Genetics of Ehlers-Danlos Syndrome Clinical Presentation

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 (types 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

Clinical forms of Ehlers-Danlos syndrome

Six discernible types of Ehlers-Danlos syndrome (EDS) are recognized as established by the Villefranche nosology. ^[13] A great deal of overlap exists among these phenotypes; hence, it can be difficult to make a clear clinical diagnosis for a specific EDS type. 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 (now The Ehlers-Danlos Society). ^[13] Villefranche nosology is currently used in the clinical setting and is regularly updated.

Table 1. Types of Ehlers-Danlos Syndrome ^{[13, 14]} (Open Table in a new window)

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. ^[19] 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. ^[20] Skin hyperextensibility is assessed 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 diagnostic feature. ^[14]

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 cites some of those variants that were a part of the original group of 11 and were 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 remains unclear.

• Ehlers-Danlos–like syndrome from tenascin-X deficiency has been described. ^[21] Tenascin is a macromolecular protein in the extracellular matrix.

• Type I collagen mutations can cause an arthrochalasia-type EDS (types VIIA and VIIB) 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 EDS 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. This EDS type is very important to diagnose 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. ^{[22, 23]}

• 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. ^[24]

• 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. ^{[25, 26]}

• EDS type VIII (OMIM #130080, autosomal dominant): In addition to the other notable features, patients with EDS type VIII have multiple skin striae and significant dental problems, including early tooth loss, periodontitis, and alveolar bone loss. The existence and classification of type VIII is presently under debate. ^[27]

• 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. This platelet defect can be corrected with fibronectin supplementation. ^[28]

A new type of EDS also has been described. Six patients from 2 consanguineous families were reported to have EDS-like features and radiologic findings of a skeletal dysplasia. ^[29] 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. Patients described in the report had a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter, SLC39A13. This data suggest a new entity designated as spondylocheirodysplasia, EDS-like. 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. ^[30] The OMIM database refers to this syndrome as the spondylocheirodysplastic form of EDS (SCD-EDS), (OMIM #612350, autosomal recessive).

In addition, a galactosyltransferase I deficiency form of progeroid EDS (OMIM #130070, autosomal recessive) has been described. ^[31]  Patients have short stature and limb anomalies (Ehlers-Danlos syndrome with short stature and limb anomalies [EDSSLA]).

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)

*Indicates classical 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. The protein abnormality type V collagen is involved in both classical forms of EDS.