Some People with Hypermobile Ehlers-Danlos Syndrome May Actually Be Fragile X Premutation Carriers

Along with our collaborators, our group recently identified an important and overlooked overlap between Fragile X premutation carriers (fXPC) and hypermobile Ehlers-Danlos syndrome (hEDS).

We recently published an article reporting on five cases of premutation carriers who either had a previous diagnosis of hEDS or who were noted to have had significant hypermobility and were subsequently given a hEDS assessment at our genetics clinic. Of the two participants with whom I was personally involved in assessing, I can say with certainty that, had they not been previously identified as premutation carriers, they would have received hEDS diagnoses since they met full 2017 inclusion criteria, including the presence of a Marfanoid habitus in one participant.

Unfortunately, as it stands now, people with the fXPC genotype and a hEDS clinical phenotype cannot receive a dual diagnosis due to exclusion criteria in the hEDS diagnostic criteria (a similar example are fibrillin-1 mutation carriers who have a hEDS phenotype rather than Marfans but technically meet criteria for neither diagnosis). In future, I hope criteria will change as I believe we will continue to find hEDS/HSD phenotypes subsumed under other hereditary connective tissue entities. Much like autism, I strongly suspect hEDS/HSD is genetically heterogeneous and may be a secondary diagnosis for some.

Although we don’t have any current prevalence rates in terms of how often these two conditions overlap one another, we are currently working on a preliminary study to fully define the clinical presentation and estimate the prevalence of the hEDS/HSD phenotype in premutation carriers. After that, we will implement a larger study to genotype people with hEDS/HSD and see if the premutation is responsible for a subset of cases. The rates of premutation in women within the general population are 1 in 200, suggesting it could be affecting a significant minority of zebras.

This will be a fascinating series of studies that I hope will dramatically help both the Ehlers-Danlos and fragile X communities. To date, connective tissue problems in fragile X spectrum disorders are largely ignored by healthcare professionals and they could benefit from some of the therapeutic approaches people with EDS utilize. Meanwhile, a subset of people with EDS may gain a greater understanding of their conditions should they be diagnosed with fXPC, although it will be vital that this connective tissue phenotype is named and quickly recognized by healthcare and insurance agencies to ensure people maintain necessary treatment interventions.

I hope that this is a first important step in recognizing that, although the Ehlers-Danlos syndromes have traditionally been thought of in a strict sense as a limited group of collagen-based disorders, they are likely far more genotypically diverse than that. Instead, EDS can truly be thought of as a “syndrome” in the classic sense: a group of clinical features that tend to co-occur. In this way, fXPC provides us information about the genotype, while a dual diagnosis of hEDS provides us important information at the gross clinical level.

I personally support the use of dual diagnosis in these types of cases and I hope the clinical and research tides eventually turn that way as well.

NOTE: If you are interested in reading the fulltext article, please email me at scienceoveracuppa at gmail dot com.

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