EHLERS-DANLOS Syndrome

 EHLERS-DANLOS Syndrome

EHLERS-DANLOS Syndrome

Dr. Kurland Norbert

Ehlers-Danlos syndrome (EDS) is the clinical expression of connective tissue damage (which constitutes 80% of the human body). It is of genetic origin, affecting almost all organs, which explains the richness of its symptomatology. If it is known to be a rare, orphan disease, as it is rarely diagnosed. The number in the world is underestimated.

Ehlers-Danlos syndrome and fibromyalgia

Fibromyalgia shows similarities of symptoms with Ehlers-Danlos syndrome: diffuse and variable pain often resistant to analgesics, fatigue, gastrointestinal disorders, migraines, hyper reactivity to stimulation, auditory and other, disorders of memory and attention. As in fibromyalgia, there is a predominance in women, an influence of climatic factors and the existence of a family context. Fibromyalgia and Ehlers-Danlos syndrome can both start in childhood or adolescence.

Rheumatologists, who are particularly concerned with fibromyalgia syndrome, do not at first mention Ehlers-Danlos syndrome in front of a woman who consults for diffuse pain and fatigue. It is impossible to diagnose what we do not think of, especially since the Ehlers-Danlos syndrome is a much more rare pathology compared to fibromyalgia, a highly publicized entity, whose number of patients reaches millions throughout the world. The resemblances of the symptomatology should encourage us to always check whether it is not, in fact, an authentic Ehlers-Danlos syndrome. I have personally found genuine Ehlers-Danlos syndromes in people who consulted me diagnosed with fibromyalgia.

Indeed, the connection of the many clinical manifestations of the Ehlers-Danlos syndrome to different pathologies is the cause of many errors and long diagnostic errors. Some patients have been treated, and sometimes simultaneously, for 4 or 5 different diseases because of symptoms that are all related, in fact, to the same cause: Ehlers-Danlos. The failure of treatments, the persistence of symptoms whose intensity contrasts with the negativity of biological tests and imaging (especially joint MRI) usually leads to an abusive psychiatrisation. For many, patients hear or are suggested that it's in their heads, or are stigmatized as hypochondriacs. It is also often the lot of sufferers of fibromyalgia.

Comparing fibromyalgia with Ehlers-Danlos syndrome, the clinical examination in both syndromes finds on palpation pain substantially the same locations (tender points). Unfamiliar with the evocative and often dominant clinical manifestations of the Ehlers-Danlos syndrome, but sometimes variable over time, will wrongly lead to genuine fibromyalgia.

 

Historical

The initial description was made by two dermatologists, Edvards Ehlers in Copenhagen, in 1900, and Alexandre Danlos in Paris, in 1908. From these initial descriptions, initially dominated by cutaneous signs, nowadays, in the most frequent forms (there are 6 different types), the syndrome is manifested by an excessive articular mobility, and a fragile, stretchable and hemorrhagic skin.

 

Curiosity of Nature

In extreme cases of Ehlers-Danlos syndrome, a contortionist can insert himself in a box and cover his face with the skin of his neck. However, the majority of cases are not demonstrative that way. Most forms have a moderate symptomatology, whereas, in other cases, the Ehlers-Danlos syndrome appears as a disease which can be, at certain moments of life, very disabling. It can result in great suffering and social exclusion.

When a physician is asked if he knows Ehlers-Danlos syndrome, he says "The hypermobility of contortionists". The general impression which has so far arisen in listening to the medical discourse is the notion of the benignity of this clinical entity, rather perceived by physicians as a curiosity of Nature without much functional consequences. This is a pathological condition that can be severely disabling.

 

Genetic character

The genetic character of the Ehlers-Danlos syndrome is one of the main features of the diagnosis: the discovery of identical family cases in the family. The transmission is autosomal and therefore sex-independent, implying that both sexes are involved, with a clear female predominance (82%).

Female patients manifests with a greater severity of symptoms compared to men. The hormonal factor is probably the cause, explaining the increase in symptoms at puberty and after childbirth, while pregnancy and lactation can be accompanied by significant reduction in clinical manifestations.

The autosomal dominant mode of genetic transmission causes the risk of contracting the syndrome to be 50%. This finding must be modulated by the fact that the symptomatic level is very diverse as well as the functional consequences. The existence of family history is an additional argument for the diagnosis, although 50% of cases are due to de novo mutations.

It is not uncommon that the father and mother of a child with Ehlers-Danlos syndrome are both carriers of the gene, with no apparent consequence on clinical severity. One or the other can transmit the disease without knowing it.

 

 

Frequency

1 case per 5000 to 10 000 births according to current estimations which probably neglect many undiagnosed forms. So this number appears to be very far from reality. In 1933, Achille Miguet, in his remarkable thesis supported at the Faculty of Medicine in Paris, had made this premonitory remark: "Typical cases are rare, a scarcity which is perhaps due to the ignorance of this affection".

 

Diagnosis

The diagnosis is clinical, based on personal history, family context, the clinical examination of the skin and the joints. There are no available genetic tests, neither reliable and specific biological or histological tests. Articular imaging is of no help in diagnosis except by excluding other orthopedic conditions.

