Facioscapulohumeral Muscular Dystrophy: Clinical, Genetic, and Diagnostic Aspects

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscle diseases in adults and is notable for its broad clinical variability. While some individuals present with mild symptoms and slow disease progression throughout life, others develop more severe forms with onset during childhood. Although the disease was first described in the 19th century, knowledge regarding its genetic basis, clinical manifestations, diagnosis, and management continues to evolve.

In this article, you will understand the key aspects of FSHD, including symptoms, clinical presentation, variability, and diagnostic approaches. You will also learn how to interpret the context of facioscapulohumeral muscular dystrophy and how it differs from other types of muscular dystrophy.

What is facioscapulohumeral muscular dystrophy (FSHD)?

Facioscapulohumeral muscular dystrophy (FSHD), also known as Landouzy-Dejerine muscular dystrophy, is an inherited neuromuscular disorder characterized by progressive muscle weakness. The disease typically follows a characteristic pattern, initially affecting the facial muscles, the shoulder girdle muscles, and the upper limbs. FSHD demonstrates wide clinical variability, both in age of onset and severity of symptoms (1).

The name FSHD derives from the terms Facio (face), Scapulo (scapula), and Humeral (humerus), describing the body regions most commonly affected at disease onset: facial muscles, muscles responsible for scapular stabilization, and arm muscles.

FSHD is considered one of the most prevalent muscular dystrophies in humans. European studies estimate a prevalence ranging from 5 to 12 cases per 100,000 individuals (2), and more than 95% of cases correspond to the FSHD1 subtype (3).

What are the symptoms of FSHD?

FSHD presents with a characteristic but highly variable phenotype among patients. In general, disease progression occurs slowly over decades (2).

The most common initial symptoms include:

• Facial muscle weakness, causing difficulty smiling, whistling, drinking through a straw, or fully closing theeyes;
• Shoulder girdle weakness, leading to the characteristic “winged scapula” and difficulty raising the arms above shoulderlevel;
• Asymmetric involvement, often more pronounced on one side of thebody;
• Progressive weakness of trunk and lower limb muscles, which may alter gait and increase the risk of falls (4).

In addition to muscle involvement, some patients may develop extramuscular manifestations, such as (5):

• respiratoryimpairment;
• hearingloss;
• retinal vascular abnormalities, rarely associated with visualloss;
• possible increased risk of cardiac arrhythmias.

Facial weakness may impair simple facial expressions and complete eyelid closure during sleep, contributing to symptoms such as dry eyes (2, 6). Weakness of the abdominal muscles may lead to abdominal protrusion and increased lumbar curvature, known as lumbar lordosis (2).

Another highly characteristic finding is scapular winging, in which the scapulae become more prominent, especially when the patient attempts to raise the arms. This alteration compromises movements above shoulder level and may impact daily activities.

In most cases, the first symptoms appear during childhood or adolescence, and many patients notice signs of the disease before 20 years of age (2). However, late-onset cases also occur, with symptoms developing after the ages of 30, 40, or even 50 years (7).

Complications, prognosis, and quality of life

FSHD progression is generally slow, and many patients maintain functional independence for decades. Overall, life expectancy does not appear to be reduced in most cases. Nevertheless, some patients may eventually lose independent ambulation over time. A study conducted in China observed loss of independent walking ability in approximately 12% of patients after around 40 years of disease progression (8).

In more advanced forms, some individuals may require partial-time or full-time wheelchair use. Recent data indicate that approximately 24% of individuals with FSHD become dependent on a wheelchair at least part of the time within six years after diagnosis (9; 10).

Chronic muscle pain and fatigue often have a major impact on quality of life, even in patients with relatively mild muscle weakness. These symptoms are commonly related to compensatory muscle effort, postural changes, and muscle overload (11). More than 50% of patients report mild to moderate pain, and fatigue is among the factors that most interfere with daily activities (9; 10).

Despite functional limitations, multidisciplinary strategies can significantly improve quality of life. Adapted physical activity, physiotherapy, orthotic devices, environmental adaptations, and psychosocial support contribute to maintaining functionality and patient autonomy.

What are the causes and genetic mechanisms of FSHD?

FSHD is an autosomal dominant disorder caused by inappropriate expression of the DUX4 gene in skeletal muscle. This gene is normally “silenced” after embryonic development, but in FSHD it becomes abnormally activated, triggering toxic processes in muscle fibers that result in progressive muscle fiber damage and degeneration (1).

The disease is classified into two main genetic subtypes, FSHD1 and FSHD2, which share a common pathogenic mechanism: abnormal DUX4 activation. What differentiates the two types is the molecular alteration responsible for this dysregulation (12).

• FSHD type 1 (FSHD1): accounts for approximately 95% of cases and is associated with contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35;
• FSHD type 2 (FSHD2): is less common and results from epigenetic alterations in the same chromosomal region, generally associated with variants in regulatory genes such as SMCHD1 and DNMT3B (1).

