. Among 93 children diagnosed before 19 years of age in the same network, hearing loss was the commonest comorbidity (20.4%), reaching 39.4% of children with FSHD1 of 1–3 units [48]. In ENMC 279, 40% of early-onset children aged 0–7 years had hearing loss [13]. The Oxford Desk Reference stresses that studies disagree on the proportion of abnormal audiograms in adults [1]. The French PNDS places hearing impairment at between 25% and 65% of patients, usually bilateral and subclinical, cochlear in origin according to auditory evoked potentials, more frequent with contractions of <4 units, and reports severe hearing loss in 68% of childhood forms with such contractions [9].

3.6. Heart

Cardiac conduction abnormalities are described in 5–13% of patients, mainly mild or asymptomatic atrial arrhythmias [2]. The Oxford Desk Reference reports an increased incidence of atrial tachyarrhythmias, rarely symptomatic [1]. The AAN does not recommend routine cardiac screening in the absence of symptoms [7]. The coexistence of FSHD1 with sarcomeric hypertrophic cardiomyopathy, described in a Portuguese case, illustrates the need to investigate another cause when structural heart disease appears, rather than regarding it as a typical manifestation of FSHD [49]. The French PNDS reports asymptomatic right bundle branch block in approximately one third of patients, more than in the general population, and exceptional cases of cardiomyopathy of uncertain attribution; it nevertheless proposes ECG, echocardiography and 24-hour Holter monitoring at the initial assessment (section 7.8) [9].

3.7. Central nervous system and other manifestations

In early-onset forms, ENMC 279 records epilepsy in 8% and developmental delay in up to 15%, with a partial correlation between contraction size and the frequency of hearing loss, cognitive impairment and epilepsy; undernutrition is associated with the very early-onset subgroup [13]. In MD STARnet, 2.0% had recorded seizures, half of them aged 10 years or younger at diagnosis [47]. Worsening of weakness after pregnancy is one of the suggestive findings listed in GeneReviews [2]. The French PNDS adds that the dysarthria and hypomimia of childhood forms may be mistaken for cognitive impairment, that neurocognitive assessment is warranted in these forms especially if there are central signs such as epilepsy, and that cognitive disorders are exceptional in adults, with occasional white matter abnormalities on brain MRI [9]. Swallowing disorders may be a cause of death in children with severe forms; in adults they are rare and mild, and neck weakness with head drop requires attention to positioning during meals [9]. In a cross-sectional study of 94 adults with FSHD1, approximately one third had vitamin D deficiency and 11% reduced bone mineral density, correlated with strength and functional status [9].

3.8. Age-of-onset forms and atypical presentations

ENMC 279 replaced “infantile FSHD” with childhood onset before 18, spanning early onset <10 with greater progression/extramuscular features to adolescent classic phenotypes [13]. Historical Brouwer criteria defined facial weakness before 5 and scapular weakness before 10 [13]. Estimated childhood prevalence is 5/100 000 and early-onset prevalence 1/100 000; approximately 40% with infant onset at 0–2 lose ambulation by 18 [13]. De novo mutations occur in 4% of classic and 46% of early forms [13]. In Italy's national registry, 72.2% of probands starting by 10 with 1–3 units were de novo, but severity did not significantly differ from later onset [50]. Among 92 Chinese de novo cases, 17.8% of FSHD1, median onset was 10 versus familial 16 with more lower-limb involvement, chiefly mediated by shorter repeats [51]. Paediatric MD STARnet FSHD1 had 1–3 units in 45.8%, early onset in 31.4% and retained ambulation at last visit in 88.2% [48].

Clinical variants include facial-sparing scapulohumeral dystrophy and late onset [2]. In the ReSolve study, 41 patients with late onset, compared with 190 with adult onset, were more often women (58.5%), had longer alleles (6.5 vs 5.7 units), less facial and upper-limb involvement and more lower-limb involvement, which was the presenting symptom in 30% [52]. When facial weakness is minimal, FSHD may be mistaken for limb-girdle dystrophy; marked scapular winging, rising of the shoulders on arm elevation, foot drop and asymmetry should guide the diagnosis [53]. The French PNDS, which predates ENMC 279, retains the term “infantile form” with the criteria of facial weakness before 5 years and scapular weakness before 10 years, and describes in it facial diplegia, hypotonia, motor delay, hyperlordosis, sucking difficulty in neonatal forms and dysarthria as a warning sign [9]. It also lists atypical forms confirmed by molecular biology: facial-sparing FSHD, a limb-girdle dystrophy picture without facial weakness or scapular winging, distal myopathy of the anterior or posterior compartment of the leg, monobrachial or highly asymmetric weakness, monomelic atrophy of one lower limb, progressive external ophthalmoplegia, camptocormia or predominant axial weakness, hemibody atrophy, isolated facial diplegia and tongue atrophy; in most of these cases, the history or examination found other subtle signs or a suggestive family history [9].