Not only the nature and the grouping of the symptoms encountered in these patients are not identified by the doctors but, in addition, the sometimes incomprehensible misunderstanding of the entourage. All this contributes to isolate, to guilt those patients who no longer understand what is happening to them. This is further aggravated by perceiving their own bodies differently since birth and lacking references between what medicine defines as a normal state or a pathological condition. The result is a very great underestimation of suffering and of the actual functional state.

In the highly diverse and variable symptomatology of this disease, the absence of a sign, which is common for stretching and more rarely for hypermobility, often lead doctors to miss the diagnosis.

 

Delay between the arrival of evocative signs and the moment of diagnosis

Diagnosis is generally made late. In practice, an average of 21 years for women, 15 years for men, often preceded by inappropriate medical and surgical therapeutic procedures, whose failure can be revealing. Thus, people with Ehlers-Danlos syndrome are during a long time the victims of inadequate therapeutic behaviors that aggravate them: aggressive physiotherapy, unnecessary orthopedic or digestive surgery, devastating neck osteopathic manipulations by vertebral artery lesions. At times, psychiatric disorders and accusation of simulation are suspected. Parents or spouses are often accused of maltreatment because of the presence of bruising or severe hematomas.

 

The three forms

The classification of Villefranche identifies 6 forms, but in current practice 3 forms are the most frequent: hypermobile (70%), classical (15%), vascular (5-10%). The three forms have identical manifestations but of variable intensity of expression:

- The "hypermobile form", characterized by the importance of articular manifestations;

- The so-called "classical form" which is characterized by the intensity of the cutaneous manifestations;

- The "vascular form", characterized by the importance of arterial, intestinal and uterine manifestations is more severe than the others due the severity of the vascular, intestinal and uterine complications.

 

 

Signs (out of 644 patients)

 

Diffuse pain (all the body is painful), variable and rebellious to analgesic medications: joint and periarticular pain (98%), muscular pain (82%), abdominal pain (77%), thoracic pain (71%), genital pain(75%), migraines (84%), cutaneous hyperesthesia (39%). Joint pain is the most common. Women suffer more than men.

Fatigue (96%), including sleep disorders.

Disorders of proprioception: obstacle strikes, falls and drops of objects; disorders of the corporal scheme and movement control: pseudo-sprains (86%), dislocations and subluxations (90%).

Hypermobility (97%)

Skin alterations: thinness (91%), skin fragility (87%), stretch marks (64%), retardation of healing (85%).

Bleeding(92%), especially bruising, nosebleed, metrorrhagia, gingivorrhagia, hemorrhagic wounds.

Digestive disorders: gastroesophageal reflux (80%), constipation (74%), bloating (70%).

All of these signs are the only ones that provide strong evidence for the diagnosis. It is reinforced by the knowledge of one or more other cases in the family. This family character includes crude, incomplete or partial forms.

One of these signs may be missed without eliminating the diagnosis. Indeed, incomplete (or limited clinical expression) forms are very common. They, however, take on their full significance when they coexist with a more complete form in the same family.

A number of other events exist. By combining them, they reinforce the diagnostic conviction but above all they must be grouped in the syndrome to avoid unnecessary errors and always traumatic medical rejections:

Respiratory symptoms: dyspnea and shortness of breath (85%); respiratory blockages and pseudo asthma (65%).

Mouth and dental manifestations: temporomandibular disorders (pain, blocking, luxation) (76%), dental maniafestations (fragility, orthodontic problems) (71%), alterations in the gums (fragility, pain) (80%).

Ear, nose and throat manifestations: hyperacusis (89%), hypoacusis (even hearing loss) (57%), tinnitus (69%), hyperosmia (69%), positional vertigo (triggered with a head movement) (80%).

Eye manifestations: visual fatigue (86%), myopia (56%).

Gynecological and obstetric manifestations: abundant menstruation (menorrhagia) (78%), difficult deliveries (78%).

Neurovegetative manifestations and thermoregulation: chilliness (77%), abnormal sweating (74%), pseudo Raynaud's syndrome (74%), unexplained fevers (52%), tachycardia (66%) and heart palpitations (51%).

Bladder and sphincter manifestations: decreased need to urinate (no perception of bladder distension which allows to remain hours or even a day without feeling the need to urinate, as well decreased need to exonerate its stools (51%), pollakiuria, incontinence, dysuria (63%).

Cognitive impairment: impairment of memory (69%), attention deficit (67%), difficulty concentrating (65%), alterations in executive functions (38%), disturbances in spatial orientation (44%).

 

Sources: statistical study of 644 patients with Ehlers-Danlos syndrome, conducted in collaboration with the Clinical Epidemiology Department of Professor Philippe Raynaud, at the Hôtel-Dieu in Paris, presented at the first International Symposium on Ehlers-Danlos syndrome, on 6-9 September 2012 in Gent (Belgium).

 

 

Pain in Ehlers-Danlos syndrome

Pain is one of the most frequent symptoms (89.7%). Disability with fatigue (89.4%) is also common. The pain is mainly situated in the joints: shoulders, wrists and fingers, elbows, hips, knees, ankles and feet, neck, back and pelvis. The skin itself is often hyperalgic, difficult to withstand contact and reacting excessively, as well as the osteoarticular system, to direct or indirect trauma.

