Clinical Guidance

D4Z4 repeat array contraction size. Evidence-based guidelines published in 2015 recommend that a large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) should alert clinicians to the increased likelihood of significant disability, earlier onset of symptoms, and increased likelihood of extramuscular manifestations . Allele size explains roughly 10% of variability in phenotype . A correlation has been reported between the degree of the pathogenic contraction of the D4Z4 locus and the age at onset of symptoms, age at loss of ambulation, and muscle strength. Individuals with a large contraction of D4Z4 (1-3 repeats) have a higher probability of earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus .

Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"

Penetrance

Penetrance is increased with smaller D4Z4 repeat arrays; however, significant variation exists. In one study, penetrance of FSHD varied by age and sex; it was 83% by age 30 years, but significantly greater for males (95%) than for females (69%) . The effect of the affected individual's sex on penetrance and disease variability is uncertain, with data showing a lack of significant effect of lifetime estrogen exposures or methylation status between sexes . Effects from epigenetic factors such as methylation status (for both FSHD1 and FSHD2) and other unknown environmental or genetic factors likely contribute .

Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"

Diagnostic Criteria

Evidence-based guidelines for diagnosis of facioscapulohumeral muscular dystrophy (FSHD) are available .

Suggestive Findings

FSHD should be suspected in individuals with the following:

• Weakness that predominantly involves the facial, scapular stabilizer, and/or foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Weakness is often asymmetric.

• Progression of weakness after pregnancy

• Prior diagnosis with inflammatory myopathy that is refractory to immunosuppression

Family history of FSHD is most often consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Supportive Findings

Serum concentration of creatine kinase (CK) is normal to elevated in individuals with FSHD and usually does not exceed three to five times the upper ...

Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"

Differential Diagnosis

Genetic disorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) are listed in . Table 3. Genetic Disorders of Interest in the Differential Diagnosis of Facioscapulohumeral Muscular Dystrophy

Management Guidelines

Clinical practice guidelines for facioscapulohumeral muscular dystrophy (FSHD) have been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FSHD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Facioscapulohumeral Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Musculoskeletal

| Physical exam | To assess strength functional limitations

Eval for PT need for assistive devices |

Pain assessment |

Neurodevelopmental

| OT speech therapy assessment | In persons w/infantile onset

Respiratory/Sleep

| • Eval for hypoventilation

• Screen for daytime somnolence, nonrestorative sleep

| • Baseline PFTs

• Low threshold for pulmonary/sleep eval if abnormal PFTs or sleep symptoms

Ophthalmologic

| Ophthalmologic eval | • In persons w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) or visual symptoms

• For presence of retinal vasculopathy

Audiologic

| Assessment of hearing | • In all affected infants children

• In adults w/symptomatic hearing loss

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of FSHD to facilitate medical personal decision making

FSHD = facioscapulohumeral muscular dystrophy; MOI = mode of inheritance; OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy

Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"

Therapies Under Investigation

Genetic treatments such as siRNA treatment to silence DUX4 are being studied, as is an epigenic 4q35 silencing treatment delivered by adenovirus, EPI-321. Losmapimod, an inhibitor of p38/ mitogen-activated protein kinase (MAPK), resulted in improved reachable workspace and strength in both treatment and placebo groups. A monoclonal antibody to myostatin is in Phase II trials. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Facioscapulohumeral Muscular Dystrophy: Recommended Surveillance

Source: GeneReviews — "Facioscapulohumeral Muscular Dystrophy"