Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations

Abstract

Ehlers-Danlos syndrome, hypermobility type, constituting a phenotypic continuum with or, perhaps, corresponding to the joint hypermobility syndrome (JHS/EDS-HT), is likely the most common, though the least recognized, heritable connective tissue disorder. Known for decades as a hereditary condition with predominant rheumatologic manifestations, it is now emerging as a multisystemic disorder with widespread manifestations. Nevertheless, the practitioners' awareness of this condition is generally poor and most patients await years or, perhaps, decades before reaching the correct diagnosis. Among the various sites of disease manifestations, skin and mucosae represent a neglected organ where the dermatologist can easily spot diagnostic clues, which consistently integrate joint hypermobility and other orthopedic/neurologic manifestations at physical examination. In this paper, actual knowledge on JHS/EDS-HT is summarized in various sections. Particular attention has been posed on overlooked manifestations, including cutaneous, mucosal, and oropharyngeal features, and early diagnosis techniques, as a major point of interest for the practicing dermatologist. Actual research progresses on JH/EDS-HT envisage an unexpected link between heritable dysfunctions of the connective tissue and a wide range of functional somatic syndromes, most of them commonly diagnosed in the office of various specialists, comprising dermatologists.

Figure 1

Typical cutaneous features of Ehlers-Danlos syndrome(s). Papyraceous (a), hemosiderotic and atrophic (b), and depressed (c) scars. Skin hyperextensibility (d). Molluscoid pseudotumor of the heel (e). Multiple ecchymoses with hemosiderotic depositions (f). Note that, except for skin hyperextensibility, such cutaneous changes are not observed in the hypermobility type.

Figure 2

Skin and mucosal features of Ehlers-Danlos syndrome, hypermobility type. Atrophic, nonpapyraceous scar—its atrophic nature is more appreciable after gentle squeezing between examinator's fingers (a). Accentuated crease reticulum of the palm (b). Keratosis pilaris in a 26-year-old woman (c). Piezogenic papules at wrists after compression (d). Extensive abdominal striae atrophicae in a 35-year-old multipara (e). Postsurgical scar with anetoderma-like herniation of the subcutaneous fat (f). Apparent absence of the lingual frenulum (g). Radiographic orthopanoramic showing extensive tooth loss in a 50-year-old man with severe gingival involvement (h). Blue sclerae (i).

Figure 3

Orthopedic features of Ehlers-Danlos syndrome, hypermobility type. Active joint hypermobility at the fingers (a), toes (b), elbow (c), and knees (genu recurvatum, (d)). Passive hyperextension at great toe (e) and heel (f). Structural changes due to joint instability: fixed subluxation of the distal ulna (g), asymptomatic fixed subluxation of the elbow (h), fixed subluxation of the first metacarpal (i), hindfoot pronation and midfoot eversion in an 11-year-old boy (j), and hallux valgus in a 24-year-old woman (k).

Figure 4

Visceroptosis of the gut in a 40-year-old woman with severely debilitating gastrointestinal functional complaints. Note marked gastroptosis (a) and pelvic localization of the small bowel (b) and transverse colon (c).

Figure 5

Illustrative examples of universal goniometer and flexible tape as essential tools for assessing joint mobility.

Figure 6

Schematic representation of extra-articular manifestations of Ehlers-Danlos syndrome, hypermobility type (alternatively termed joint hypermobility syndrome). The dark grey circle symbolizes the phenotypic spectrum of this condition, which includes a series of functional somatic syndromes and tissue/organ-specific dysfunctions (i.e., the white triangles, whose tips are indeed comprised within the dark circle). Outside the clinical spectrum of Ehlers-Danlos syndrome, hypermobility type, the single phenotypic components may be observed in isolation or, perhaps, in incomplete associations within the general population (the larger and light grey circle). It is expected that, in the future, the study of heritable dysfunctions of the connective tissue will move from the dark gray circle to the light gray one, as a prominent field of interest. ¹Mostly including fibromyalgia, myofascial pain and complex regional pain syndromes. ²Comprising xerophthalmia, xerostomia, vaginal dryness, and abnormal sweating. ³Asthma, atopy, gluten sensitivity, inflammatory bowel disease, and recurrent cystitis are all possible manifestations of an underlying immune system dysregulation.