Ehlers-Danlos Syndrome (EDS) refers to a set of genetic disorders that result in excessive weakening and laxity of the connective tissue

Ehlers-Danlos Syndrome (EDS) is named after the dermatologists, Edvard Lauritz Ehlers and Henri-Alexandre Danlos

They classified the condition as a series of connective tissue disorders caused by abnormalities in collagen production.

Connective tissue and collagen

To understand the importance of this disease, a specification must be made: connective tissue supports and protects the various anatomical structures, as well as linking them together.

An alteration at the level of genes that produce or interact with the production of collagen, its main component, results in poorly functional collagen that, therefore, causes weakening and consequent more or less serious problems at the level of

• joints;
• skin;
• bones;
• eyes;
• heart and blood vessels;
• internal organs (intestines, lungs, etc.).

Causes and transmission of EDS (Ehlers-Danlos syndrome)

All of these diseases develop as a result of a genetic mutation affecting 1 of several genes, depending on the type from which the individual is affected.

Depending on the various forms, these anomalies can be transmitted in 1 or more of the following ways

• autosomal dominant AD: if one of the parents, who is often ill, is affected by the mutation, the children of the couple will have a 50% chance of it being passed on to them;
• autosomal recessive AR: this occurs in individuals who inherit the mutation from both parents, who are usually healthy carriers of the mutation. In this case, the risk of transmission to offspring is around 25%;
• x-linked: the abnormality is located on the x chromosome, one of the 2 sex chromosomes;
• de novo: the mutation is not inherited, but manifests itself for the first time in the individual during the earliest gestational stages.

The 13 Types of EDS (Ehlers-Danlos Syndrome)

The evolution of science and study techniques has recently allowed (2017) the elaboration of an updated international classification of Ehlers-Danlos Syndrome, with the identification of no less than 13 types.

Specifically, these are:

Classical EDS (cEDS) with abnormality in the COL5A1, COL5A2 genes, which encode type V collagen or, more rarely, in the COL1A1 gene, which encodes type I collagen, and Autosomal Dominant AD transmission mode;

Classical-like EDS (clEDS) with an abnormality in the TNXB gene, which encodes Tenascin XB protein, and Autosomal Recessive AR transmission mode;

cardio-vascular EDS (cvEDS) with an abnormality in the COL1A2 gene, which encodes type I collagen, and an AR recessive autosomal mode of transmission;

vascular EDS (vEDS) with abnormality in the COL3A1 gene, which encodes type III collagen, or, more rarely, in the COL1A1 gene, which encodes type I collagen, and Autosomal Dominant AD transmission mode;

hypermobile EDS (hEDS) with an abnormality whose genetic cause is still unknown and Autosomal Dominant AD transmission mode;

EDS arthrocalasia (aEDS) with abnormality in the COL1A1, COL1A2 genes, which encode type I collagen, and Autosomal Dominant AD transmission mode;

Dermatosparasitic EDS (dEDS) with an abnormality in the ADAMTS2 gene, which encodes the ADAMTS-2 enzyme, and Autosomal Recessive AR transmission mode;

kyphoscoliotic EDS (kEDS) with an abnormality in the PLOD1 gene, which encodes the LH1 enzyme, or in the FKBP14 gene, which encodes the FKBP22 enzyme, and an AR-recessive autosomal mode of transmission;

brittle cornea (BCS) EDS with an abnormality in the ZNF469 gene, which encodes the ZNF469 protein, or in the PRDM5 gene, which encodes the PRDM5 protein, and an AR-recessive autosomal mode of transmission;

spondylodysplastic EDS (spEDS) with an abnormality in the B4GALTZ gene, which encodes the β4GalT7 enzyme, or in the B4GALT6 gene, which encodes the β4GalT6 enzyme, or in the SLC39A13 gene, which encodes the ZIP13 protein, and an AR recessive autosomal mode of transmission;

Musculocontractural EDS (mcEDS) with an abnormality in the CHST14 gene, which encodes the D4ST1 enzyme, or in the DSE gene, which encodes the DSE enzyme, and an AR recessive autosomal mode of transmission;

Myopathic EDS (mEDS) with an abnormality in the COL12A1 gene, which encodes type XII collagen, and Autosomal Dominant AD or Autosomal Recessive AR mode of transmission;

Periodontal EDS (pEDS) with an abnormality in either the C1R gene, which encodes the C1r protein, or the C1S gene, which encodes the C1s protein, and Autosomal Dominant AD transmission mode.