4. Clinical Recognition and Warning Signs

GeneReviews suggests FSHD with predominantly facial, scapular stabiliser and/or foot-dorsiflexor weakness without ocular/bulbar weakness, often asymmetric; worsening after pregnancy; prior inflammatory myopathy refractory to immunosuppression; or autosomal dominant-compatible family history [2]. Absent family history does not exclude de novo mutation, mosaicism or incomplete penetrance [5].

The 2024 genetic guidance recommends testing with one or more typical signs, especially positive family history, while cautioning against false positives without a suggestive phenotype because 8–10U alleles are frequent in the population [5].

The French PNDS (French National Diagnosis and Care Protocol) advises considering FSHD in the presence of weakness with marked asymmetry, upper-limb predominance, thoraco-abdominal involvement, or predominant paravertebral weakness with subtle facial weakness; in forms with onset in early childhood, the presence of hearing loss or vascular retinopathy makes the diagnosis almost certain [9]. CK above 1,000 U/L is considered atypical and should suggest another myopathy, a lower threshold than the 1,500 IU/L of GeneReviews [2, 9]. When FSHD is suspected, the primary care physician refers the patient to neurology, preferably at a neuromuscular disease reference or competence centre [9].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Confirmation criteria

FSHD1 is diagnosed in a proband with a characteristic clinical picture and a heterozygous pathogenic contraction of the D4Z4 array at 4q35 on a permissive haplotype; FSHD2 is diagnosed in a proband with a characteristic picture and hypomethylation of a shortened D4Z4 array (but not to FSHD1 level) on a permissive haplotype, due to a heterozygous variant in SMCHD1 or DNMT3B, biallelic variants in LRIF1, or an unknown cause [2]. The 2024 consensus adds the category “clinical FSHD, unknown genetic cause” for patients with a typical phenotype, at least one permissive 4qA allele and no hypomethylation [5]. The AAN attributes to FSHD1 testing a sensitivity of approximately 93% and a specificity of approximately 98%, and recommends genetic confirmation in atypical presentations without a confirmed first-degree relative (level B) [7]. The French PNDS (French National Diagnosis and Care Protocol) places genetic testing of the FSHD1 locus first-line, despite it being neither fully sensitive nor fully specific, and reserves muscle biopsy for atypical or sporadic phenotypes without molecular confirmation [9].

5.2. Non-molecular investigations

Serum CK is normal or elevated, rarely above 3–5 times the upper limit of normal; values above 1,500 IU/L suggest another diagnosis [1, 2]. Electromyography may show mild myopathic changes in symptomatic muscles [2]. Muscle biopsy shows non-specific chronic myopathic changes and is reserved for suspected cases not confirmed genetically [1, 2]. Muscle MRI and ultrasound are not primary diagnostic tools but serve as biomarkers in trials; on MRI, STIR-hyperintense muscles predict radiological worsening [13, 43]. When testing does not confirm FSHD1, the French PNDS recommends: electroneuromyography to establish the myogenic nature and exclude neuropathy, plexopathy (Parsonage–Turner syndrome) or neuromuscular junction disease; muscle biopsy, which has no specific finding but shows, in approximately 30–40% of cases, a perifascicular or endomysial mononuclear infiltrate of CD8+ T lymphocytes without partial invasion of fibres, which distinguishes it from polymyositis; systematic dried blood spot acid alpha-glucosidase assay to exclude Pompe disease, which can also cause asymmetric scapular winging; and quantitative or semi-quantitative muscle MRI to document distribution and follow progression [9].

5.3. D4Z4 molecular techniques

Conventional sequencing is unsuitable: short-read exome/genome cannot establish D4Z4 size/haplotype [2, 5].

Technical pitfalls include a p13E-11-probe-region deletion rendering contraction invisible in standard testing in approximately 3% of European FSHD1 families. These proximal deletion alleles (DPED) may also remove DUX4c, FRG2 and myogenic enhancers; half derive from an ancient founder [2, 55]. DPED, cis duplications, hybrids and translocations may together represent 5% of FSHD1, particularly initially false-negative cases [5]. 4qA-S/4qA-L are equally pathogenic; 4qA-L appears European-specific [5]. Telomere-to-telomere reference reanalysis identified D4Z4-like sequences on other chromosomes, highlighting incomplete-reference limitations for read-based analyses [56].

5.4. Diagnostic algorithm

1. Clinical suspicion (section 4), three-generation pedigree and careful relative examination, frequently revealing minimally symptomatic carriers [1, 57].
2. Simultaneous D4Z4 sizing/haplotyping: permissive 4qA 1–10U confirms FSHD1, with cautious 8–10U interpretation [2, 5].
3. Sporadic cases: seek proband mosaicism and test parents [5].
4. No contraction but at least one permissive allele: D4Z4 methylation; hypomethylation leads to SMCHD1, DNMT3B, LRIF1 sequencing, then deletion/duplication analysis if negative [2].
5. Panel-identified SMCHD1: confirm permissive allele/hypomethylation before concluding FSHD2 [5].
6. Typical phenotype, permissive allele, normal methylation: “clinical FSHD, unknown genetic cause”; consider complex-allele methods and differentials [5].
7. Clinical–molecular severity discordance: review complex alleles, second disease or modifier [5].

