Facioscapulohumeral muscular dystrophy (FSHD) is the third most common neuromuscular disorder after Duchenne muscular dystrophy and myotonic dystrophy. It is character- ized by progressive weakness and atrophy of the facial and shoulder girdle muscles. The other muscles are also involved.
Its prevalence is estimated to be 1 in 20,000.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant
b. Almost complete penetrance (95%) 2. FSHD1 gene
a. Mapped to the subtelomeric region of chromosome 4q35 b. Closely linked to the highly polymorphic locus D4F104S1 c. Deletion of 3.3-kb tandemly repeated units within the EcoRI fragment on chromosome 4q35: associated with the disease in 85–95% of FSHD families d. Candidate genes for FSHD not yet elucidated e. Nature of the precise mutation: still unknown
f. Approximately 5% of FSHD families fail to exhibit linkage to 4q35, presumably indicating the presence of a second FSHD1 locus
3. Genotype–phenotype correlation a. Patients with a large gene deletion
i. Tendency to have a higher chance of exhibiting severe clinical phenotypes
ii. Higher chance of central nervous system abnor- malities
b. Patients with small EcoRI fragments i. Tendency to have earlier-onset disease ii. More rapid progression
c. Correlation between the size of the disease-associated 4q35-EcoRI fragment and the following parameters
i. Age at onset of symptoms ii. Age at loss of ambulation
iii. Muscle strength as measured by quantitative isometric myometry
d. De novo mutations
i. Association with smaller EcoRI fragments (on average) than those segregating in families ii. Tendency of patients with de novo mutations to
have findings the more severe end of the pheno- typic spectrum
e. Reduced penetrance in females bearing the FSHD small fragment as compared to the penetrance in males with the FSHD small fragment
CLINICAL FEATURES
1. Marked clinical variability a. Age at onset
i. Usually between the first and second decade ii. Progress gradually over time
b. Pattern of muscle involvement
i. Progressive weakness and atrophy of the facial and shoulder girdle muscles
ii. Other muscles affected in a specific order a) Abdominal muscles involved first
b) Followed by foot-extensor and upper arm muscles
c) Finally involving pelvic girdle and lower arm muscles
c. Intra-familial variability d. Inter-familial variability
e. Phenotype ranging from almost asymptomatic forms to more severe wheelchair-bound forms
2. A distinctive distribution of progressive muscular weak- ness involving the following muscles
a. Facial muscles
i. Typically involved:
a) Obicularis oculi b) Orbicularis oris ii. Clinical signs
a) Often asymmetric involvement b) Facial weakness
c) Unable to turn up the corners of the mouth when smiling
d) Difficulty in whistling e) Unable to purse lips
f) Sleeping with eyes partially open, the most common early sign
g) Bury eyelashes when attempting to close eyelids tightly
h) Sparing of extraocular, eyelid, and bulbar muscles
b. Scapular stabilizer muscles i. Affected muscles
a) Latissimus dorsi b) Trapezius c) Rhomboids d) Serratus anterior ii. Clinical signs
a) Sloping shoulder posture at rest b) Anterior axillary folds
c) Straight (horizontally placed) clavicles d) Pectoral muscle atrophy
e) Scapular winging, the most common initial finding
f) Preferential weakness of the lower trapezius muscle, resulting in characteristic upward movement of the scapula when attempting to flex or abduct the arms
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c. Proximal arm muscles
i. Biceps and triceps selectively involved, resulting in atrophy of the upper arm
ii. Distal progression of wasting and weakness of upper arm muscles, leading to eventual weak- ness of wrist and finger extensors
iii. Deltoids minimally affected until late in the disease iv. Sparing of the forearm muscles, resulting in
so-called “popeye arms” appearance d. Abdominal muscles
i. Abdominal muscle weakness resulting in:
a) Protuberance of the abdomen b) Exaggerated lumbar lordosis
ii. Selective involvement of the lower abdominal muscles, resulting in Beevor’s sign (upward dis- placement or occasionally downward movement of the umbilicus upon flexion of the neck in a supine position)
a) Present in 90% of patients
b) Helpful early sign in patients with equivocal findings, as it is rarely found in other muscle disorders
e. Lower extremity muscles
i. Anterior compartment muscles of the distal leg (anterior tibial and peroneal muscles)
a) Usually the first and most severely affected b) Resulting in the typical complaints of a foot
slap while walking or frank foot drop c) Frequent tripping or unstable walking, par-
ticularly on uneven ground ii. Pelvic girdle muscles
a) Less common
b) Involving hip flexors and hip abductors c) Resulting in early and relatively severe gait
involvement 3. Degree of muscle involvement
a. Extremely variable
b. Wide range of muscle involvement
i. Very mildly affected patients unaware of the disease symptoms
ii. Isolated facial weakness iii. Severe generalized weakness
iv. Eventually requiring a wheelchair in approxi- mately 20% of patients
c. Sex difference in penetrance: males more severely affected than females
4. Clinical course of muscle involvement
a. Early involvement of facial and scapular muscles with eventual spreading to pelvic and lower limb muscles b. A slowly progressive course
c. A stepwise course with periods of rapid deterioration occurring against a background of stability
d. Aggravation of muscle weakness during pregnancy but recover quickly in the puerperium
e. Bulbar and pharyngeal muscles, extraocular muscles, and respiratory muscles typically spared
5. Extra muscular involvement (uncommon) a. Coats syndrome
i. Neurosensory hearing loss (64%) ii. Retinal vasculopathy (49–75%)
a) Tortuosity of retinal arterioles (microa- neurysms)
b) Telangiectasia b. Mental impairment c. Cardiac involvement (5%)
