How to diagnose Facioscapulohumeral Muscular Dystrophy (FSHD)?

Diagnosing Facioscapulohumeral Muscular Dystrophy (FSHD)

The diagnosis of FSHD is established through genetic testing for 4q35 D4Z4 repeat deletions (1-10 repeats versus normal 11-150 repeats), combined with clinical recognition of the characteristic pattern of facial, scapular, and humeral muscle weakness. 1

Clinical Recognition

Classic Presentation Pattern

• Facial weakness: Look for inability to close eyes completely, difficulty whistling, or asymmetric smile 2
• Scapular involvement: Prominent scapular winging, anterior axillary folds, and horizontally positioned clavicles are characteristic features 3
• Upper extremity pattern: Weakness of shoulder and pelvic girdle muscles with relative preservation of deltoids 3
• Asymmetric involvement: Asymmetric muscle weakness is significantly more common in FSHD compared to other muscular dystrophies 4

Atypical Presentations to Recognize

• Facial-sparing scapular myopathy: Some patients present without facial weakness 3
• Limb-girdle pattern: May mimic limb-girdle muscular dystrophy 3
• Distal myopathy: Occasionally presents with distal rather than proximal weakness 3
• Asymmetric brachial weakness: Can be the predominant feature 3

Diagnostic Algorithm

Step 1: Genetic Testing (First-Line)

• Order 4q35 D4Z4 repeat analysis on blood sample as the primary diagnostic test 1
• Testing identifies deletions resulting in 1-10 D4Z4 repeats (versus 11-150 in unaffected individuals) 1
• Critical caveat: Request 4qA/4qB allele determination, as an almost identical repeat array exists at 10q26 that can cause diagnostic confusion 5, 1
• FSHD only occurs with three specific "permissive" haplotypes that include a polyadenylation signal distal to the last D4Z4 unit 1

Step 2: Muscle MRI (When Genetic Testing is Equivocal or to Support Diagnosis)

• Upper girdle MRI is highly sensitive for identifying the specific FSHD pattern 4
• Most characteristic muscles affected: Trapezius, teres major, and serratus anterior show fatty replacement and atrophy even in paucisymptomatic patients 4
• Asymmetric involvement on MRI significantly favors FSHD over other myopathies 4
• MRI can detect involvement of non-clinically testable muscles and differentiate FSHD from other muscular dystrophies 4

Step 3: Muscle Biopsy (Rarely Needed)

• Reserve for cases where genetic testing is negative but clinical suspicion remains high 5
• May show inflammation in addition to dystrophic changes 2
• Important limitation: Biopsy findings are not specific for FSHD and cannot establish the diagnosis alone 5

Diagnostic Pitfalls to Avoid

Genetic Testing Challenges

• 10q26 confusion: The high sequence identity between 4q35 and 10q26 repeat arrays requires specific testing to distinguish them 1
• Haplotype requirement: Not all 4q35 deletions cause FSHD—only those with permissive haplotypes 1
• Detailed 4qA/4qB allele determination may be necessary in challenging cases 5

Clinical Variability

• Extreme clinical variability exists even within families carrying the same deletion 2
• Some patients may be paucisymptomatic or severely affected, requiring high index of suspicion 4
• Facial weakness may be absent in atypical presentations 3
• Combined genetic conditions can occur (e.g., FSHD with limb-girdle muscular dystrophy 2A) 5

When Diagnosis Remains Uncertain

• Consider whole-body muscle MRI to identify the characteristic pattern of trapezius, teres major, and serratus anterior involvement 4
• Repeat genetic testing with specific 4qA/4qB allele determination if initial testing was inconclusive 5
• Evaluate for alternative diagnoses including mitochondrial myopathy, which can occasionally mimic FSHD 5
• Genetic counseling is essential given the autosomal dominant inheritance pattern in most cases 2