In France, according to the 2022 PNDS, molecular diagnosis of FSHD1 is performed in two laboratories, in Marseille (the only one with a molecular combing platform) and in Paris (Cochin Hospital), with a mean turnaround time of 6–8 months; Southern blotting requires a large-volume blood sample and DNA extraction optimised for long fragments, and molecular combing requires fresh blood [9]. Prescription follows bioethics law: the test is requested by a physician working with a clinical genetics team, after prior information on the implications of the result and on how to inform relatives [9]. Molecular investigation of FSHD2 was not offered routinely and was being transferred from research to diagnostic practice, with indications discussed at a dedicated multidisciplinary team meeting and with no predictive or prenatal use [9].

5.5. Interpretation by ancestry

Japanese/South Korean FSHD1 alleles range 1–6 units, suggesting lower 7–10U pathogenicity. Report 8U as likely pathogenic in European patients but less certain in Japanese patients; ancestry should accompany testing [5]. Indian, Japanese and South Korean patients have lower 8–10 penetrance, while Chinese 1–6-unit alleles exceed 7–10-unit alleles in frequency [2]. Approximately 91% of African alleles are 4qA, yet few sub-Saharan-ancestry patients are recognised, suggesting unidentified protective factors [5].

Over 800 Italian/Brazilian controls included 3% healthy individuals with 4–8 units, one third (1.3%) with 4A161PAS; only 50.1% of 253 Italian probands had classic 1–8-unit 4A161PAS signatures. The authors proposed revising molecular criteria [58]. Subsequent consensus retained permissive contraction, explaining overlap through grey-zone alleles, incomplete penetrance and modifiers; results still require phenotype/family interpretation [2, 5].

5.6. Genetic reporting requirements

Reports should specify complete-unit sizes and corresponding fragments, haplotype and chromosome 4/10 origin, mosaicism and estimated cell fraction, methods/limitations; FSHD2 reports add methylation, permissive-allele size, versioned-transcript HGVS, zygosity and ACMG/AMP classification [5, 42]. Partial SMCHD1 VUS segregation alone cannot establish pathogenicity; D4Z4 hypomethylation provides required functional evidence [5]. Requests should include a structured clinical form [5].

6. Differential Diagnosis

Asymmetric facioscapulohumeral distribution is the principal distinguishing feature. Oxford's Emery-derived appendix figure compares predominant weakness in Duchenne/Becker, Emery–Dreifuss, limb-girdle, FSHD, distal and oculopharyngeal dystrophies [59].

Shared SMCHD1 aetiology does not imply Bosma/FSHD2 clinical overlap and should not be presented as cross-risk in counselling [33, 38].

7. Treatments and Risk Management Strategies

7.1. Principles and initial assessment

By 6 October 2026, neither the US Food and Drug Administration (FDA) nor European Medicines Agency (EMA) had authorised an FSHD medicine. Symptomatic, preventive, multidisciplinary management follows AAN guidance, ENMC 171 standards and GeneReviews tables [2, 7, 10, 12]. The European patient association emphasises that absent disease-modifying therapy does not mean absent treatment: effective multidisciplinary symptom care remains central [44].

The French PNDS gives specific attention to the disclosure of the diagnosis: it should be made early, by an experienced physician in coordination with the primary care physician, in a dedicated consultation and in a setting that guarantees confidentiality; in childhood forms it is made to both parents and to the child, with information adapted to the child's understanding [9]. In sporadic cases, the shock of disclosure may prevent retention of information, so a further consultation is planned within weeks to a few months, together with validated written documents, contact with patient associations and psychological support from the time of disclosure [9].

7.2. Manifestation-specific treatment

None of the symptomatic medicines above (anti-inflammatory drugs, antidepressants, antiepileptics) has an FSHD-specific indication or dosage in any label; the reference dose is the label dose of each medicine for the type of pain closest to the patient's (off-label use in FSHD), and the label dosages of amitriptyline, duloxetine, gabapentin, pregabalin and carbamazepine for neuropathic pain are tabulated, with the differences between the FDA, the EMA and INFARMED, in section 7.4 of the Charcot-Marie-Tooth chapter. The AAN recommends against prescribing albuterol (salbutamol), corticosteroids or diltiazem to increase strength (level B), based on negative trials, and records that the anti-myostatin antibody MYO-029 did not improve strength [7]. Spinal interventions (for example, arthrodesis for hyperlordosis) and anaesthesia require prior respiratory assessment [2, 7].

