Facioscapulohumeral dystrophy (FSHD)
This 73 year old woman had symptoms of weakness and pain for many years, beginning with neck flexor weakness. Throughout her working life, these difficulties produced minimal disability. She subsequently developed pelvic girdle weakness, but it was her pain that prompted her to seek medical evaluation. Her family history suggested a genetically transmitted disease, and initial biopsy evaluation suggested a dystrophic myopathy. Although the muscular dystrophies, taken as a group, are characterized by painless weakness, the history of a prominent pain component does not exclude a diagnosis in this category of disease. Among the adult-onset muscular dystrophies, facioscapulohumeral dystrophy (FSHD) is well known for presentations similar to that encountered in this patient.
Neurological examination revealed facial diplegia, mild and asymmetric scapular winging, moderate neck flexor weakness, and abdominal muscle weakness, as well as proximal muscle weakness in all four extremities. Interestingly, biceps strength was actually more impaired than deltoid strength, a feature often seen in FSHD. Sensory deficits were minimal and deep tendon reflexes were essentially normal. The serum creatine kinase (CK) level was repeatedly within normal limits. Both the muscle biopsy (right gluteus minimus) and electromyographic results suggested a myopathic process. A pelvic MRI, performed at an outside institution, suggested a chronic degenerative process with fatty replacement of the gluteus minimus muscle. Genetic testing revealed chromosome 4 restriction fragments consistent with the 4q35 deletion seen in facioscapulohumeral dystrophy.
Various disorders may mimic FSHD, with reports of spinal muscular atrophy and other muscular dystrophies simulating the typical asymmetry and pattern of involvement of FSHD. The presence of inflammatory cells within and about muscle fibers frequently occurs in FSHD, as well as in a number of different neuromuscular conditions such as infective myopathies, dermatomyositis, polymyositis and dystrophinopathies, and may lead to misdiagnosis of a primary inflammatory myopathy. In addition, histological changes suggesting denervation have also been seen in biopsies of patients with typical FSHD (Munsat et al., 1972), raising the possibility of an unrecognized neuropathic disorder in occasional patients. In our evaluations, we found no evidence of one of these disorders to warrant an alternative diagnosis.
This patient received supportive therapy and counseling, and was satisfied with knowing a more definite diagnosis. This case therefore illustrates not only a known presentation of a common adult-onset muscular dystrophy, but also the potential psychological benefit that a diagnosis may bring to the patient. After seeing multiple practitioners without a definite diagnosis, the patient became despondent and questioned her own psychological well being. Receiving this diagnosis provided her with closure, validated her physical complaints and allowed her to move on with her life.
Although initial complaints of some patients with FSHD relate to pain or muscle fatigue, weakness is by far the most common presenting manifestation of FSHD (reviewed in Kissel, 1999). The clinical features of FSHD consist of weakness of the facial muscles, upper extremities in the scapulohumeral distribution, and lower extremities involving the proximal and peroneal muscles. An initial symptom may be the patient being unable to whistle or drink through a straw or having an unusual smile. However, weakness of the shoulder girdle typically is what brings most patients to seek medical attention. The scapular fixation muscles affected include the latissimus dorsi, trapezius, rhomboids, and serratus anterior, so that at rest, the patients often have a sloped-shouldered posture with anterior rotation of the shoulders and elevation of the scapula from the rib cage (Kissel, 1999). The biceps is often severely affected, and the peroneal muscles, tibialis anterior, may be involved early, causing a foot drop. Pelvic girdle involvement may be severe, involving hip flexors and abductors, resulting in marked gait abnormality. Although initial descriptions of FSHD portrayed sparing of deltoids and knee extensors, more recent studies have shown that essentially every major muscle group is affected (Tawil et al., 1994). In 50% of affected patients, pelvic girdles are spared, as are bulbar, pharyngeal, extraocular and respiratory muscles. Speech is usually normal early in the course, although as lip muscles become more involved, patients have increasing difficulty articulating plosives (reviewed in Kissel, 1999).
Onset of symptoms can range from the first to past the fifth decade with clinical signs present in more than 90% of affected individuals by age 20 (Lunt et al., 1989; Orrell et al., 1999). However, many affected individuals may be unaware of their weakness. Infantile cases are also reported, and these apparently have little difference clinically or genetically from more typical forms of FSHD (Brouwer et al., 1994). One distinguishing feature of FSHD is the typical asymmetric muscle involvement, which frequently has led to erroneous diagnoses early in the course. Another distinguishing feature occasionally seen is abdominal muscle weakness. Beevor's sign, or the vertical movement of the umbilicus on flexion of the neck in the supine position, is present in 90% of FSHD patients (Awerbuch and Nigro, 1990). Other reported clinical signs of the FSHD phenotype include retinal vasculopathy and sensorineural hearing loss, which are observed in approximately 50%-70% of cases (Padberg et al., 1995).
FSHD often progresses in a slow descending manner, with weakness of facial muscles first, followed by scapular and humeral muscles, and later with pelvic girdle muscles. However, variation in the pattern of progression may be considerable. Because of the typically slow progression, many patients adapt surprisingly well even to profound weakness, and life span does not appear to be significantly shortened in FSHD patients (Lunt, 1989). However, over 20% of patients eventually require a wheelchair (Orrell et al., 1999).