On chromosome 4, there is a region called D4Z4, composed of multiple repeated DNA sequences (each approximately 3.3 kilobases long). In unaffected individuals, these repeats maintain chromatin in a more “closed” state, preventing activation of the DUX4 gene in skeletal muscle (13).

In FSHD, alterations in this silencing mechanism make chromatin more open and allow inappropriate DUX4 expression in muscle tissue. This may occur either through contraction of the D4Z4 repeats or through defects in genes involved in epigenetic regulation and DNA methylation (2).

In FSHD1, contraction of the D4Z4 repeats leads to disease development only when it occurs on a permissive haplotype known as the A allele. This is because only the A allele contains a functional polyadenylation sequence required to generate stable DUX4 messenger RNA (5).

De novo mutations (without family history) may also occur in up to 30% of cases, along with mosaicism and incomplete penetrance, contributing to disease variability.

Genetic differences between FSHD1 and FSHD2

How is FSHD diagnosed?

The diagnosis of FSHD is based on the combination of detailed clinical evaluation and specific genetic testing. The pattern of muscle weakness, especially when involving the face and shoulder girdle asymmetrically, is an important clinical indicator of the disease (4).

During clinical evaluation, characteristic signs may include:

• wingedscapula;
• difficulty raising thearms;
• facialweakness;
• Beevor’ssign;
• slow progression ofsymptoms;
• compatible family history.

Laboratory and complementary tests may aid in the investigation, although they are not diagnostic on their own:

• creatine kinase (CK) levels may be normal or mildlyelevated;
• electromyography (EMG)generally demonstratesa myopathic pattern;
• muscle magnetic resonance imaging (MRI) may reveal muscle atrophy and fatty replacement of affected muscles.

Diagnostic confirmation is achieved through molecular testing, considered the gold standard for FSHD diagnosis.

In FSHD1, genetic testing evaluates the number of D4Z4 repeats at the 4q35 locus on a permissive haplotype. In FSHD2, the methylation pattern of the D4Z4 region and variants in epigenetic regulatory genes such as SMCHD1 and DNMT3B are investigated.

More recent methods, such as long-read sequencing, are increasing diagnostic accuracy in atypical or inconclusive cases, especially in specialized centers (14).

When Should Facioscapulohumeral Muscular Dystrophy Be Suspected?

The clinical suspicion of facioscapulohumeral muscular dystrophy (FSHD) should primarily be considered in the presence of a characteristic pattern of muscle weakness, especially when there is asymmetric involvement of the facial muscles, shoulder girdle, and upper limbs.

According to the American Academy of Neurology, the regional distribution of muscle weakness is one of the main elements for the clinical recognition of the disease (5).

The disease should be particularly suspected in individuals with (2):

• facial weakness associated with difficulty smiling, whistling, or fully closing theeyes;
• prominent winged scapula, especially in adolescents and youngadults;
• shoulder girdle weakness with difficulty raising thearms;
• asymmetric muscleinvolvement;
• foot drop associated with facial or scapularweakness;
• absence of significant ocular or bulbarweakness;
• family historyconsistent withinherited muscle disease.

Some clinical situations may also serve as warning signs for FSHD, including:

• worsening muscle weakness afterpregnancy;
• previousdiagnosis of inflammatory myopathy without adequate response to immunosuppressive therapy;
• cases initially interpreted as other myopathies due to atypical clinical presentation.

Early recognition of these signs is important to guide appropriate genetic investigation and avoid diagnostic delays, which are still common in patients with FSHD.

Differences Between FSHD and Other Muscular Dystrophies

Treatment and Management of FSHD

Currently, there is no curative treatment or disease-modifying therapy approved for FSHD. Management is multidisciplinary and primarily aims to preserve functionality, reduce symptoms, and improve patients’ quality of life (1, 15).

The main therapeutic strategies include:

• personalized physical therapy, including strengthening, stretching, and mobility maintenanceexercises;
• occupational therapy and functional adaptations for dailyactivities;
• use of orthotic devices, such as shoulder or ankle supports, to improve mobility and preventfalls;
• management of pain and fatigue through physical and pharmacologicalapproaches;
• postural care and prevention of musculoskeletalcomplications;
• respiratory follow-up in severecases;
• genetic counseling for patients and family members.

In selected patients, surgical scapular fixation may improve arm elevation and upper limb functionality.

Although respiratory insufficiency is uncommon, patients with severe forms of the disease should undergo regular pulmonary function monitoring.

Some extramuscular manifestations also require specific follow-up. Patients with large deletions may develop retinal vascular abnormalities and should undergo ophthalmologic evaluation. Children with early-onset FSHD may develop significant hearing loss, making audiometric assessment recommended in these cases (5).

Musculoskeletal pain is common and should be routinely investigated during clinical follow-up. Low-intensity aerobic exercise appears to be safe and potentially beneficial, contributing to functional improvement and fatigue reduction.

Despite the challenges imposed by FSHD, advances in research have expanded knowledge about the disease and opened new perspectives for diagnosis and treatment. Multidisciplinary follow-up, combined with appropriate genetic diagnosis, plays a fundamental role in improving quality of life and providing individualized patient care.

