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The syndrome of facioscapulohumeral muscular dystrophy (FSHD) was first described by Landouzy and Dejerine in 1884. Inheritance in this disease is autosomal dominant with high frequency of sporadic cases. It is the third most common dystrophy after the dystrophinopathies and myotonic muscular dystrophy. It’s prevalence is approximately 1:20.000. Clinical presentation varies considerably from barely noticeable affection to wheelchair confinement. Most typically FSHD muscular dystrophy presents with weakness of the facial muscles and is followed by weakness of the scapular, humeral, truncal and lower extremity muscles. The asymmetry in muscle involvement is one of the most prominent characteristics of this disease. Other systems in addition to skeletal muscles may also be involved. This includes often asymptomatic sensorineural hearing loss, Coats’ disease (retinal telangectasia & detachment), rarely also cardiac arrhythmia and conduction block, and in largest deletions also CNS involvement (mental retardation, epilepsy). FSHD is linked to the distal end of the long arm of chromosome 4. A polymorphic megasatellite repeat, called D4Z4, is contained in this region, which contraction is associated with FSHD phenotype. D4Z4 deletion is found in more than 95% of patients with clinical syndrome of FSHD. Other forms of muscle diseases can mimic FSHD. Some of such cases, e.g. some patients with Beceker muscular dystrophy, show clinical features indistinguishable from FSHD. Other imitating diseases are proximal myotonic myopathy, hereditary inclusion body myositis, Emery-Dreifuss muscular dystrophy, and scapuloperoneal syndromes. Among hereditary myopathies that may present with asymmetric muscle weakness and could in this respect sometimes mimic FSHD are McLeod’s syndrome, glycogen storage disorders (McArdle’s disease, acid maltase deficiency), distal myopathies (e.g. atypical Myoshi myopathy), and manifesting female carriers of dystrophinopathy. However, some families that are in accordance with clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscular weakness, and myopathic changes on muscle biopsies without inflammatory or mitochondrial pathology and in whom other possible causess were excluded, do not have D4Z4 repeat deletions and are not linked to 4q35 (FSHD 1B). A second FSHD locus has not yet been identified. Such cases nevertheless demonstrate genetic heterogeneity in FSHD and are important for genetic counseling and for the elucidation of the etiology of this disease. D4Z4 deletion is on the other hand found also in patients with phenotypes that differ from the classic Landouzy-Dejerine FSHD criteria. These atypical phenotypes include patients with chronic progressive external ophthalmoplegia, patients with facial- sparing, limb-girdle muscular dystrophy, distal myopathy, asymmetric brachial weakness, or monomelic lower limb atrophy. No clear-cut correlation between the ytpe of atypical variant and the DNA fragment size has been identified. The clinical expression of FSHD thus seems to be broader than thought initially and the possibility of DNA testing may even expand such variety.