Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

Abstract

Background: The Ehlers-Danlos syndromes (EDS) are rare connective tissue disorders consisting of 13 subtypes with overlapping features including joint hypermobility, skin and generalized connective tissue fragility. Classical EDS (cEDS) is principally caused by heterozygous COL5A1 or COL5A2 variants and rarely by the COL1A1 p.(Arg312Cys) substitution. Current major criteria are (1) skin hyperextensibility plus atrophic scars and (2) generalized joint hypermobility (gJHM). Minor criteria include additional mucocutaneous signs, epicanthal folds, gJHM complications, and an affected first-degree relative. Minimal criteria prompting molecular testing are major criterion 1 plus either major criterion 2 or 3 minor criteria. In addition to these features, the clinical picture also involves multiple organ systems, but large-scale cohort studies are still missing. This study aimed to investigate the multisystemic involvement and natural history of cEDS through a cross-sectional study on a cohort of 75 molecularly confirmed patients evaluated from 2010 to 2019 in a tertiary referral center. The diagnostic criteria, additional mucocutaneous, osteoarticular, musculoskeletal, cardiovascular, gastrointestinal, uro-gynecological, neuropsychiatric, and atopic issues, and facial/ocular features were ascertained, and feature rates compared by sex and age.

Results: 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. Abnormal scarring was the most frequent and characteristic sign, skin hyperextensibility and gJHM were less common, all without any sex and age bias; joint instability complications were more recurrent in adults. Some orthopedic features showed a high prevalence, whereas the other issues related to the investigated organ systems were less recurrent with few exceptions and age-related differences.

Conclusions: Our findings define the diagnostic relevance of cutaneous and articular features and additional clinical signs associated to cEDS. Furthermore, our data suggest an update of the current EDS nosology concerning scarring that should be considered separately from skin hyperextensibility and that the clinical diagnosis of cEDS may be enhanced by the accurate evaluation of orthopedic manifestations at all ages, faciocutaneous indicators in children, and some acquired traits related to joint instability complications, premature skin aging, and patterning of abnormal scarring in older individuals.

Keywords: Atrophic scars; COL1A1; COL5A1; COL5A2; Classical Ehlers-Danlos syndrome; Joint hypermobility; Multisystemic involvement; Natural history; Nosology; Skin hyperextensibility.

Fig. 1

A) Representative images of different atrophic scars on cEDS patients’ knees. A healing scar in a 6-year-old girl (a); a papyraceous, non-hemosiderotic scar in a 22-year-old female (b); a cigarette paper scar in a 39-year-old female (c); multiple papyraceous, hemosiderotic scars in a 40-year-old female (d); multiple papyraceous scars in a 57-year-old male (e); combination of multiple, papyraceous, hemosiderotic scars, and cigarette paper scars in a 34-year-old female (f). B) Evolution of papyraceous, and hemosiderotic scars in 2 children assessed at increasing ages. On the left, a single scar on the knee and multiple scars at the pretibial area in a girl at 6 (a, b) and 11 years of age (c, d); on the right, multiple scars on the knee in a boy at 9 (e) and 12 years of age (f)

Fig. 2

A) Representative images of characteristic ocular features in cEDS patients from different ages. Epicanthal folds in 2 boys at 3 (a) and 12 years of age (b); palpebral ptosis (c) and sunken eyes (d) in two over 30 years old females. B) Evolution of facial gestalt in 2 children assessed at increasing ages. On the left, infraorbital creases and bluish sclerae in a girl at 6 (a) and 11 years of age (b); on the right, infraorbital creases and facial scars in a girl at 10 (c) and 15 years of age (d)

Fig. 3

Frequencies of mucocutaneous (a), osteoarticular (b), facial/ocular (c), and orthopedic (d) features in the cEDS patients’ cohort. *presence of statistically significant differences by age; #presence of statistically significant differences by gender (for frequencies and p-values see Additional Table 2)

Fig. 4

Frequencies of cardiovascular (a), muscular (b), gastrointestinal (c), uro-gynecological (d), neuropsychiatric (e), and atopic (f) features in the cEDS patients’ cohort. *presence of statistically significant differences by age; #presence of statistically significant differences by gender (for frequencies and p-values see Additional Table 2)