Phenotypic Clusters and Multimorbidity in Hypermobile Ehlers-Danlos Syndrome

Abstract

Objective: To perform a retrospective clinical study in order to investigate phenotypic penetrance within a large registry of patients with hypermobile Ehlers-Danlos syndrome (hEDS) to enhance diagnostic and treatment guidelines by understanding associated comorbidities and improving accuracy in diagnosis.

Patients and methods: From May 1, 2021 to July 31, 2023, 2149 clinically diagnosed patients with hEDS completed a self-reported survey focusing on diagnostic and comorbid conditions prevalence. K-means clustering was applied to analyze survey responses, which were then compared across gender groups to identify variations and gain clinical insights.

Results: Analysis of clinical manifestations in this cross-sectional cohort revealed insights into multimorbidity patterns across organ systems, identifying 3 distinct patient groups. Differences among these phenotypic clusters provided insights into diversity within the population with hEDS and indicated that Beighton scores are unreliable for multimorbidity phenotyping.

Conclusion: Clinical data on the phenotypic presentation and prevalence of comorbidities in patients with hEDS have historically been limited. This study provides comprehensive data sets on phenotypic presentation and comorbidity prevalence in patients with hEDS, highlighting factors often overlooked in diagnosis. The identification of distinct patient groups emphasizes variations in hEDS manifestations beyond current guidelines and emphasizes the necessity of comprehensive multidisciplinary care for those with hEDS.

Figure 1

Demographic characteristics and inclusion criteria. (A) 2491 patients completed registry intake; 240 were excluded owing to no hEDS diagnosis; 52 and 50 additional patients were excluded owing to other type of EDS diagnosis or other CTDs; 2149 patients were included in statistical analyses. (B) Participant demographic characteristics reporting total number and percentage of patients based on sex, ethnicity, race, and a family history of hEDS. Non-Hispanic, White women make up the majority of those with hEDS and 70% have a family history. CTD, connective tissue disorder; EDS, Ehlers-Danlos syndrome; hEDS, hypermobile Ehlers-Danlos syndrome.

Figure 2

Phenotypes and comorbid conditions with hEDS. (A) hEDS diagnostic phenotypes are conditions based on 2017 hEDS diagnostic criteria. Comorbid conditions are not included in the 2017 hEDS diagnostic criteria. Beighton criteria are presented. Color outlines of boxed phenotypes represent distinct clinical specialties. (B, C) Prevalence of diagnostic conditions and comorbidities by gender. Note that females are more frequently affected compared with males, except in the case of autism and abdominal hernia. (D) Additional demographic characteristics reporting females are affected by more conditions. Nonbinary individuals appear to have more conditions and are diagnosed earlier than those who designate as females or males.

Figure 3

K-means clusters and multimorbidity profiles for hEDS. (A) K-means cluster plot illustrating the grouping of all patients with hEDS based on their reported clinical demographic characteristics. The plot reveals the presence of 6 distinct and independent clusters within the patient population with hEDS. (B) Graphical representation of the distribution and frequency of chronic conditions reporting differences between each cluster. (C-E) Prevalence of total multimorbidity, diagnostic phenotypes, and comorbid conditions per cluster.

Figure 4

Subgroups and prevalence of chronic conditions per hEDS cluster. (A, B) Percentage prevalence of each chronic condition per cluster and totals across all clusters. Note that lower prevalence of diagnostic and comorbid conditions in Clusters 1 and 2 compared with Cluster 3, which has a high prevalence of neurologic conditions. (C) Mean number of conditions, age and total number of patients within each cluster. Note that Cluster 2 individuals have a lower prevalence of nearly all diagnostic and comorbid conditions, whereas Cluster 3 has the highest prevalence.