Enrichment of an Ehlers-Danlos-like phenotype in women with the FMR1 premutation: a pilot study

Previous research identified an Ehlers-Danlos (EDS)-like phenotype in fragile X premutation (FXPC) women. This preliminary research examines associations between the presence of this connective tissue phenotype, FMR1 genotype and immune-mediated, autonomic-mediated and endocrine-mediated symptoms.

Women with FXPC (n=11; mean age=44 years, SD=9.9) were recruited from Greenwood Genetic Centre and southern Louisiana. Most participants were mothers or close female relatives of individuals with fragile X syndrome. Participants were assessed for hypermobile Ehlers-Danlos syndrome (hEDS) according to the 2017 criteria. They also underwent an active stand test and completed a health-related survey.

Observed co-occurrence of this EDS-like phenotype in women with the premutation (n=5) was substantially higher than expected under statistical independence (one-sided OR 15.83, 95% CI 4.67 to 53.65, p=1.119 × 10^-4]. Preliminary data also indicate that FXPC women with <90 FMR1 CGG repeats may be at higher risk of developing this phenotype compared with those with >90 repeats (p=0.016, Cohen's d=-1.928). FXPC women with the EDS-like phenotype also reported more immune-mediated symptoms (Benjamini-Hochberg (BH) adjusted p=0.032), a trend towards greater autonomic symptom burden (BH adjusted p=0.054), and had significantly higher supine/standing HR and BP during an active stand test compared with FXPC women without the connective tissue phenotype (p=0.003-0.034).

Despite small sample numbers, the observed co-occurrence exceeded expectations under statistical independence and suggests a potential association warranting validation in larger cohorts.