EDS affects both males and females, belonging to various ethnic groups

The most common forms are

• hypermobile: 1 case every 5/10,000
• classic: 1 case every 20/40,000;
• vascular: 1 case every 50,000/250,000;
• kyphoscoliotic: 1 case every 100,000.

The other forms, however, are rarer.

Symptoms of Ehlers-Danlos Syndrome

The different types of Ehlers-Danlos syndrome are characterised by symptoms that vary depending on the location of the malfunctioning collagen.

Generally speaking, what characterises the disease clinically in its various forms is:

• hyperextensibility of the skin, which is abnormally raised in relation to the musculoskeletal system, and then returns to normal;
• hypermobility of the joints, which stretch with an excessive elasticity compared to the physiological natural limits;
• fragility of the tissues, which then tear easily.

These 3 symptoms are considered key clinical manifestations.

Various clinical manifestations

Other symptoms that may mark certain types of EDS, often also related to or determined by the 3 key clinical manifestations, may be

• atrophic scars: enlarged scars with thin skin, forming a depression;
• stretch marks;
• delayed wound healing;
• velvety skin with the consistency of ‘dough’;
• tendency to bruising and haematomas, even in the absence of trauma;
• molluscous pseudotumours (subcutaneous protuberances);
• joint injuries, such as sprains, dislocations, etc., due to hypermobility and consequent joint instability;
• hypotonia (weak muscle tone);
• muscle fatigue and weakness;
• muscle and/or joint pain (myalgia and/or arthralgia);
• hernias;
• anal prolapse;
• valvulopathies;
• weakness of the walls of blood vessels that tend to dilate or rupture (dissections, aneurysms, etc.);
• hypertension;
• weakness of internal organs (rupture of the uterus, perforation of the sigmoid colon etc.);
• concomitance of joint pathologies such as hallux valgus, valgus knee, recurved knee, flat feet etc;
• presence of certain facial features (lack of or partial development of ear lobes and/or eyebrows, protruding ears);
• delay in physical and/or psychic development;
• vision problems (severe myopia, blindness);
• bone disorders (osteopenia, osteoporosis)’.

Prognosis and complications

The prognosis of EDS varies depending on the severity of the form, from which the patient is affected, even within the same type, and which organs are affected.

Life expectancy for almost all types is normal; however, complications for more complex forms such as vascular EDS can be fatal. Therefore, establishing a general prognosis is not possible.

The diagnosis of Ehlers Danlos syndrome is essentially based on:

• clinical analysis, thanks to the objective examination and family history, also excluding pathologies that may lead to a similar symptomatology such as, for example, rheumatology and heart disease;
• genetic testing which, with the exception of the hypermobile form (hEDS), the causes of which are still unknown, is able to identify any genetic mutations and the type of syndrome.

In addition, the following may also be useful

• echocardiogram, to assess possible vascular complications;
• skin biopsy, which can help diagnose the classic, hypermobile and vascular forms.

The importance of early diagnosis in childhood

EDS unfortunately cannot be prevented, but early diagnosis is important in order to be able to develop appropriate therapeutic support to prevent any or all possible complications.

The clinical manifestations of the disease, in fact, often occur at birth or in infancy, so it is very important to have an initial check-up with the paediatrician so that, if necessary, he or she can subsequently turn to medical specialists with whom to establish a course of action that follows the child over time, also involving collaboration within different disciplines.

How Ehlers-Danlos syndrome is treated

To date, there is no definitive cure for Ehlers Danlos syndrome, but only treatments that act on the symptoms encountered, such as

• anti-inflammatories and painkillers to reduce the pain and inflammation linked to muscular-articular instability;
• hypotensive drugs, capable of lowering blood pressure so as to protect weaker blood vessels;
• physiotherapy, to strengthen muscles and improve joint stability, reducing the risk of sprains and injuries;
• use of braces and orthopaedic devices, to stabilise the joints and reduce the possibility of injury;
• vascular and/or orthopaedic surgery, in the case of cardiovascular or osteoarticular injuries for which medical therapy is inadequate. In this case, given the laxity of the tissues, special attention must be paid to sutures;
• lenses for the correction/mitigation of vision defects.

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Source:

GSD