Ehlers Danlos syndrome by A.Griguolo

Generality

Ehlers Syndrome Danlos is the medical name of a grouping of 13 genetic diseases of connective tissue, which mainly cause problems to the skin, joints and blood vessels.

12 genes are certainly involved in the onset of the different variants of Ehlers Danlos syndrome, whose task, under normal conditions, is to produce a functional collagen.

From Ehlers Danlos syndrome it is not possible to cure; however, those suffering from this unpleasant disease can count on various symptomatic treatments, which allow to control the main disorders quite effectively.

Short revision of connective tissue

Deriving from the mesenchyme, the connective tissue is the particular tissue of the human body that provides structural and metabolic support to the other tissues.

The connective tissue includes cells (including fibroblasts, macrophages, mast cells, plasma cells, leukocytes, adipocytes, chondrocytes, osteocytes, etc.) and a substance of variable consistency interposed between the aforementioned cells, which is called an extracellular matrix .

Connective tissue belongs to tissues such as: the connective tissue proper, the mucous tissue, the adipose tissue, the cartilage tissue, the bone tissue, the blood, the lymph and the dermis.

What is Ehlers Danlos Syndrome?

Ehlers syndrome Danlos is the name that unites 13 particular genetic diseases of connective tissue, which mainly affect skin, joints and blood vessels.

Important note before proceeding with the reading

Although it is more correct to speak of Ehlers Danlos syndromes, the singular version "Ehlers Danlos syndrome" represents the most used way to refer to the totality of the aforementioned 13 diseases.

Ehlers Danlos syndrome is also known as EDS, which is the English acronym of Ehlers-Danlos Syndrome .

The 13 diseases: what are they?

The 13 diseases reported under the heading "Ehlers Danlos syndrome" are:

• The hypermobile type EDS;
• The classic type EDS;
• Vascular EDS;
• EDS with kyphoscoliosis;
• Artrocalasic EDS;
• EDS with dermatosparassi;
• The EDS of a similar type to the classic;
• The EDS of the spondylo-cheiro-dysplastic type;
• EDS of a muscle-contracture type;
• EDS with myopathy;
• The EDS with periodontitis;
• Cardio-valvular EDS.

This classification is very recent (it dates back to 2017) and is, in fact, the result of the revision of an old classification of Ehlers Danlos syndrome (year 1997), which included only 6 of these diseases.

Epidemiology

According to the most reliable estimates, one individual out of 5, 000 would be born with Ehlers Danlos syndrome.

Studies concerning the spread in the general population of the 13 types of Ehlers Danlos syndrome have shown that:

• The hypermobile Ehlers Danlos syndrome and the classical Ehlers Danlos syndrome are, with one case every 5, 000-20, 000 and one case every 20, 000-40, 000, the two most common pathological variants;
• The syndromes of Ehlers Danlos different from those previously mentioned are to be considered very rare diseases, affecting very few individuals in the world (eg, the worldwide cases of Ehlers Danlos syndrome with dermatosparassi are, according to the latest news, only 10).

Causes

Ehlers Danlos syndrome is due to a mutation - ie an abnormal change - in one or more of the following 12 different genes : COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, TNXB, ADAMTS2, PLOD1, B4GALT7, DSE, D4ST1 and CHST14.

In an individual, the mutations against these genes can be hereditary - that is, transmitted by one or both parents - or acquired completely spontaneously during embryonic development - that is, after the sperm has fertilized the egg and embryogenesis began.

Curiosity

According to recent genetic studies, still to be confirmed, the appearance of Ehlers Danlos syndrome would depend on a further 7 different genes, in addition to the 12 above.

What are the normal functions of the 12 EDS-associated genes? What happens when they have changed?

Premise: the genes present on human chromosomes are DNA sequences that have the task of producing fundamental proteins in biological processes indispensable to life, including cell growth and replication.

When they are healthy (that is, free of mutations), the 12 genes related to Ehlers Danlos syndrome produce enzymes and fibrous proteins that are fundamental to the correct production, processing and final structuring of collagen . Located in the extracellular matrix, collagen is the most important protein with structural function of the various connective tissues of the human body.

When instead they are carriers of mutation, the 12 genes associated with Ehlers Danlos syndrome lose the ability to generate the aforementioned enzymes or fibrous proteins and this involves the final composition of a poorly functional collagen, not sufficiently effective in its structural action; the weakening of the connective tissues of the skin, bones, joints, blood vessels, etc. from the generalized presence (that is, in the whole body) of a defective collagen

The table below shows the precise functions of the 12 genes connected to the Ehlers Danlos syndrome, also specifying, for most of them, in which pathological types are involved (when, of course, they are changed).

Is the hereditary form or the non-hereditary form more common?

It is difficult to determine whether Ehlers Danlos syndrome is more often hereditary or a result of a mutation acquired during embryonic development. The numerous typologies of the disease in question and the different tendency to spontaneous mutation phenomena of the various genes involved hinder the conclusions on this aspect.

