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FSHD is a rare familial disease with an estimated prevalence of 1/20,000. It is the 3rd most common form of hereditary myopathy.

Onset occurs between 3 and 60 years of age. Disease progression is usually slow but some patients display periods of stability followed by periods of rapid deterioration. Early onset of FSHD is associated with more widespread muscle weakness. The initial manifestation is facial weakness (difficulties whistling, smiling and closing the eyes) but the main complain is shoulder involvement (difficulties rising the arms, scapular winging and sloping shoulders). The disease progresses to include wrist extension weakness, involvement of the abdominal muscles, and weakness of the lower limbs principally affecting foot then knee extensor muscles. Significant clinical variability exists and atypical presentations have been reported. Sensory, cardiac and neurological signs may be present in rare cases.

Two genetic subtypes of FSHD have been identified: the classical form (FSHD1) which is associated with D4Z4 pathogenic contraction on a 4qA chromosome 4 and FSHD2 which is associated with mutations in SMCHD1 (18p11.32). In FSHD1, repeat contractions are associated with local hypomethylation and change in chromatin relaxation on chromosome 4 that increases the likelihood of toxic DUX4 (4q35.2) gene expression in skeletal muscle. In FSHD2, patients harboring mutation in SMCHD1 have a profound hypomethylation of chromosomes 4 and 10, allowing chromosome 4 to express the toxic DUX4 transcript. It is hypothesized that SMCHD1 may act as a genetic modifier of FSHD1 because SMCHD1 gene mutations are identified in individuals with more severe phenotype and SMCHD1 protein directly binds to D4Z4 and suppresses somatic expression of D4Z4.

Diagnosis of FSHD1 is achieved by identification of D4Z4 pathogenic contraction (D4Z4 repeat number less than 10) on a 4qA chromosome 4 (permissive). In this situation, the residual number of D4Z4 units inversely correlates with severity. SMCHD1 mutations should be screened when FSHD phenotype is not associated with the D4Z4 pathogenic contraction and in FSHD1 families diagnosed with a number of D4Z4 repeats up to 5-7 in which individuals present with severe phenotype.

Differential diagnosis mainly includes limb-girdle muscular dystrophy but also neuromuscular diseases presenting with scapular winging as glycogen storage disease due to acid maltase deficiency, late-onset, endocrine myopathy, inclusion body myopathy with Paget disease of bone and frontotemporal dementia (see these terms), proximal neuropathies or neuronopathies.

Transmission is autosomal dominant in both FSHD1 and FSHD2. Penetrance in FSHD1 is incomplete and around 30% of carriers do not manifest the disease. Mosaicism may explain the occurrence of severe forms in children born to parents showing no signs of the disease. In some families, digenic inheritance of both FSHD1 and FSHD2 genetic conditions can modify the severity. Genetic counseling and prenatal diagnosis are therefore challenging.

Treatment is symptomatic, aiming towards prevention of joint stiffness and pain by passive mobilization and administration of antalgics. In severe cases, ventilatory support may be required. Surgical treatment involves fixation of the scapula and may lead to an improvement in the range of motion of the arms.

Prognosis depends upon the extent of loss of functional capacity but life expectancy is not reduced, unless in rare occurrence where respiratory functions are affected.