FSHD is an autosomal dominant myopathy with an estimated prevalence of 1: 20.000 and a normal live expectancy. The presenting clinical features are usually dominated by facial and shoulder girdle weakness. Involvement of abdominal, foot extensor  and pelvic muscles occur at a later stages of disease. In contrast to other neuromuscular disorders, shoulder girdle weakness is often asymmetrical with relative sparing of the deltoid muscles. Worldwide, about 98 % of cases are linked to chromosome 4 and routine DNA analysis is now available. Therapy is so far only symptomatic.

G.W.A.M. Padberg, M.D., Ph.D.
S.M. van der Maarel, M.D., Ph.D.

Symptoms start on average at age 16 in males and 20 in females, but onset may vary from the first to the sixth decade. In fully examined families, a large number of gene carriers (25-30%) have signs but no complaints of muscle dysfunction. Most patients note shoulder girdle weakness as the first symptom of FSHD; a minority of patients presents with foot-extensor weakness, when examined , all these patients have shoulder girdle weakness. Facial muscle involvement, often mild and asymmetrical, and frequently not recognized by the patients, can be demonstrated in more than 90% of the cases at the time of diagnosis. The disease progresses with varying rates, usually to abdominal and foot-extensor muscles first, and than to upper-arm and pelvic muscles. In contrast to other neuromuscular diseases, shoulder girdle weakness is often asymmetrical with relative sparing of the deltoid Read more

The estimated prevalence of FSHD is 1: 20.000. Fitness was calculated 0.8 if sporadic cases were included. As progression of the disease is, as a rule, quite slow, it is impossible to indicate with some precision the onset of disease. Onset has been defined as the moment a patient becomes aware of having FSHD, or as the moment a patient suffers impairment caused by FSHD. With the latter definition, approximately one third of patients (clinically detectable gene carriers) do not complain of the disease.

Disorders that are similar clinically to FSHD include: desmin storage (myofibrillar) myopathy, polymyositis, inclusion body myositis, mitochondrial myopathies, acid maltase deficiency, and congenital myopathies. Most of these conditions are easily differentiated from FSHD by their distinct muscle histopathology. More difficult are some of the limb girdle muscular dystrophy syndromes and scapuloperoneal muscular dystrophy syndromes (including myotonic dystrophy) that have mild facial weakness and non-specific histopathologic changes that cannot be differentiate the condition from FSHD. Careful attention to distribution of weakness (asymmetric limb muscle involvement and early facial involvement in FSHD), associated findings, and mode of inheritance will often differentiate these conditions from typical FSHD. Molecular diagnosis of many of these disorders greatly facilitates the differential diagnosis.

The diagnosis of FSHD is based to a large extent on the clinical picture and family examination if possible. DNA confirmation should be attempted in each case.

Laboratory evaluation in FSHD is usually non-specific but is helpful in excluding alternative diagnoses.

• Serum concentration of creatine kinase (CK) is normal to elevated in patients with FSHD and usually does not exceed three to five times the upper limit of the normal range. An extreme high serum concentration of CK suggests an alternate diagnosis.
• EMG usually shows mild myopathic changes.

Muscle biopsy, when taken from a symptomatic muscle, often shows non-specific chronic myopathic, dystrophic changes. In addition, small angular fibres and moth eaten fibres are not uncommon. An occasional small group of atrophic fibres may be observed. Mononuclear inflammatory reaction is present in muscle biopsies in up to 40% of patients with FSHD. Rarely, the inflammatory reaction is intense enough to suggest inflammatory myopathy. At present only in cases without a deleted D4Z4 fragment a muscle biopsy is recommended to differentiate between different FSH syndromes.

Recent advances in the molecular genetics of FSHD have brought to light some unusual mechanisms regarding the pathogenesis of this autosomal dominant myopathy. A high rate of new mutation, often somatic in origin, leads to contraction of a 3.3 kb D4Z4 repeat array at the subtelomeric region of chromosome 4q. As these repeats do not yield transcripts, the contraction is assumed to cause position effect variegation and a variable, muscle specific dysregulation of transcription. Worldwide, about 2% of FSHD cases are not linked to chromosome 4. Their linkage to any other chromosome or genetic feature is under investigation.

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