i. Conduction defects
ii. Supraventricular arrhythmia d. Neurologic manifestations
i. Preserved sensation ii. Often diminished reflexes
6. Diagnostic criteria include the following 4 main elements:
the diagnosis of FSHD often remains a clinical diagnosis a. Onset of disease in the facial or shoulder girdle mus-
cles, sparing the eyes, pharynx, tongue, and heart b. Facial weakness in more than 50% of affected family
members
c. Autosomal dominant inheritance in familial cases d. Evidence of myopathic disease by electrodiagnostic
studies and muscle biopsy in at least one affected family member
DIAGNOSTIC INVESTIGATIONS
1. Serum creatine kinase (CK) a. Normal to elevated levels
b. Usually not exceeding 3–5 times the upper limit of the normal range
2. Audiogram for sensorineural hearing loss
3. Fluorescein angiography to demonstrate retinal vascu- lopathy
4. EMG: nonspecific myopathic features a. Fibrillations
b. Positive waves in resting muscle
c. Early recruitment of short duration motor unit action potentials
5. Muscle biopsy: nonspecific features
a. Underlying process: myopathic and help to exclude the following primary muscle diseases that can present with a FSHD-like phenotype:
i. Congenital myopathies a) Nemaline (rod) myopathy b) Centronuclear myopathy ii. Inflammatory myopathies
a) Polymyositis
b) Inclusion body myositis iii. Other dystrophies
a) Scapuloperoneal dystrophy b) Limb-girdle dystrophy iv. Others: desmin-storage myopathy b. Increased variation in fiber size c. Increased internalized nuclei
d. Variable degrees of endomysial inflammatory cells e. Angulated “neuropathic-like” myofibers
f. Mononuclear inflammatory reaction (75%) 6. Molecular genetic testing
a. Mutation analysis
i. Detection of the short fragment in affected indi- viduals
a) High sensitivity and specificity of the 4q35 deletion for FSHD
b) Using probe p13E-11 (D4F104S1), which hybridized to 4q35, to detect small EcoRI digestion fragments
c) Deletion within the D4Z4 repeat region of chromosome 4q35 (demonstrable short frag- ment), observed in 95% of patients clinical- ly affected with FSHD, whether familial or sporadic
d) Approximately 98% of patients with such a short fragment have clinically demonstrable FSHD
e) Confirms the diagnosis with a high degree of certainty
ii. Large deletions in the 4q35 region (producing a smaller short fragment)
a) Associated with more severe expression of the disease
b) Manifest earlier onset of disease c) More severe degree of weakness
d) Shorter fragment size generally associated with sporadic cases with an earlier age of onset than with familial cases
iii. Variability in fragment size: unable to explain the significant clinical variability sometimes seen within FSHD families, since the deletion size appears to remain stable from generation to generation
iv. Findings of a short but less intensively hybridiz- ing p13E-11/EcoRI/BlnI fragment strongly sug- gest germinal mosaicism. Minor clinical signs in parents may point towards germline mosaicism b. Absence of identifiable D4Z4 deletions in approxi-
mately 5% of individuals with FSHD
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. 10% risk for a sib of a de novo case being a carrier.
The figure of 10% is based on the observation that both somatic and germinal mosaics are detected, indicating that both types of mutations occur early in embryogenesis and therefore will give rise to a high percentage of mutated germ cells
ii. 50% recurrence risk if a parent is affected b. Patient’s offspring: each offspring of an affected indi-
vidual having a 50% chance of inheriting the deleted region within the D4Z4 repeat motif for FSHD 2. Prenatal diagnosis
a. Available for fetuses at 50% risk for FSHD
b. Molecular genetic testing: follow a de novo mutation in a subsequent generation by analyzing DNA extracted from fetal cells obtained by:
i. CVS
ii. Amniocentesis 3. Management
a. Lack of effective treatment
b. Unpredictability of the clinical course
c. Management of pain in the shoulders, back, abdomen, and leg
i. Use of nonsteroidal anti-inflammatory drugs ii. Range-of-motion exercise
iii. Gentle stretching through a physical therapy program
d. Physiotherapy
e. Supportive treatment of complications from progres- sive weakness
i. Judicial use of bracing
ii. Ankle and foot orthoses to improve mobility and prevent falls in patients with foot drop
iii. Surgical fixation of the scapula to the chest wall (thoracoscapular fusion) or to the ribs (scapulo- costal fusion)
a) Often improving range of motion of the arms b) Short-lived effect in patients with rapidly
progressive disease f. Pharmacologic treatment
i. Limited to the use of corticosteroids in patients with evidence of inflammation on muscle biopsy ii. Possible effect of albuterol, a β2 adrenergic agent
a) Improvement of lean body mass b) Modest improvement in strength
g. Required assistance in caring the infants after deliv- ery due to weakness in the shoulder girdle
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Fig. 1. A child with FSHD showing periscapular wasting and weak- ness resulting in scapular winging and inability to abduct the arm above the horizon.
Fig. 2. An adult with FSHD showing scapular winging and wasting of proximal arm muscles.
Fig. 3. An adult with FSHD showing facial weakness and inability to smile, purse the lips, and whistle.
Fig. 4. A 14-year-old boy with FSHD showing sloping shoulders, inability to raise arms above shoulders, and inability to close his eye- lids completely. In addition, he had difficulty in pursing the lips and could not whistle (onset at about 2 years of age). His CPK was 1295 (normal: 0–200 U/L). Molecular genetic analysis revealed FSHD allele 1 of 18 kb and FSHD allele 2 of >48 kb (FSHD deletion, 12–37;
marginal, 38–41; no deletion,≥42). The mother and several other fam- ily members are also affected.