Regarding scapular fixation, the French PNDS is more restrictive than the AAN: it regards it as exceptional and a last resort, because there are no prospective controlled studies and peri- and postoperative complications are significant, and it excludes patients with significant deltoid or triceps weakness (<4/5 on the Medical Research Council scale) [7, 9]. In growing patients with open growth plates, it describes temporary scapulopexy to the rib cage or to the contralateral scapula with a tendon allograft; in adults, scapulothoracic arthrodesis, which requires a functional rotator cuff and a deltoid that is little or not affected [9]. Risks include pneumothorax or haemothorax, local infection, pseudarthrosis and hardware discomfort; the gain in forward flexion is limited and abduction decreases, so surgery is proposed only when a real functional gain is anticipated, in a specialised centre [9]. Tendon transfer for disabling foot drop, cosmetic pectoral surgery (without functional gain) and eyelid, lip or abdominal plasty are discussed on a case-by-case basis [9].

7.3. Perioperative care and anaesthesia

The AAN recommends pulmonary function testing before procedures under general anaesthesia (level B), and GeneReviews includes a respiratory medicine consultation before surgery under anaesthesia in its surveillance [2, 7]. In Ciafaloni's pregnancy series, anaesthetic complications were more frequent than in the general population [63]. The French PNDS identifies no FSHD-specific anaesthetic precautions or increased risk of malignant hyperthermia, and applies the precautions common to neuromuscular diseases; in its section on pregnancy, however, it recommends avoiding halogenated inhalational anaesthetics and suxamethonium, because of the risk of rhabdomyolysis and hyperkalaemia, and using non-depolarising neuromuscular blockers at reduced dose with monitoring of neuromuscular blockade, an internal inconsistency in the document that the anaesthetist must resolve case by case [9]. The same document provides for the patient to be given a care and emergency card, updated throughout follow-up [9]. In respiratory failure, it contraindicates mucolytics and respiratory depressant drugs; for statins, it follows the 2002 position of the French medicines agency — no absolute muscular contraindication, with cardiovascular risk weighed against muscle fragility and close muscle monitoring during treatment; vaccines are not contraindicated [9].

7.4. Investigational treatments: completed trials

These trials establish three interpretative points. ReDUX4 exploratory phase 2 signals did not replicate in REACH phase 3; no expected 48-week placebo decline limited short-term functional sensitivity in heterogeneous, slowly progressing disease [64, 65]. Myostatin-pathway muscle-volume gains with ACE-083/emugrobart did not yield function gains [66, 69]. Biopsy DUX4 biomarkers vary substantially between people/over time, motivating circulating markers [13, 28].

The French PNDS, drafted in 2021, also records as negative the trials of albuterol with or without oxandrolone (NCT00004685, NCT00027391), corticosteroids, diltiazem, MYO-029 (NCT00104078) and ACE-083; a trial of four antioxidants (vitamins C and E, zinc and selenium) against placebo improved quadriceps strength and endurance without changing walking distance, and supplementation with folic acid and methionine did not alter DNA methylation; it also cites a randomised, double-blind phase 2 trial of creatine monohydrate in children (NCT02948244), with change in MFM at 3 months as the outcome [9]. The description of losmapimod in that document — significant improvement in strength and reduction in fatty infiltration in the 80-participant phase 2 study, with a phase 3 planned for 2022 — is outdated: the primary endpoint of ReDUX4 was negative and REACH met none of its endpoints (table above) [9, 24, 64].

7.5. Developing therapies and developments in the last 12 months

The hierarchy of evidence must be explicit. The quantitative del-brax data come from company press releases, not peer-reviewed articles; the 2026 announcement did not disclose effect sizes; the statement that the accelerated approval pathway “is open” is a sponsor statement about its dialogue with the FDA, not an accepted application, an opinion or an authorisation [10, 71, 72]. The EPI-321 and SRP-1001 data are preliminary results from small open-label series [73, 75]. Reductions in KHDC1L and CK demonstrate target engagement, but the relationship between biomarker and clinical benefit has not yet been established; Novartis itself and the FSHD Society note that clinical benefit remains to be studied [10, 28]. The doses cited for investigational medicines are trial regimens, not recommendations for use.

7.6. Comparative regulatory status

Without an authorised medicine, US/EU label differences, paediatric extensions, Portuguese INFARMED reimbursement or Brazilian ANVISA/CONITEC incorporation do not apply. ENMC 279 anticipates that future EMA-approved therapies may face national reimbursement and age/subtype/progression restrictions producing cross-country access inequality; it advocates including children/non-ambulant patients in trials [13].

7.7. Risk management and surveillance

Surveillance by system, with the intervals and thresholds of GeneReviews, the AAN, ENMC 279 and the French PNDS (French National Diagnosis and Care Protocol), is brought together in the table in section 11.3 [2, 7, 9, 13].

7.8. Divergences between the French PNDS and other guidance

The PNDS gives no medicine doses for FSHD; as there is no medicine authorised for this indication, there is no label comparison to make, and analgesic dosages are those of the respective labels for the corresponding type of pain, as set out in section 7.2 [9].

