Genetics of Ehlers-Danlos Syndrome Clinical Presentation

Updated: Jul 20, 2017
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Presentation

History

The main approach used to identify individuals affected with Ehlers-Danlos syndrome (EDS) is by completing a thorough medical history and physical examination to reveal salient diagnostic clues. Currently, some of the known EDS types can be confirmed and diagnosed using molecular or biochemical laboratory testing; namely, vascular type (type IV), kyphoscoliosis type (type VI), arthrochalasia type (type VII A and B), and dermatosparaxis type (type VIIC). All EDS types share the following clinical features to varying degrees:

Cutaneous features include the following:

  • Loose, hyperextensible, fragile skin
  • Poor wound healing
  • Tendency to bruise easily
  • Atrophic scars that are wide and thin, known as "cigarette paper scars"

Extracutaneous features include the following:

  • Fragility of blood vessels
  • Hyperextensible, hypermobile joints
  • Propensity for spontaneous joint dislocations/subluxations
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Physical

Clinical forms of Ehlers-Danlos syndrome

Six discernible types of Ehlers-Danlos syndrome (EDS) are recognized as established by the Villefranche nosology. [11] A great deal of overlap exists among these phenotypes; hence, making a clear clinical diagnosis for a specific EDS type can be difficult. About 50% of patients diagnosed with EDS do not have a type that can be classified easily on clinical basis alone. This complicates the diagnostic process, because specific molecular diagnosis for confirmation (if available) may not be possible until a clinical EDS type has been diagnosed.

Table 1 below lists the identifiable EDS types (termed the Villefranche nosology) established in 1997, by a group of clinicians on the medical advisory board of the Ehlers-Danlos National Foundation. [11] Villefranche nosology is currently used in the clinical setting and is regularly updated.

Table 1. Types of Ehlers-Danlos Syndrome [11, 12] (Open Table in a new window)

Type Inheritance Previous Nomenclature Major Diagnostic Criteria Minor Diagnostic Criteria
Classical Autosomal dominant Types I and II Marked skin hyperextensibility, wide atrophic scars, joint hypermobility Smooth, velvety skin; easy bruising; tissue fragility; molluscoid pseudotumors (calcified hematomas over pressure points, eg, elbows); subcutaneous spheroids (fat-containing cysts on forearms and shins); joint hypermobility (eg, sprains, dislocations, subluxations); flat feet; muscle hypotonia; gross motor delays; postoperative complications (eg, hernia); manifestations of tissue fragility (eg, hiatal hernia, anal prolapse, cervical insufficiency); positive family history
Hypermobility Autosomal dominant Type III Generalized joint hypermobility, affecting both large (elbows, knees) and small (fingers, toes) joints; skin involvement (soft, smooth and velvety) Recurrent joint dislocations and subluxations of shoulder, patella, and temporomandibular joints; chronic joint pain; limb pain; musculoskeletal pain; bruising tendencies; positive family history
Vascular



*Considered most serious EDS type, owing to risk of spontaneous arterial or organ rupture



Autosomal dominant Type IV Thin, translucent skin, easy to see vasculature through the skin, especially chest and abdomen; arterial/intestinal fragility or rupture; extensive bruising with minor trauma; characteristic facial appearance of large eyes, thin nose, lobeless ears; short stature; thin scalp hair Acrogeria, aging skin; decrease of subcutaneous tissue in the face and extremities; gingival recession; hypermobile small joints; tendon/muscle rupture; clubfoot; early onset varicose veins; arteriovenous fistula; carotid-cavernous fistula; pulmonary conditions, pneumothorax, pneumohemothorax; positive family history; sudden death in close relative
Kyphoscoliosis Autosomal recessive Type VI



(Lysyl hydroxylase deficiency-collagen-modifying enzyme)



