Diagnostic Criteria for Classical EDS May Need Update, Study Suggests

People with classical Ehlers-Danlos syndrome (EDS) appear to have less multi-organ involvement than those with other types, suggesting that the diagnostic criteria for this type of EDS may require an update, according to a recent study.

The study, “Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives,” was published in the Orphanet Journal of Rare Diseases.

EDS is currently divided into 13 different types. Among these, classical EDS (cEDS) is one of the most common, affecting an estimated 1 in 20,000 people.

cEDS is somewhat poorly defined on clinical grounds, and it is usually diagnosed by expert opinion rather than using systematically acquired data.

In combination, skin hyperextensibility (abnormally stretchy skin) and atrophic scarring (scars that heal below the normal layer of skin) are considered the major diagnostic criterion for cEDS. Typically, this criterion must be present in combination with other major criteria such as joint hypermobility, and/or with at least three of several minor criteria, which include easy bruising, hernia, skin fragility, and family history.

Genetic testing to identify cEDS-associated mutations is usually required for a conclusive diagnosis, though it may not be definitive in every case as not all cEDS-causing mutations are thought to be known.

In addition to the above criteria, problems in several organs have been reported in people with cEDS. However, research is lacking about how the disease tends to manifest in various bodily systems.

To address this, a team led by researchers at the University of Brescia, Italy, presented clinical data for 75 people with cEDS from 44 families.

Among these 75 individuals, 45 (60%) were female, 30 (40%) were male, and the average age at last examination was 27 years, ranging from 3 to 67 years.

The primary major criterion — skin hyperextensibility plus atrophic scarring — was present in 78.7% of the included individuals. Joint hypermobility, the second major criterion, was present in 58.7%.

The most common minor criteria were skin fragility (89.3%), easy bruising (86.7%), and soft doughy skin (78.7%). Some minor criteria were more common in younger individuals, such as hernias and epicanthal folds, while others were more common in older individuals, including sprains, joint pain, and dislocations.

In all, 59 of the 75 (78.7%) individuals met the typical criteria for cEDS — that is, the first major criterion in combination with the second major criterion and/or three or more minor criteria. The remaining 16 patients did not fulfill the combined major criteria.

“Our results suggest the need of a future update of the currently defined diagnostic criteria for cEDS,” the researchers wrote.

They offered some suggestions for such revisions, writing, “we recommend that atrophic scarring should be considered independently from skin hyperextensibility as an alone-standing major criterion 1. … A family history with a documented pathogenic variant [known disease-causing mutation] is sufficient for genetic testing in individuals not fulfilling the criteria.”

The most common orthopedic (muscle/bone-related) features reported were minor asymmetry in the lower limbs or other body areas (83.6%), mild scoliosis (74.3%), spine abnormalities (57.9%), abnormalities at joints (53.3%), and unusually shaped palate in the mouth (50%). The most common muscular feature was aches/cramps (41.3%).

With the exception of easy bruising, the most common cardiovascular (heart-related) symptoms were a valve abnormality called mitral valve prolapse (42.4%) and frequent bleeding from the gums or nose (41.3%). Another valve abnormality, valvular regurgitation with mild hemodynamic involvement (34.8%), as well as varicose veins (20%), were also reported. Of note, mitral valve prolapse was significantly more common in older individuals — 56.4% vs 22.2% in younger people.

Gastroesophageal reflux (also called acid reflux) was the most common gastrointestinal (gut-related) feature reported (40%); it was significantly more common in older than younger individuals — 52.3% vs 22.6%. Difficulty defecating was also somewhat common (33.3%).

The most common neuropsychiatric (brain-related) feature was headache/migraine (41.3%), which was more common in females than males, though the difference was not statistically significant. Motor problems (36.5%) and chronic fatigue (36%) were also reported.

Issues with allergies were reported in 32% of the assessed individuals.

Among females of reproductive age, the most commonly reported gynecological features were disabling pain during periods (22.6%) and abnormally heavy periods (16.1%).

“Our study confirms that cEDS is mainly characterized by cutaneous and articular involvement, though none of their hallmarks was represented in all cases and suggests a milder multisystemic involvement and a more favorable natural history compared to other EDS subtypes,” the researchers wrote.

“Moreover, our results suggest the need of a future update of the currently defined diagnostic criteria for cEDS. Additional studies on large cEDS cohorts are expected to confirm the limited multisystemic involvement and rather favorable natural history of cEDS,” they added.