Hypermobile Ehlers-Danlos syndromes:

Complex phenotypes, challenging diagnoses, and poorly understood causes.

Cortney Gensemer1 | Randall Burks1 | Steven Kautz2 | Daniel P. Judge3 |
Mark Lavallee4 | Russell A. Norris1

Abstract
The Ehlers-Danlos syndromes (EDS) are a group of heritable, connective tissue
disorders characterized by joint hypermobility, skin hyperextensibility, and tissue
fragility. There is phenotypic and genetic variation among the 13 subtypes.
The initial genetic findings on EDS were related to alterations in fibrillar collagen,
but the elucidation of the molecular basis of many of the subtypes revealed
several genes not involved in collagen biosynthesis or structure. However, the
genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is
the most common type of EDS and involves generalized joint hypermobility,
musculoskeletal manifestations, and mild skin involvement along with the
presence of several comorbid conditions. Variability in the spectrum and severity
of symptoms and progression of patient phenotype likely depend on age,
gender, lifestyle, and expression domains of the EDS genes during development
and postnatal life. In this review, we summarize the current molecular, genetic,
epidemiologic, and pathogenetic findings related to EDS with a focus on the
hypermobile type.

KEYWORDS
#Ehlers-Danlos syndrome, #hypermobility, #musculoskeletal

CONCLUDING REMARKS AND PERSPECTIVES

Modification of the ECM likely play a major role in impairing the mechanical stability of the affected tissues in EDS patients. These ECM alterations likely feedback to the cells, resulting in altered mechanosensing and cell phenotype, probably through an integrin-dependent mechanism. As a consequence, propagation of altered mechanical, cellular and physiological result in a chronic feed-forward disease responses with profound effects on tissue damage and instability. Stabilizing the ECM environment may set in motion positive mechanical cues that
can revert cell and physiological phenotypes with longterm benefits for patients. This highlights the necessity for careful physiotherapy while taking into consideration already compromised connective tissues. While this concept may apply broadly for EDS, its application to hEDS is not yet known. The clinical spectrum of hEDS has been described for decades, with significant advancements made in recent years in regard to diagnostic guidelines, knowledge of comorbidities, treatment options, and awareness among healthcare practitioners. However,
most of the available data on the underlying biology of hEDS is broad in scope and lacks clear information regarding genetic pathways that contribute to disease etiology and pathogenesis. Establishing this information will not only provide molecular pathways for hEDS but also other diseases that affect musculoskeletal, ocular, neurological, and cardiovascular tissues. To date, basic sciences discoveries on EDS diseases are woefully lacking. Collective research networks should continue identifying genetic factors that contribute to disease. But, we as a scientific community most move these genetic discoveries into appropriate, genetically accurate animal
models to understand the molecular, biochemical, mechanical, and physiological mechanisms that contribute to disease origin and its progression. Without this fundamental knowledge, diagnostic tools and more effective or curative therapeutics for hypermobile EDS and
EDS disease subtypes will remain enigmatic. EDS patients may endure years without proper diagnoses and/or treatments. Increased awareness in the 16 GENSEMER ET AL. medical community is needed to ensure proper care for this group of affected individuals. This medical deficiency may originate during training as medical students are taught “when you hear hoofbeats, look for horses not zebras.” This means to look for the more common diagnosis
and not the rare one. As such, the zebra has become the symbol for EDS. Just like zebras in the wild, no two EDS zebras have the same stripes. All patients’ symptoms and experiences are different, but the community comes together as a group of zebras, called a dazzle.
A mission of this review is to inform the scientific and lay community of the necessity for increased awareness and involvement in connective tissue disease societies like the EDS society. This, in turn, will lead to a brightening, or dazzling of research and provide new hope to patients with these life altering diseases.273

ACKNOWLEDGMENTS
The work at MUSC was performed in a facility constructed with support from the National Institutes of Health grant number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Other funding sources include: National Institutes of Health: HL131546 (R. A. N.), GM103444 (R. A. N.), and HL149696 (R. A. N.); T32GM132055 and T32HL007260 (C. G.); Grant Sponsor: American Heart Association; Grant Numbers: 19TPA34850095 (R. A. N.), 17CSA33590067 (R. A. N.). We would also like to thank the reviewers for their insightful comments as well as the Ehlers Danlos Society (https://www.ehlers-danlos.com), especially Nancy Feracco, RN and Susan Chalela, PT, who work tirelessly for EDS awareness and outreach. They are constant beacons of hope and light for the many that are so adversely affected by EDS and related connective tissue diseases.

AUTHOR CONTRIBUTIONS
Cortney Gensemer: Conceptualization; investigation; writing-original draft; writing-review and editing. Randall Burks: Conceptualization; investigation; writingreview and editing. Steven Kautz: Conceptualization; investigation. Daniel Judge: Conceptualization; investigation; writing-review and editing. Mark Lavallee: Conceptualization; investigation; writing-review and editing. Russell Norris: Conceptualization; investigation; writing-original draft; writing-review and editing.
ORCID Russell A. Norris https://orcid.org/0000-0001-8462-5726