As new DUX4-targeted therapies continue to advance in clinical studies, expectations are growing for increasingly effective approaches to disease management.

Which Tests Does SYNLAB Offer for the Investigation of Facioscapulohumeral Muscular Dystrophy?

SYNLAB offers genetic testing for the investigation of facioscapulohumeral muscular dystrophy, covering both FSHD1 and FSHD2 cases. The molecular evaluation includes analyses targeting the D4Z4 region of chromosome 4, which are essential for confirming FSHD1 diagnosis, as well as tests aimed at investigating epigenetic alterations and variants in regulatory genes associated with FSHD2.

For FSHD1, tests are available to evaluate D4Z4 repeat contraction by Southern blot and permissive haplotype analysis by SSLP fragments, both essential for the proper interpretation of the clinical relevance of molecular findings.

For FSHD2, SYNLAB offers analysis of D4Z4 region hypomethylation by Southern blot and investigation of variants in the SMCHD1 gene by next-generation sequencing (NGS), allowing for a broader and more precise diagnostic approach in suspected cases.

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Frequently Asked Questions (FAQ)

What is facioscapulohumeral muscular dystrophy?

It is an inherited genetic disorder that causes progressive muscle weakness, mainly affecting the face, shoulders, and arms; it is also called FSHD.

What does FSHD mean and why is it called that?

FSHD stands for Facioscapulohumeral Muscular Dystrophy. The name describes the initial sites of weakness: face (facio), scapula (scapulo), and humerus/arm (humeral).

What are the first symptoms?

They usually include facial weakness (for example, difficulty frowning or smiling), difficulty raising the arms, shoulder blades that appear “loose” or winged, and asymmetry between body sides.

Is there a cure for FSHD?

No, there is currently no cure. Treatment is supportive and multidisciplinary, aiming to maintain function, control pain and fatigue, and improve quality of life.

What is the life expectancy for someone with FSHD?

Life expectancy is generally normal or near normal. Disease progression is often slow, although there is variability among individuals.

Which tests confirm the diagnosis?

Genetic testing confirms the diagnosis: for FSHD1, analysis of the number of D4Z4 repeats on chromosome 4q; and for FSHD2, analysis of variants in regulatory genes and methylation studies. Complementary tests may help but do not replace molecular confirmation.

Is FSHD the same as “scapulohumeral” muscular dystrophy?

Not exactly. “Scapulohumeral” is an older and more general term that may refer to weakness affecting the shoulders and arms, whereas FSHD also involves facial muscles and has specific genetic causes. Therefore, the term scapulohumeral may be incomplete or imprecise when referring to FSHD.

References

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2. Schätzl T, Todorow V, Kaiser L, et al. Meta-analysis towards FSHD reveals misregulation of neuromuscular junction, nuclear envelope, and spliceosome. Commun Biol. 2024;7:640.

3. Preston MK, Wang LH. Facioscapulohumeral Muscular Dystrophy. 1999 Mar 8 [Updated 2025 Jul 10]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

4. Mul K, Lassche S, Voermans NC, Padberg GW, Horlings CG, van Engelen BG. What’s in a name? The clinical features of facioscapulohumeral muscular dystrophy. Pract Neurol. 2016;16(3):201-7. doi: 10.1136/practneurol-2015-001353.

5. Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. 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. Neurology. 2015 Jul 28;85(4):357-64. doi: 10.1212/WNL.0000000000001783.

6. Facioscapulohumeral muscular dystrophy. 2014. National Library of Medicine (MedlinePlus). Disponível em: https://medlineplus.gov/genetics/condition/facioscapulohumeral-muscular-dystrophy/

7. Mah JK, Chen YW. A Pediatric Review of Facioscapulohumeral Muscular Dystrophy. J Pediatr Neurol. 2018 Aug;16(4):222-231. doi: 10.1055/s-0037-1604197.

8. Wang Z, Qiu L, Lin M, et al. Prevalence and disease progression of genetically-confirmed FSHD1 in China between 2001 and 2020: a nationwide population-based study. Lancet Reg Health West Pac. 2021;18:100323.

9. Tawil R, Wagner KR, Hamel JI, Leung DG, Statland JM, Wang LH, Genge A, et al. Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2024 May;23(5):477-486.

10. Brun BN, Camarta N, Johnson N, Schoser B, Statland J, Voermans NC. Overview of facioscapulohumeral dystrophy clinical features and diagnostic pathway. Neuromuscul Disord. 2026 Apr;61:106389.

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13. Gatica LV, Rosa AL. A complex interplay of genetic and epigenetic events leads to abnormal expression of the DUX4 gene in facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2016 Dec;26(12):844-852.

14. Giardina E, Strafella C. Long-read sequencing and the evolving landscape of facioscapulohumeral muscular dystrophy diagnosis. Brain. 2026;149(5):1428–1430.

15. Daxinger L, Tapscott SJ, van der Maarel SM. Genetic and epigenetic contributors to FSHD. Curr Opin Genet Dev. 2015 Aug;33:56-61.