Inheritance of Ehlers Danlos syndrome

Where the transmission of Ehlers Danlos syndrome occurs by parental means, heredity varies from autosomal dominant to autosomal recessive depending on the pathological type considered.

Among the syndromes of Ehlers Danlos comparable to an autosomal dominant disease, include: the hypermobile type, the classical type, the vascular type, the artrocalasic type and the periodontitis type; among the Ehlers Danlos syndromes comparable to an autosomal recessive disease, they include: the classic-like type, the type with dermatosparassi, the type with kyphoscoliosis, the spondylo-cheiro-dysplastic type, the cardio-valvular type and the muscle type contractural.

From these lists, only the myopathic type remains out, which, for reasons that are still unclear, can behave both as an autosomal dominant disease and as an autosomal recessive disease.

To understand briefly ...

• Each human gene is present in two copies, called alleles, one of maternal origin and one of paternal origin.
• An inherited disease is autosomal dominant when the mutation of only one copy of the gene that causes it is sufficient to occur.
• An inherited disorder is autosomal recessive when mutation of both copies of the gene that causes it is required to occur.

Symptoms and Complications

Due to the absence of a functional collagen, the symptoms and signs of Ehlers Danlos syndrome vary according to the pathological type considered, although - it should be pointed out - some of them (eg: joint problems and skin changes) occur in almost the totality of the variants.

Hypermobile type

The hypermobile type Ehlers Danlos syndrome is due to:

• Joint hypermobility affecting large and small joints (knee, ankle, shoulder, elbow, fingers and toes, etc.). Articular hypermobility is an important factor favoring the phenomena of distortion and joint dislocation;
• Smooth, soft, velvety and bruised skin;
• Chronic pain in the muscles and bones.

The main complications derive from joint hypermobility; in fact, this can lead to extensive damage to the joints and consequent disability .

Classic type

The classical type Ehlers Danlos syndrome causes:

• Extremely elastic skin ( hyperextensibility of the skin ), smooth, brittle, easily bruised and badly healed;
• Joint hypermobility in large and small joints;
• Predisposition to hematomas, especially in anatomical points subject to pressure (eg: elbows);
• Hypotonia.

The main complications consist of damage to the joints (consequences of joint hypermobility) and deep scars due to skin abnormalities.

Vascular type

The vascular type Ehlers Danlos syndrome is responsible for:

• Very thin, translucent, fragile and easily bruised skin;
• Fragility of blood vessels and organs such as the uterus and intestines;
• Short stature, large eyes, thin nose, ears lacking lobes and fine hair;
• Joint hypermobility limited to small joints (eg: fingers and toes);
• Acrogeria (premature aging of hands and feet);
• Tendon and muscle problems;
• Early-onset varicose veins;
• Equine foot;
• Gum recession;
• Reduced presence of fatty tissue under the skin.

Typical complications are: rupture of the most important blood vessels and organs such as the intestine (depending on the extreme fragility of these organs), the tendency to suffer from pneumothorax and the recurrent lesion of muscles and tendons.

Type with kyphoscoliosis

Ehlers Danlos syndrome with kyphoscoliosis is typically associated with: hypotonia at birth, delayed motor development, progressive scoliosis combined with kyphosis ( kyphoscoliosis ) and fragility of the ocular sclera; in addition, in a fair number of patients, it can also be due to: arterial fragility, bruising predisposition, osteopenia, corneal anomalies, abnormally long and thin fingers (arachnodactyly), unusually long limbs, pectus excavatum and carinated chest.

Artrocalasic type

Arthralkas type Ehlers Danlos syndrome is related to: severe articular hypermobility, congenital dislocation of the hip, fragile and elastic skin, skin predisposition to bruising, hypotonia, kyphoscoliosis and mild osteopenia.

Type with dermatosparassi

Ehlers Danlos syndrome with dermatosparassi is the cause of: fragile skin, prone to bruising and healing badly, altered healing process of the skin, sagging skin (especially on the face), recurrent hernias, fragile corneal syndrome, early onset progressive keratoglobus and blue sclera.

Type similar to the classic

Ehlers Danlos syndrome similar to the classical type presents a symptomatology similar to that of the classic Ehlers Danlos syndrome.

Spondyl-cheiro-dysplastic type

Ehlers Danlos syndrome of spondyloid-dysplastic type is associated with: short stature, muscular hypotonia and bowing of the limbs.

Muscle-contracture type

Ehlers Danlos syndrome of muscle-contracture type is responsible for: equine foot, craniofacial anomalies, skin hyperextensibility, bruising ease, skin fragility, impaired scarring, unusual increase in palmar wrinkles and multiple congenital flexion contractures.

Type with myopathy

Ehlers Danlos syndrome with myopathy is typically related to: congenital muscular hypotonia, major joint problems (eg, elbow, knee and hip) and hypermobility of the distal joints (eg, ankle, fingers, toes, etc.).

