Estrogen has been suspected to be a protective factor that accounts for this discrepancy. One study found that estrogen reduced DUX4 activity. However, another study found no association between disease severity and lifetime estrogen exposure in females. The same study found that disease progression was not different through periods of hormonal changes, such as menarche, pregnancy, and menopause. History
The first description of a person with FSHD in medical literature appears in an autopsy report by Jean Cruveilhier in 1852. In 1868, Duchenne published his seminal work on Duchenne muscular dystrophy, and as part of its differential was a description of FSHD. First in 1874, then with a more commonly cited publication in 1884, and again with pictures in 1885, the French physicians Louis Landouzy and Joseph Dejerine published details of the disease, recognizing it as a distinct clinical entity, and thus FSHD is sometimes referred to as Landouzy Dejerine disease. In their paper of 1886, Landouzy and Dejerine drew attention to the familial nature of the disorder and mentioned that four generations were affected in the kindred that they had investigated. Formal definition of FSHDs clinical features did not occur until 1952 when a large Utah family with FSHD was studied. Beginning about 1980 an increasing interest in FSHD led to increased understanding of the great variability in the disease and a growing understanding of the genetic and pathophysiological complexities.
Deletion of the entire D4Z4 repeat array does not result in FSHD because then there are no complete copies of DUX4 to be expressed, although other birth defects result. One contracted D4Z4 repeat array with an adjoining 4qA allele is sufficient to cause disease, so inheritance is autosomal dominant. De novo (new) mutations are implicated in 10 - 30% of cases, 50% of which exhibit somatic mosaicism.It has been proposed that FSHD1 undergoes anticipation, a trend primarily associated with trinucleotide repeat disorders in which disease manifestation worsens with each subsequent generation. As of 2019, more detailed studies are needed to definitively show whether or not anticipation plays a role. If anticipation does occur in FSHD, the mechanism is different than that of trinucleotide repeat disorders, since D4Z4 repeats are much larger than trinucleotide repeats, an underabundance of repeats (rather than overabundance) causes disease, and the repeat array size in FSHD is stable across generations. FSHD2
FSHD without D4Z4 contraction is classified as FSHD2, which constitutes 5% of FSHD cases. Various mutations cause FSHD2, all resulting in D4Z4 hypomethylation, at which the genetic mechanism converges with FSHD1. Approximately 80% of FSHD2 cases are due to deactivating mutations in the gene SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18. SMCHD1 is responsible for DNA methylation, and its deactivation results in hypomethylation of the D4Z4 repeat array. Another cause of FSHD2 is mutation in DNMT3B (DNA methyltransferase 3B), which also plays a role in DNA methylation.