8. Reproductive Options and Family Counselling

8.1. FSHD1: autosomal dominant inheritance

Approximately 70–90% of FSHD1 probands have a parent with clinical signs/contracted allele; 10–30% have constitutional or mosaic de novo contraction [2]. Test parents of apparently isolated cases: reduced penetrance, early death, late onset or non-recognition may obscure disease [2]. If neither parent has blood contraction and parentage is confirmed, possibilities are de novo proband contraction, a parental probe-region deletion producing false negativity, or gonadal/gonadosomatic mosaicism of unknown incidence [2]. Oxford recommends parental mosaicism assessment because sibling risk may be substantial [1].

Penetrance increases with age/shorter alleles. Among 52 Brazilian families, age-30 penetrance was 83% overall, 95% male and 69% female. Mosaic new mutations were more frequent in women; severe cases more often followed new mutation/maternal transmission [1, 81]. GeneReviews cites these values attributing them to a Dutch 2018 study; that study's 10 probands with 4–9 units and 140 relatives showed size-dependent penetrance increasing into late adulthood, with 25% asymptomatic carriers having subtle signs and 17% non-penetrance [2, 57]. At least 50% have weakness, particularly facial, by 12 [1]. Severity generally follows similar intrafamilial patterns; markedly discordant siblings are unusual [1].

8.2. FSHD2: digenic inheritance

FSHD2 parents may each carry one alteration asymptomatically, or one carry both [2]. Identify/inform pathogenic SMCHD1 relatives: usually asymptomatic, they can transmit the variant and produce affected offspring with a partner's permissive <20U allele [5]. A child inheriting a chromatin modifier plus permissive 4qA ≤10 units combines FSHD1/FSHD2 contributions and may be more severe [2, 5]. SMCHD1-containing 18p deletion FSHD2 risk depends on 4qA and requires counselling [39, 40].

8.3. Predictive testing and minors

Predictive testing is possible when the familial alteration has been identified and should be preceded by formal counselling on consequences, capabilities and limitations [2]. Testing of asymptomatic minors for a typically adult-onset disease without benefit from early intervention should be deferred until they can decide; in symptomatic children, testing has a diagnostic role [1, 2]. The Oxford Desk Reference stresses that FSHD is usually penetrant by early adulthood and that predictive testing is feasible if the proband has a short fragment [1]. For 8–10U alleles, phenotype prediction is impossible despite a reliable genetic diagnosis [5]. In France, the PNDS (French National Diagnosis and Care Protocol) points out that a patient with a genetic abnormality that may cause serious disease amenable to preventive or care measures has a legal obligation to inform at-risk relatives (Decree No. 2013-527 of 20 June 2013) [9]. Predictive testing is possible only when the contraction has previously been identified in an affected first-degree relative, is carried out within a multidisciplinary medical and psychological support protocol and is always confirmed on a second sample; in asymptomatic minors it is not permitted, although it may exceptionally be discussed after 10 years of age, for example when questions of career guidance arise [9]. When the diagnosis remains clinical, with no molecular abnormality identified, genetic counselling is still necessary, but there is no predictive test to offer relatives; in FSHD2, the digenic mechanism and the lack of a routine test preclude predictive testing and prenatal diagnosis in France [9].

8.4. Prenatal and preimplantation diagnosis

In FSHD1 with a known familial alteration, prenatal diagnosis is possible by chorionic villus sampling (10–13 weeks) or amniocentesis (15–17 weeks, requiring cell culture), with confirmation by indirect markers to exclude maternal contamination [2, 5]. Preimplantation genetic testing depends on indirect testing with 4q35 markers (D4S2390, D4S1652, D4S2930, D4S1523), has an estimated 5% risk of error due to recombination and must be confirmed by prenatal diagnosis [2, 5]. Long-read sequencing of the proband has recently been applied to the preparation of preimplantation testing, so far in small series [54]. GeneReviews considers prenatal and preimplantation diagnosis for FSHD2 unavailable; the 2024 consensus allows that, in families with a known variant, the first step may be to test for that variant and, if present, to genotype the haplotype and the parental origin of the alleles [2, 5]. The Oxford Desk Reference observes that requests for prenatal diagnosis tend to arise in severe forms, because FSHD is usually an adult disease with normal cognition and near-normal life expectancy [1]. The French PNDS performs prenatal diagnosis of FSHD1 by chorionic villus biopsy at around 12 weeks of gestation, only when the parental abnormality is well characterised and often after study of several affected and unaffected relatives, with joint management by the multidisciplinary prenatal diagnosis centre, the reference centre and the accredited laboratory, and not on a systematic basis; the couple should be informed about the fetal material required, new parental samples, the molecular strategy and the long turnaround times [9]. Preimplantation diagnosis is not offered in France for reasons of technical feasibility and reliability, although it is available in other countries, such as the USA or Belgium, by indirect study of polymorphic markers with family analysis [9].

