Rare Disease Report

May is Ehlers-Danlos Syndrome Awareness Month

MAY 04, 2017
RDR Staff
May is Ehlers-Danlos Syndrome (EDS) Awareness month.  EDS is a group of connective tissue disorders generally characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Even though the patient may appear healthy at a quick glance, the syndrome often involves a life of pain.
A prime example is Victoria Graham (Miss Frostburg).
Graham is a beauty contest winner and also an EHS patient. On the outside, she looks well but she has underdone 10 surgeries and currently takes 20-25 pills every 2 hours to control her pain and keep her body functioning properly.
Below is a Facebook video Victoria posted to commemorate EDS Awareness Month:

EDS Subtypes

Diagnosing a subtype of EDS can be tricky but once done, it can help guide treatment.
Below are the 2017 international diagnostic criteria for each subtype, courtesy of the Ehlers-Danlos Society.
Classical-like EDS
Major criteria are:
1.     Skin hyperextensibility with velvety skin texture and absence of atrophic scarring;
2.     Generalized joint hypermobility (GJH) with or without recurrent dislocations (most often shoulder and ankle); and
3.     Easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath).
There are seven minor criteria. Minimal clinical standards suggesting clEDS are all three major criteria plus a family history compatible with autosomal recessive transmission.
Cardiac-valvular EDS
Major criteria are:
1.     Severe progressive cardiac-valvular problems (aortic valve, mitral valve);
2.     Skin involvement: skin hyperextensibility, atrophic scars, thin skin, easy bruising; and
3.     Joint hypermobility (generalized or restricted to small joints).
There are four minor criteria. Minimal clinical standards suggesting cvEDS are the first major criterion plus a family history compatible with autosomal recessive transmission, and either one other major criterion or at least two minor criteria.
Vascular EDS
Major criteria are:
1.     Family history of vEDS with documented causative variant in COL3A1;
2.     Arterial rupture at a young age;
3.     Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology;
4.     Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears; and
5.     Carotid-cavernous sinus fistula (CCSF) formation in the absence of trauma.
There are twelve minor criteria. Minimal clinical standards suggesting vEDS diagnostic studies should be performed are: a family history of the disorder, arterial rupture or dissection in individuals less than 40 years of age; unexplained sigmoid colon rupture: or spontaneous pneumothorax in the presence of other features consistent with vEDS. Testing for vEDS should also be considered in the presence of a combination of the other “minor” criteria.
Hypermobile EDS
The clinical diagnosis of hEDS needs the simultaneous presence of criteria 1 and 2 and 3. This is a complex set of criteria, and there is much more detail than presented in this overview; please see the page for hypermobile EDS.

1.     Generalized joint hypermobility (GJH); and
2.     Two or more of the following features must be present (A & B, A & C, B & C, or A & B & C):
            Feature A—systemic manifestations of a more generalized connective tissue disorder (a total of five out of twelve must be present)
            Feature B—positive family history, with one or more first degree relatives independently meeting the current diagnostic criteria for hEDS
            Feature C—musculoskeletal complications (must have at least one of three); and

 All these prerequisites must be met: absence of unusual skin fragility, exclusion of other heritable and acquired connective tissue disorders including autoimmune rheumatologic conditions, and exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity.
There are a range of conditions commonly found within the hEDS patient population, although direct links cannot be made to be used for diagnostic criteria. Some of these include sleep disturbance, fatigue, postural orthostatic tachycardia, functional gastrointestinal disorders, dysautonomia, anxiety, and depression. These conditions may be more debilitating the joint symptoms; they often impair daily life, and they should be considered and treated.
A diagnosis of hEDS should be assigned only in those who meet all of the criteria, which should help research efforts to discover the underlying genetic cause(s) which, in turn, may help clinical management. As this is a clinical diagnosis, it’s important to be relatively confident that the diagnosis is not instead one of the many other disorders of connective tissue.
Arthrochalasia EDS
Major criteria are:
1.     Congenital bilateral hip dislocation;
2.     Severe GJH, with multiple dislocations/subluxations; and
3.     Skin hyperextensibility.
There are five minor criteria. Minimal criteria for aEDS are congenital bilateral hip dislocation (major criterion 1) plus either: skin hyperextensibility (major criterion 3); or severe GJH (major criterion 2) with at least two minor criteria.
Dermatosparaxis EDS
There are nine major criteria and eleven minor criteria. Minimal criteria suggestive of aEDS include the two major criteria of extreme skin fragility and characteristic craniofacial features, plus either: one other major criterion, or three minor criteria.
Kyphoscoliotic EDS
Major criteria are:
1.     Congenital muscle hypotonia;
2.     Congenital or early onset kyphoscoliosis (progressive or non-progressive); and
3.     GJH with dislocations/subluxations (shoulders, hips and knees in particular)
There are ten minor criteria, as well as gene-specific minor criteria (four for PLOD1 and four for FKBP14). Minimal criteria suggestive for kEDS are 1 and 2 of the major criteria—congenital muscle hypotonia and congential/early onset kyphoscoliosis—plus either: major criterion 3, or three minor criteria (either general of gene-specific).
Brittle Cornea Syndrome
Major criteria are:
1.     Thin cornea, with or without rupture (central corneal thickness often <400 µm);
2.     Early onset progressive keratoconus;
3.     Early onset progressive keratoglobus; and
4.     Blue sclerae.
There are fourteen minor criteria. Minimal criteria required to suggest BCS are the first major criterion, plus either: at least one other major criterion; or three minor criteria.
Spondylodysplastic EDS
Major criteria are:
1.     Short stature (progressive in childhood);
2.     Muscle hypotonia (ranging from severe congenital, to mild later-onset); and
3.     Bowing of limbs.
There are five general minor criteria, plus gene-specific criteria for B4GALT7B3GALT6, and SLC39A13. Minimal criteria required to suggest a diagnosis for spEDS are the first and second major criteria, plus characteristic radiographic abnormalities and at least three minor criteria (either general or gene-specific).
Musculocontractural EDS
Major criteria are:
1.     Congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot);
2.     Characteristic craniofacial features, which are evident at birth or in early infancy; and
3.     Characteristic cutaneous features including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling.
There are fifteen minor criteria. The minimum criteria required to suggest mcEDS are: at birth or in early childhood, major criteria 1 and 2; in adolescence and adulthood, major criteria 1 and
Myopathic EDS
Major criteria are:
1.     Congenital muscle hypotonia, and/or muscle atrophy, that improves with age;
2.     Proximal joint contractures (knee, hip and elbow); and
3.     Hypermobility of distal joints.
There are four minor criteria. The minimal criteria required to suggest a diagnosis of mEDS are the first major criterion plus either: one other major criterion, or three minor criteria.
Periodontal EDS
Major criteria are:
1.     Severe and intractable periodontitis of early onset (childhood or adolescence);
2.     Lack of attached gingiva;
3.     Pretibial plaques; and
4.     Family history of a first-degree relative who meets clinical criteria.
There are eight minor criteria. The minimal criteria required to suggest pEDS are the first criterion or the second criterion, plus at least two other major criteria and one minor criterion.

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