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.
Risk factors
Risk factors for premature birth or stillbirth due to cervical weakness include:
diagnosis of cervical weakness in a previous pregnancy
previous preterm premature rupture of membranes
history of conization (cervical biopsy)
diethylstilbestrol exposure, which can cause anatomical defects, and
uterine anomaliesRepeated procedures (such as mechanical dilation, especially during late pregnancy) appear to create a risk. Additionally, any significant trauma to the cervix can weaken the tissues involved. Diagnosis
Diagnosis of cervical weakness can be challenging and is based on a history of painless cervical dilation usually after the first trimester without contractions or labor and in the absence of other clear pathology. In addition to history, some providers use assessment of cervical length in second trimester to identify cervical shortening using ultrasound. However, short cervical length has actually been shown to be a marker of preterm birth rather than cervical weakness. Other diagnostic tests that have been suggested which have not been validated include hysterosalpingography and radiographic imaging of balloon traction on the cervix, assessment of the patulous cervix with Hegar or Pratt dilators, the use of a balloon elastance test, and use of graduated cervical dilators to calculate a cervical resistance index.Normally, the cervix should be at least 30 mm in length. Cervical weakness is variably defined. However, a common definition is a cervical length of less than 25 mm at or before 24 weeks of gestational age.