8.5. Pregnancy and childbirth

In a study of 105 pregnancies in 38 women with FSHD, outcomes were generally favourable, but there were more low-birthweight newborns, instrumental deliveries, caesarean sections and anaesthetic complications than in the general population; weakness worsened in 24% of pregnancies, beginning during pregnancy and generally without recovery after delivery [2, 63]. The Dutch reviews of 2022 and 2026 propose a care framework spanning contraception and fertility, preconception counselling, pregnancy, delivery and the postpartum period, with individualised counselling, a multidisciplinary team and preconception discussion with obstetrics [5, 82, 83]. The French PNDS summarises the data in a similar way: worsening of weakness in 12–27% of pregnant women, sometimes persisting after delivery; prolonged labour with a significant increase in instrumental extraction, even in women unaware of the diagnosis, and a non-significant increase in caesarean sections; lower birthweight in one series, without intrauterine growth restriction; and no excess of pre-eclampsia, hypertension or preterm birth [9]. It regards pregnancy as at risk and requiring monitoring, especially with severe motor weakness; epidural analgesia and spinal anaesthesia are permitted [9]. If there is known respiratory failure with vital capacity <70% of predicted, it recommends serial measurements — a value from the year before pregnancy or, failing that, one in the first and another in the third trimester — to decide on mask ventilation before delivery if vital capacity falls with nocturnal hypopnoea, and delivery mandatorily in a level 3 maternity unit if there is pre-existing respiratory failure or worsening during pregnancy [9].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence

The estimated prevalence of FSHD lies between 4 and 10/100 000 in GeneReviews, and the 2024 guidance describes FSHD as the second commonest muscular dystrophy in adults [2, 5]. The French PNDS (French National Diagnosis and Care Protocol) classifies it as the commonest muscular dystrophy in adults and the third commonest at all ages, although its summary for the primary care physician describes it as the second commonest myopathy in adults, and estimates the proportion of cases without a family history at approximately 30% [9]. The frequencies in the table refer to FSHD as a whole; FSHD2 accounts for approximately 5% and SMCHD1-related FSHD for approximately 4% of all FSHD, so the overall frequency should not be transferred to individual subtypes or genes [2].

9.2. Population genetic variation and founder effects

Pathogenic thresholds derive chiefly from European/North American ancestry [5]. Japanese/South Korean alleles are 1–6 units; Indian 8–10 penetrance is lower; Chinese 1–6 alleles predominate, with national median 5 units/onset 16 [2, 5, 86]. 4qA-L appears European-specific [5]. Worldwide subtelomere analysis found only four human-evolution 4q/10q interchromosomal transfers, explaining hybrid/translocated alleles [87]. Half of characterised European/North American DPED alleles derive from an ancient founder [55]. African 4qA frequency is 91% but few patients are identified [5].

9.3. Brazil and Portugal

Mayana Zatz's São Paulo group contributed Brazil's classical 52-family study of 83% age-30 penetrance with sex differences, a non-severer FSHD1 homozygote, and controls with short alleles [32, 58, 81]. Brazilian experts joined 2024 diagnostic consensus/ENMC paediatric workshop [5, 13]. Portuguese consulted sources include treated exudative maculopathy in Porto and coexisting sarcomeric hypertrophic cardiomyopathy in Lisbon [46, 49]. No national Brazilian/Portuguese prevalence estimates were found in these sources; this does not establish absence of published studies.

9.4. Sex and other special populations

Sex effects remain controversial. Brazil found greater male penetrance/severity and more asymptomatic women; GeneReviews reports higher male mosaic penetrance, but later studies found no severity difference or lifetime oestrogen effect [2, 5, 81]. ReSolve late onset was more frequent in women [52]. Childhood research should include severe/non-ambulant patients, with age-adapted consent/assent [13].

10. Illustrative Clinical Case

10.1. Two siblings with FSHD1 and clinically normal parents (Jiang et al., 2024)

Jiang and colleagues at West China Second University Hospital, Chengdu, described non-consanguineous parents without symptoms and two affected siblings, investigated by exome, optical genome mapping and distal D4Z4 bisulphite sequencing [88]. Original images include the pedigree/clinical photographs and optical maps: Figure 1 — pedigree and phenotype and Figure 3 — optical mapping.

The first-born female proband noted limited right-arm elevation at 17, when her 15-year-old brother sought assessment for two years of bilateral upper-limb weakness [88]. CK was 840 IU/L (reference 24–194), EMG myopathic, and rehabilitation gave no significant improvement. Arm atrophy worsened by 20 with stair, running and jumping difficulty; at 27 she remained independent but struggled to comb her hair [88]. Her 2022 examination showed hypomimia, incomplete eyelid closure, thick lips from orbicularis oris pseudohypertrophy, inability to purse lips, puff cheeks or whistle, asymmetric arm weakness and winging, with normal reflexes, sensation, cognition and hearing [88]. MRI showed gluteal/thigh, right-arm and paravertebral abnormalities. DMD MLPA (2015) and exome (2021) were negative. Pregnancy planning prompted preconception assessment: mild restrictive function (88.1% ventilatory reserve), sinus arrhythmia on Holter, normal echocardiogram and mild left ventricular trabeculation with normal systolic function on cardiac MRI [88].