As was seen in this patient, muscle pain may be the presenting complaint, and may remain the most disabling symptom for patients with FSHD. In one French survey, only 5.6% of patients with FSHD reported having no pain, and 32% reported having pain every day (reviewed in Bushby et al., 1998). In some FSH patients, the pain may be related to postural problems (especially pains in shoulders, hips and lower back), however, forearm and thigh pains appear myalgic in origin, and may be particularly intractable to treatment. In some patients, the reported pain complaints may assume a neuropathic character (e.g., burning, dysesthetic), whereas in others, the reported pain may be radiating in nature, occasionally mimicking that of the common radiculopathies. Metabolic investigations and muscle biopsy evaluation of FSH patients have not revealed the pathogenesis of pain in at least one recent report (Bushby et al., 1998).
With the current availability of DNA testing for FSHD, more atypical presentations of this disorder recently have been described in patients harboring the 4q35 deletion, such as absence of facial weakness or a clinical presentation more typical for a distal myopathic process (Felice and Moore, 2001).
General laboratory findings in patients with FSHD are nonspecific and are similar to those seen in any chronic disease affecting muscle. General serologic and immunologic studies are normal. A modest elevation of serum creatine kinase (CK) is seen in 75% of patients, with normal values in the other 25%. Findings of a chronic myopathic process are noted on electromyography (Furukawa, 1995), with most patients having polyphasic motor unit potentials of low amplitude and short duration.
Muscle biopsy reveals increased variability of fiber size with hypertrophic muscle fibers. Inflammatory changes may be seen, consisting of mononuclear cells in perivascular distribution or in perimysial and endomysial connective tissues (Arahata et al., 1995). A muscle biopsy is especially important in diagnosis of patients with an apparently negative family history, as it may suggest the features of a dystrophic myopathy as opposed to a primary inflammatory process or one of the congenital myopathies. However, no pathognomonic histopathologic changes are associated with FSHD (reviewed in Kissel, 1999).
Facioscapulohumeral dystrophy is the third most common muscular dystrophy after Duchenne and myotonic dystrophy (Felice and Moore, 2001). The prevalence is as high as one per 20,000 (Tawil et al., 1998; Orrell et al., 1999). FSH is transmitted in an autosomal dominant fashion in 70-90% with sporadic mutation in 10-30%. The penetrance of FSHD is remarkably complete and related to age with figures of less than 5 percent for ages 0 to 4, 21% for ages 5 to 9, 58% for ages 10 to 14, 86% for ages 15 to 19, and 95% penetrance for age 20 years and older (Lunt et al., 1989). However, as previously noted, affected patients may not complain of mild weakness.
The genetic defect in the majority of FSH cases is a deletion on chromosome 4q35 (Wijmenga et al., 1990). The deletions are of an integral number of tandem 3.3 kilobase repeats, termed the D4Z4 locus, which occur in a noncoding region. Chromosome 4q35 genes located upstream of D4Z4 are inappropriately expressed, and an element within D4Z4 has been shown to bind with a multiprotein complex of a known transcriptional repressor, architectural protein and nucleolin, mediating transcriptional repression of 4q35 genes. This suggests that the D4Z4 deletion leads to inappropriate transcriptional derepression of 4q35 genes resulting in disease (Gabellini et al., 2002). A reliable molecular diagnostic protocol for FSH has been established which involves the visualization of this deletion as EcoRI restriction fragments which are smaller than normal with double digestion using additional restriction sites (BlnI) followed by pulsed field gel electrophoresis (Orrell et al., 1999). Molecular analysis of 4q35 rearrangements has also been shown to be a reliable prenatal diagnosis of FSH as well (Galluzzi et al., 1999).
No specific treatment is currently available for the weakness of FSHD, and supportive care remains the cornerstone of management. Nonsteroidal anti-inflammatory drugs, and range-of-motion and stretching exercises, alleviate or prevent some of the pain associated with FSHD. Ankle-foot orthoses (AFOs) are frequently useful in patients with foot drop, and occasionally braces may reduce pain associated with postural weakness. In patients with scapular weakness, surgical scapular fixation to the rib cage has been beneficial in some individuals, resulting in improvement in the patient's ability to carry and lift objects (Bunch and Siegel, 1993).
No pharmacologic therapy has been shown to improve strength or slow progression of FSH. Early reports described variable effectiveness of prednisone, however a recent prospective, natural history controlled trial of prednisone in eight FSH patients, showed no clear benefit when patients were assessed through computerized muscle testing (Tawil et al., 1997). Initial studies were encouraging that albuterol could possibly increase strength and muscle mass in FSH patients (Kissel et al., 1997), but subsequent studies have not shown significant effect.
We thank Drs. Hannes Vogel, now at Stanford University, and Dr. Andrew Engel, of the Mayo Clinic, for their reviews of the muscle biopsy from this patient. Most of all, we thank the patient, who gave consent for her case to be posted in this forum.
Two observations in the discussion by Drs. Kwan and Hartman merit further comment. One is the occurrence of significant numbers of patients carrying the 4q35 deletion, but with few or no symptoms, and minimal signs of clinical involvement. Even within the same family, one may see marked variation in the severity of the muscle disorder. For this reason, an "apparently negative" family history in a patient with an undiagnosed adult-onset muscular dystrophy should be viewed with caution. Clinical and electromyographic evaluation of reportedly unaffected family members may provide key clues to the diagnosis. A second observation is that the widespread availability of DNA testing for the 4q35 deletion has expanded the recognized phenotypic range of FSHD. Symmetric presentations, involvement of unusual muscle groups, and neurogenic components are now reported as phenotypes associated with this genetic deletion. The reasons for the variability in clinical severity and phenotypic range associated with the 4q35 deletion are presently unclear.
-- Dennis R. Mosier, M.D., Ph.D.
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