This study of 33 patients with FSHD2, the largest cohort to date, critically assessed the FSHD2 phenotype compared to that of FSHD1 and determined the effect of the specific genotype and methylation patterns on the clinical manifestations.
The clinical characteristics of our cohort of patients with FSHD2 were identical to FSHD1 in almost all aspects. In fact, all the patients in the cohort, given their typical presentation, were assumed to be FSHD1 and the possibility of FSHD2 was only raised when routine genetic testing was negative. The pattern of skeletal muscle weakness with initial onset of facial and scapular weakness, often with notable side-to-side asymmetry, in FSHD2 was identical to FSHD1. Abdominal muscle weakness resulting in a Beevor sign, a highly specific sign in FSHD1, was present in most patients with FSHD2 tested.2,14
As for rare FSHD-specific extramuscular manifestations, 6 patients in our cohort had symptomatic hearing loss. None had symptomatic retinal vasculopathy; this is not surprising given the size of the cohort and the infrequent occurrence of symptomatic retinal vasculopathy. Systematic retinal examination with fluorescence angiography is required to assess whether this extramuscular manifestation also occurs in FSHD2.
As a group, the present FSHD2 cohort had an average disease severity similar to that reported in an FSHD1 cohort.15
In some FSHD1 reports, women were found to be less severely affected than men.21,22
In our cohort of clinically affected FSHD2 subjects, there were no gender differences in disease severity. However, 3 unaffected relatives of patients with FSHD2, all female, had genotypes and methylation profiles suggesting that they are asymptomatic nonpenetrant gene carriers (see next paragraph). These findings suggest that female FSHD2 gene carriers are less severely affected. A more systematic genotyping of all at-risk individuals within familial cases is needed to confirm this finding. Another difference between FSHD1 and FSHD2 was the age at symptom onset, nearly a decade later in FSHD2.1
This may suggest that FSHD2 is milder but more likely it is due to the high incidence of sporadic cases. In dominant FSHD1, the vigilance of affected parents leads to earlier recognition of symptoms in affected offspring.
The overall striking similarity in the clinical presentation of our FSHD2 cohort to FSHD1 may be in part due to ascertainment bias. Screening for FSHD2 in patients with undefined dystrophies may reveal a wider clinical spectrum in FSHD2 than is reflected in our cohort.
The genotyping data from this cohort reinforce an earlier FSHD2 study demonstrating the co-occurrence of hypomethylation on 4q and 10q D4Z4 repeats on the background of at least 1 permissive 4A161 chromosome.10
As demonstrated by 3 unaffected relatives (6.4, 7.2, and 13.10), D4Z4 hypomethylation occurring on a background other than the permissive 4A161 haplotype is not associated with FSHD2. However, 3 other relatives (12.2, 16.2, and 16.5) carry the 4A161 haplotype and are hypomethylated but do not show signs of FSHD. There may be several explanations for this. First, these female individuals may be regarded as asymptomatic nonpenetrant gene carriers. In FSHD1, approximately 20% of gene carriers either never present with symptoms or become symptomatic at a later age.23,24
Second, unaffected relatives who show D4Z4 hypomethylation may carry a relatively large D4Z4 repeat on the permissive 4A161 chromosome (12.2 carries a 4A161 D4Z4 repeat of 49 units, 16.2 and 16.5 carry a 4A161 D4Z4 repeat of 27 units). It is indeed remarkable that most patients with FSHD2 present with a medium-sized 4A161 D4Z4 repeat, an observation for which we currently have no explanation.
Our data show that the genotype (D4Z4 repeat size) does not influence disease severity in FSHD2. Additionally, the presence of more widespread hypomethylation does not make patients with FSHD2 more severely affected than patients with FSHD1. However, the data raise the possibility of a small effect of the degree of hypomethylation on disease severity in patients with FSHD2 but this finding needs further corroboration in a larger cohort.
The mode of transmission in FSHD2 remains unclear. Twenty of the 33 patients were sporadic. One explanation for this phenomenon is that FSHD2 development results from 2 independent events: 1) D4Z4 hypomethylation by an as yet unknown mechanism and 2) the presence of at least 1 repeat on the permissive 4A161 haplotype. The limited numbers of cases with familial FSHD2 show both dominant inheritance (affected parent-child pairs) and recessive inheritance (affected sibling pairs lacking an affected parent). It will be important to study additional relatives and to determine the mode of inheritance of D4Z4 hypomethylation. An important family to determine this is family 6; although all 4 siblings have the same mother, 3 different fathers are involved ().