Her brother noted arm atrophy at 13; at 15 CK was 1,153 IU/L, EMG myopathic and biopsy showed primary dystrophy, initially suspected myotonic dystrophy [88]. At 25 he had complete facial weakness, shoulder/arm/chest atrophy, winging, abdominal/foot weakness, abnormal gait and difficulty rising from squatting. Severity exceeded his sister's: clinical FSHD 9 versus 8, age-adjusted severity 533 versus 353 [88].

Optical mapping identified compound heterozygous 4qA contractions of 4 and 8 units in the proband; her brother had 4-unit 4qA and 28-unit 4qB. The neurologically normal father carried 8-unit 4qA; the unaffected mother had 49-unit 4qA and low-level 4-unit 4qA mosaicism, leading the authors to infer maternal germline mosaicism [88]. Distal CpG6 methylation was 60% in the proband, 20% in her brother and 90% in both parents, tracking severity [88].

10.2. Interpretation and limitations

The case brings together several points of this article: a proband with no apparent family history; a negative exome, because short-read sequencing does not detect D4Z4 contraction; late diagnosis, about 10 years after the first symptoms; the grey-zone 8-unit allele in an unaffected father; and low-level parental mosaicism, which changes the recurrence risk [5, 88]. Compound heterozygosity did not result in a more severe phenotype than that of the brother with a single 4-unit allele, in agreement with the observation that allele dosage does not by itself predict severity [2, 32, 88]. The brother's CK, about 6 times the upper limit, exceeded the usual range of 3–5 times, a reminder that these thresholds guide but do not exclude [2]. The correlation between methylation and severity within a single family is illustrative and does not constitute a validated predictive test. The proband's preconception respiratory and cardiac assessment reflects the authors' practice; the guidelines do not recommend routine cardiac screening in asymptomatic patients but support baseline respiratory testing and preconception counselling [7, 82].

11. Prognosis and Long-Term Follow-up

11.1. Natural history

FSHD does not reduce life expectancy in most patients; approximately 20% eventually require a wheelchair [1, 2]. In a US registry of 313 genetically confirmed patients (2002–2011), the risk of becoming a wheelchair user within 6 years was 24.0% (95% CI 18.6–29.3), with a bimodal distribution: a peak in the second decade associated with large contractions and a later age-dependent rise [89]. In the Chinese national FSHD1 series, 12.0% lost independent ambulation, with an expected duration of 40 years between onset of weakness and loss of ambulation; loss was associated with fewer units and earlier onset [86]. The ENMC 279 report summarises loss of ambulation at approximately 10% in the classic form (10–20% above 50 years) and 40% of symptomatic infants by 18 years [13]. These figures describe different cohorts — a patient registry, a referral-centre series and a workshop synthesis — and are not interchangeable. The French PNDS (French National Diagnosis and Care Protocol) describes a functional impact usually compatible with near-normal activity until 30–40 years of age and need for a wheelchair in 15–20% of patients by 50 years [9].

Early onset/large contractions increase disability. AAN recommends 10–20 kb fragments signal increased significant-disability probability, earlier onset and symptomatic extramuscular features, level B [2, 7]. Fujian data show onset mediating repeat-size effects on severity [90]. Conversely, Italy found no significant severity difference before/after onset age 10; ascertainment bias may inflate associations [2, 50]. Respiratory dysfunction increases severe-patient morbidity/mortality [45].

11.2. Assessment instruments

Instruments used in clinical practice and research include the FSHD clinical score (0–15), the Ricci severity scale (0–5) and its age-corrected version, reachable workspace, dynamometry and quantitative strength testing, the 10 m run/walk, the 6-minute test, the FSHD-COM composite measure (also in a paediatric version), the neuromuscular disease independence scale and questionnaires such as the paediatric FSHD-HI, the PedsQL neuromuscular module and the Neuro-QoL fatigue domain [13, 78, 88]. Whole-body MRI (fat fraction, STIR-positive muscles), ultrasound and electrical impedance myography are imaging and tissue biomarkers sensitive to change over 1–2 years [13]. In children, growth may mimic improvement on ultrasound or MRI [13]. For physical medicine and rehabilitation assessment, the French PNDS proposes the Walton scale (from 0, normal activity, to 10, bedridden and dependent), the Brooke scale for the upper limbs (1–6) and the Vignos scale for the lower limbs (1–10), the Motor Function Measure (MFM-32 in adults and a 20-item version in children, in three dimensions — standing and transfers, axial and proximal motor function, distal motor function — administered by trained staff), timed tests (climbing and descending 4 steps, rising from a chair, Timed Up and Go, 10 m, 6 minutes) and the Ricci severity scale, graded from 0 to 5 in half points; the choice depends on local practice but should be maintained over time [9].