Generalized joint laxity; severe hypotonia at birth; delayed gross motor development; progressive scoliosis (present at birth); scleral fragility or ocular globe rupture post minor trauma Tissue fragility; atrophic scars; easy bruising; spontaneous arterial rupture; marfanoid habitus; microcornea; osteopenia; positive family history (affected sibling)
Arthrochalasia Autosomal dominant Type VII A and B Congenital hip dislocation; severe generalized joint hypermobility; recurrent subluxations Skin hyperextensibility with easy bruising; tissue fragility with atrophic scars; muscle hypotonia; kyphoscoliosis, mild osteopenia
Dermatosparaxis Autosomal recessive Type VIIC Severe skin fragility; marked bruising; saggy, redundant skin, especially of the face; scars not atrophic Soft, doughy skin; premature rupture of membranes; hernias (umbilical and inguinal)

 

The major diagnostic criteria are highly specific for each EDS type. The presence of one or more major criteria is highly indicative, required for clinical diagnosis, and warrants laboratory confirmation, whenever possible. One or more minor diagnostic criteria aid in the clinical diagnosis but are not sufficient.

Hypermobility and joint laxity can be objectively determined and are measured by the Beighton Hypermobility Score. [16] The Beighton scale adds 1 point for extreme range of motion in each of 9 joints. Normal joint laxity in a young adult has a score ranging from 4-6. High scores (>6), alone, cannot be used to diagnose EDS. [17] Assessment of skin hyperextensibility is by pulling the skin outward until there is resistance. An ideal location to test is the palmar side of the forearm. Typical skin stretch height in a patient without EDS is 1-1.5 cm. The skin area tested cannot be damaged or scarred or show evidence of redundancy. Not every skin site must show hyperextensibility to confirm this clinical finding. [12]

Historically, EDS was subdivided into 11 distinct types (types I-XI). This list was pared down to 6 in 1997, with the resulting Villefranche nosology. The following list is some other variants cited in the original group of 11 and within the EDS spectrum:

  • Type V was described in a single family and is inherited as X-linked recessive.
  • Type VIII is similar to classical type EDS (types I and II), but is associated with periodontal (gum) disease; it is not considered a distinct clinical entity.
  • Type IX, also known as occipital horn syndrome, has been reclassified as a variant form of Menkes disease. It is inherited as an X-linked recessive.
  • Type X was described in one family. Hematological abnormalities, such as a platelet aggregation defect, are present.
  • Type XI was called familial joint hypermobility syndrome and has been removed from EDS classification. Its relationship to EDS is remains unclear.
  • Ehlers-Danlos–like syndrome from tenascin-X deficiency has been described. [18] Tenascin is a macromolecular protein in the extracellular matrix.
  • Type I collagen mutations can cause an arthrochalasia type EDS (type VII A and B) with a predisposition to arterial rupture in early adulthood.

The Online Mendelian Inheritance in Man (OMIM) database provides updated information on the clinical and molecular understanding of single gene (monogenic) disorders. The inheritance pattern, OMIM number, and original clinical descriptions of 10 major types of Ehlers-Danlos syndrome are listed below. The OMIM entries were reviewed to assist in the development of the Villefranche nosology in 1997 and include the following:

  • EDS type I (OMIM #130000, autosomal dominant): Distinguishing features include easy bruising, mitral valve prolapse, premature rupture of the fetal membranes, and premature birth.
  • EDS type II (OMIM #130010, autosomal dominant): This phenotype is similar to type I, but with milder clinical effects.
  • EDS type III (OMIM #130020, autosomal dominant): Features include striking joint hypermobility and minimal skin changes.
  • EDS type IV (OMIM #130050, autosomal dominant): Type IV is the vascular/ecchymotic form. Patients with EDS type IV have prominent venous markings, which are readily visible through the skin. Diagnostically, this type is very important because patients are at risk for spontaneous rupture of the bowel, medium-sized arteries, or both. Often, rupture leads to early death. Median life expectancy in these patients is 45-50 years. [19, 20]
  • EDS type V (OMIM #305200, X-linked recessive): This phenotype is similar to, if not indistinguishable from, type II; however, in familial cases, type V exhibits X-linked recessive inheritance.
  • EDS type VI (OMIM #225400, autosomal recessive): Patients may present with retinal detachments, microcornea, myopia, and scoliosis. Differentiating hypermobility from neuromuscular hypotonia in these patients may be difficult. [21]
  • EDS type VII (OMIM #130060, types VIIA and VIIB, autosomal dominant; OMIM #225410, type VIIC, autosomal recessive): Patients exhibit arthrochalasis multiplex congenita (hyperflaccidity of the joints without hyperelasticity of the skin), short stature, and micrognathia. Multiple congenital skull fractures have been reported in EDS type VIIC. [22, 23]
  • EDS type VIII (OMIM #130080, autosomal dominant): In addition to the other notable features, patients with type VIII EDS have multiple skin striae and significant dental problems, including early tooth loss, periodontitis, and alveolar bone loss. Its existence and classification of type VIII is presently under debate. [24]
  • EDS type IX (OMIM #304150, X-linked recessive): Features include occipital exostoses, bladder diverticula or rupture, bony dysplasias, and decreased copper and ceruloplasmin. EDS type IX is no longer a subtype. Once the gene was identified, type IX was removed from the EDS classification. The gene is related to a condition termed cutis laxa or occipital horn syndrome (see Causes).
  • EDS type X (OMIM #225310, autosomal recessive): Patients exhibit poor wound healing, petechiae, and a platelet aggregation defect, which can be corrected with fibronectin supplementation. [25]

Since this EDS type classification was recognized, a new type has been described. Six patients from 2 consanguineous families were reported to have EDS-like features and radiological findings of a skeletal dysplasia. [26] Findings included hyperelastic, thin, and easily bruisable skin; hypermobile small joints with a tendency toward contractures; atrophy of the thenar muscles; tapering fingers; and protuberant eyes with bluish sclerae. The affected individuals had platyspondyly with moderate short stature, osteopenia, and widened metaphyses.

All patients in the initial report had a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter SLC39A13. These data suggest a new entity designated as spondylocheiro dysplastic type EDS. The medical terminology indicates a generalized skeletal dysplasia that mainly involves the spine (spondylo) and striking clinical abnormalities of the hands (cheiro), in addition to the EDS-like features. [27] The OMIM database refers to this syndrome as the spondylocheiro dysplastic form of EDS (SCD-EDS), (OMIM #612350, autosomal recessive).

In addition, a galactosyltransferase I deficiency form of progeroid EDS (OMIM #130070) has been described. [28]

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Causes

The Human Genome Project (HGP) and further advances in molecular genetics have provided much information regarding the molecular basis of Ehlers-Danlos syndrome (EDS). Physical positions of involved genes and their locations on chromosomal maps are cited in Table 2 below.

Table 2. Molecular Basis of EDS (Open Table in a new window)

Type Old Nomenclature Protein Abnormality Gene Abnormality Chromosome Locus
Classical Types I and II Type V collagen *COL5A1,COL5A2



COL1A1



*9q34.3



2q32.3



17q21.3



Hypermobility Type III Type III collagen



Tenascin-XB



COL3A1



TNXB



2q32.2



6p21.3



Vascular Type IV Type III collagen COL3A1 2q32.2
Kyphoscoliosis Type VI Lysyl hydroxylase deficiency (some) PLOD1 1p36.22
Arthrochalasia Type VII A and B Type I collagen A: COL1A1



B: COL1A2



17q21.33



7q21.3



Dermatosparaxis Type VIIC N-proteinase ADAMTS2 5q35.3

*Indicates type II has a specific gene abnormality COL5A1 with locus 9q34.3, whereas all 3 gene abnormalities and corresponding loci are present for type I. Type V collagen is involved in both types of these classical forms of EDS.

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