Type with periodontitis

Ehlers Danlos syndrome with periodontitis causes severe, progressive and early onset periodontitis (or periodontitis ) and gum problems.

Cardio-valvular type

Cardio-valvular Ehlers Danlos syndrome is typically related to: progressive cardio-valvular problems, articular hypermobility in small joints and skin alterations (eg, skin hyperextensibility, fragile skin, predisposition to bruising and abnormal healing process).

Diagnosis

As a rule, doctors use information from: to make the diagnosis of Ehlers Danlos syndrome

• The objective examination, ie the medical observation of the symptoms and signs exhibited by the patient;
• The anamnesis, that is the critical study of the symptomatology through specific questions, combined with an examination of the family history of the patient;
• A genetic test, ie DNA analysis aimed at detecting mutations of critical genes. The evaluation of the patient's genetic profile is always the last step in the diagnostic process, as it is the confirmation test, both when the physical examination and the medical history were sufficiently exhaustive and (a fortiori) when the physical examination and medical history were poor in information.

Genetic test: confirmation test but not only

The genetic test is important not only because it represents the diagnostic confirmation test, but also because, by detecting the precise mutated gene, it allows defining with absolute certainty the type of Ehlers Danlos syndrome present. Until before the genetic test, in fact, every conclusion concerning the variant of Ehlers Danlos syndrome in progress was based solely on the observation of the symptomatology.

Therapy

Currently, the Ehlers Danlos syndrome is incurable (in the sense that it is not possible to recover from it) and the only treatments available to those who wear it are symptomatic, ie aimed at alleviating the symptoms and preventing the most serious complications.

Did you know that ...

To be able to recover from a disease such as Ehlers Danlos syndrome, it would be necessary to eliminate the genetic mutation or cancel its effects in such a way that collagen is normal and functional.

Symptomatic therapy: what does it consist of?

The list of symptomatic treatments for the management of Ehlers Danlos syndrome includes:

• Pain medication;
• Hypotensive drugs;
• Physiotherapy;
• Occupational therapy;
• The use of orthopedic tools;
• Joint surgery;
• Vascular surgery.

ANTIDOLORIFYING DRUGS

Painkillers serve to mitigate the pain related to joint, muscle or skeletal problems, which, depending on the type of Ehlers Danlos syndrome, may be more or less present.

Among the painkillers most used in the presence of Ehlers Danlos syndrome, naproxen (an NSAID), ibuprofen (another NSAID), paracetamol and opioid analgesics (reserved for the most critical cases) deserve a mention.

HYPOTENSIVE DRUGS

The hypotensive drugs - that is the medicines used to reduce blood pressure - are used to protect the fragile blood vessels of those who are carriers of Ehlers Danlos syndrome. In fact, low blood pressure means that the circulating blood has a less powerful impact on blood vessel walls (high pressure, on the other hand, has the opposite effect).

PHYSIOTHERAPY

Physiotherapy for those suffering from Ehlers Danlos syndrome consists of exercises aimed at strengthening the muscles and improving joint stability. Stronger muscles and more stable joints, in fact, reduce the risk of distortion and joint dislocation.

OCCUPATIONAL THERAPY

Occupational therapy for those suffering from Ehlers Danlos syndrome includes:

• The adaptation of the domestic environment according to its physical needs;
• The teaching of how to best use and preserve the joints most at risk of complications;
• Inclusion in a social context, in order to lighten the awareness of being a chronic patient.

ORTHOPEDIC INSTRUMENTS

Orthopedic tools serve to protect the joints from the worst consequences that Ehlers Danlos syndrome can have on them.

Among the most used orthopedic tools in the presence of Ehlers Danlos syndrome are the wheelchair, the knee brace and the ankle brace.

ARTICULAR SURGERY

Including interventions such as joint debridement, arthroplasty, capsulorrhaphy and replacement of injured tendons with prosthesis, joint surgery is used for patients with Ehlers Danlos syndrome to prevent some serious joint complications or to cure some serious problems affecting the latter (eg: unbearable pain, extensive damage, severe instability, etc.).

VASCULAR SURGERY

In the presence of Ehlers Danlos syndrome, vascular surgery is indicated when there is a real risk of complicating the blood vessels or when there is a serious injury to the blood vessels.

Prognosis

The prognosis for those suffering from Ehlers Danlos syndrome varies according to the pathological type present. In fact, some types of Ehlers Danlos syndrome are more serious and dangerous than others (eg, the vascular type is among the most serious).

It should, however, also be pointed out that, for unknown reasons, the severity of the symptoms may differ considerably among patients with the same type of Ehlers Danlos syndrome (some patients are better than others); this makes every speech related to the prognosis more complex than it was in the beginning.

Prevention

Ehlers Danlos syndrome is an impossible condition to prevent .