11.3. Follow-up plan

In summary: physiotherapy at least annually; pain assessment at every visit; baseline respiratory testing repeated according to severity, with specialist assessment if FVC <60% or sleep symptoms; annual ophthalmoscopy for large contractions; audiometry in children; cardiac assessment only if symptomatic; and, in children, multidisciplinary visits every 6–12 months, with attention to school, psychological support and transition to adult care, understood as a process planned from adolescence until after 20 years of age [2, 7, 13]. At-risk relatives should be examined carefully, because many carriers have subtle signs without complaints [57]. In France, the PNDS (French National Diagnosis and Care Protocol) recommends an annual multidisciplinary assessment at a reference or competence centre — neurological, rehabilitation, respiratory, cardiological, neurosensory and, if necessary, neuropsychological — or approximately every 2 years in mild or slowly progressive forms, with a summary report sent to the patient and the professionals involved, ideally within 15 days [9].

11.4. Reference networks and patient organisations

ERN EURO-NMD includes FSHD and several 2024 guidance authors [5, 14]. Founded in 2021, FSHD European Trial Network coordinates genetics, outcomes, biomarkers, imaging and childhood onset with the US Clinical Trial Research Network, FSHD Society, TREAT-NMD and ERNs [13]. FSHD Europe represents eleven countries' organisations [13]. GeneReviews lists FSHD Society, Friends of FSH Research, FSHD Global Research Foundation, Canadian Neuromuscular Disease Registry and Rochester's US myotonic dystrophy/FSHD registry; Oxford lists Muscular Dystrophy UK [1, 2]. Portugal's Associação Portuguesa de Neuromusculares (APN) and Brazil's Associação Brasileira de Distrofia Muscular (ABDIM) support neuromuscular patients [91, 92].

In France, care is organised within the FILNEMUS neuromuscular disease filière, with multidisciplinary clinics accredited as reference or competence centres (listed in the PNDS appendix), two molecular diagnostic laboratories (Marseille and Paris) and the national FSHD Observatory, a registry based at Nice University Hospital that collects clinical, genetic and demographic data for epidemiology, research and trial readiness [9]. Severe FSHD falls within long-term condition No. 9 (severe forms of neurological and muscular diseases), with 100% coverage initiated by the specialist and renewed by the primary care physician; the patient receives a patient card and a care and emergency card; the departmental centre for persons with disabilities (MDPH) grants the mobility card and the disability compensation benefit for human and technical assistance and, in childhood forms, school adaptations, a support worker for pupils with disabilities (AESH) and the allowance for the education of a child with a disability (AEEH); workplace adaptation or invalidity are assessed case by case [9]. The reference patient association is AFM-Téléthon (French Association against Myopathies) [9].

12. Summary and Final Considerations

FSHD is one of the commonest muscular dystrophies in adults, with a prevalence of 4–12/100 000 in the European populations studied, and results from ectopic expression of DUX4 in muscle, possible only on a permissive 4qA haplotype [2, 6, 8]. In approximately 95% of patients, the cause is contraction of the D4Z4 array to 1–10 units (FSHD1, autosomal dominant, with 10–30% de novo cases and frequent mosaicism); in the remainder, hypomethylation due to variants in SMCHD1, DNMT3B or LRIF1 combines with a permissive allele (FSHD2, digenic) [2, 5]. Diagnosis requires dedicated techniques — Southern blotting, optical mapping, molecular combing or long-read sequencing — with haplotyping and, when FSHD2 is suspected, methylation analysis; a negative exome does not exclude FSHD, and 8–10-unit alleles, complex alleles and the patient's ancestry affect interpretation [5]. The clinical picture combines asymmetric facial, scapular, humeral and peroneal weakness with pain, fatigue, hearing loss and retinal vasculopathy in subgroups, particularly with large contractions and childhood onset [2, 13]. Counselling differs fundamentally between FSHD1 (50% for offspring, with penetrance dependent on age, allele size and possibly sex) and FSHD2 (risks of 25% or 37.5% depending on the partner's haplotype) [2, 81]. Care is multidisciplinary and symptomatic, with AAN and ENMC recommendations on exercise, pain, respiration, eyes and hearing; the trials of losmapimod, ACE-083 and emugrobart were negative for clinical outcomes, and products targeting DUX4 RNA, with del-brax in phase 3, are not yet authorised in any jurisdiction [7, 10, 24, 66, 69]. The 2022 French PNDS (French National Diagnosis and Care Protocol) adds to this foundation an explicit exercise prescription, exclusion criteria for scapular fixation, annual paediatric surveillance of hearing and retina, guidance for pregnancy and a national care organisation centred on the reference centres of the FILNEMUS filière, with divergences from the AAN chiefly regarding cardiac screening [7, 9].

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