Pain can predominate in the tendons, resulting in tendinitis, often resistant to local treatments by infiltrations.

Pains are also related to hypermobility, each subluxation being particularly painful with lasting pain.

Severe muscular pain manifests as cramps, especially nocturnal, sometimes associated with uncontrollable painful muscle twitches, even to produce a restless legs syndrome. Some "muscular crises" are impressive, occurring in periods sometimes spread over several days, associated with limitation of movements and very disabling. They maybe associated with vasomotor disorders with a painful sensation of frozen extremities.

Other manifestations include diffuse tingling, burning sensations or electric shocks.

Elsewhere, it is a continuous and prolonged activity (writing, use of the computer...) that generates pain. In all cases, one characteristic is the "remanence" of the pain, which persists long after the causal factor (several days sometimes). The outbreak of the first painful manifestations or the significant and lasting aggravation of the pain syndrome after a road accident has been observed.

Cutaneous pain in the limbs, neck, back can be very intense, increased by supports, movements, imposing changes of position, frequent stretching, difficult to calm by even powerful painkillers. We speak of a "painful impatience" by the impossibility of remaining in the same position and the need to move in his chair, for example, or even to sit down by adopting analgesic postures more inspired by Yoga poses than "good behavior" that is usually required of students. They often lead to extravagant positions of extreme stretching and amplitude of limbs or back for an analgesic purpose. Teachers should be informed not to accuse the children of becoming turbulent.

The body being hyper-reactive to the pain, touches and inadvertently shocks are a suffering, walking is painful.

This excess of sensory reactions exists at other levels: auditory with exacerbated auditory sensitivity, "absolute ear" in a musician or excessive auditory, noise intolerance, very frequent tinnitus. Also hyper sensitive olfactory. For some patients, their sense of smell allows them to detect a gas leak at a great distance, others perceive foul odors that do not feel other people, others have discovered the gift of wine tester equaling the "nose" of the finest oenologists.

The pains are variable, negatively influenced by the cold (there is often a sever chilliness), and positively by the heat.

The pain is often rebellious to the usual therapeutic painkillers, analgesics, antiepileptics, antidepressants, whose effectiveness is quickly exhausted. They are readily resistant to local anesthetics, dental care, local steroid infiltration.

 

Hypermobility and joint instability

It is one of the most important manifestations of the Ehlers-Danlos syndrome which has contributed to its notoriety, especially through the spectacular forms in which people can touch the ground with their palms of their hands, legs stretched out, bring a foot behind the head, suck their big toes, touch the inner edge of their forearms by turning their thumbs, obtain a complete extension of the fingers, wrist straight, perform a total rotation of the thumb on its axis, put the legs wide open without difficulty, etc.

It is not always so marked, and especially varies in time. It may have been important in childhood and almost absent thereafter. This should not deny the diagnosis. What is important, as for the other manifestations of the syndrome, is that at some point in the life of the person it has existed.

Scoliosis is common but moderate and has no functional consequences. The flat feet also.

Dislocations and subluxations, shoulders, fingers, elbows, knees, hips, and "pseudo-sprains" are common (stretching of the ligaments does not bring them to rupture in the majority of cases).

The frequency and location of dislocations and subluxations is not strictly related to the importance of hypermobility.

 

Fatigue and Ehlers-Danlos syndrome

Fatigue is with pain the symptom that dominates the syndrome and that evolves alongside with it during crises. It is often present early in the morning and more marked at the end of the day. It is accentuated by efforts which can result in sudden drowsiness. It creates a state of weakness in all the acts of everyday life, increased by pain, joint instabilities and shortness of breath.

 

Skin and Ehlers-Danlos syndrome

The first descriptors of Ehlers-Danlos syndrome were attracted by the skin signs. The skin is fine and translucent, fragile, tearing easily, and leaving significant support marks. There is bruising with minimal trauma, and in many cases bruising occurs without history of trauma. These bruises are a sign of capillary fragility and not a disorder of the blood clotting.

These bruises may constitute true subcutaneous hematomas which may be important. They are accompanied by bleeding gums, bleeding nose (epistaxis), but also by urinary, intestinal and bronchial hemorrhages, and bleeding wounds. This can lead to iron deficiency anemia that may play a role in the pathophysiology of fatigue.

Care must be used in the use of aspirin and anti-inflammatories drugs.

In males and females, the skin is often streaked with stretch marks on the buttocks, abdomen, thighs and breasts or on the back even in the absence of pregnancies.

The healing delays are long, with suture releases, the scars are often of poor quality, and often pigmented.

The skin is very elastic, impressive in rare cases, but most often this sign is discreet. Its absence should not preclude the diagnosis.

The color and warmth of the skin may vary as a result of vasomotor disorders, which are also part of the syndrome. Variable edema can be observed. Chilliness is frequent. The occurrence of cysts may also occur. Synovial cysts (especially on the wrist) is more frequent and especially painful.

The nose and ears can be very flexible, easy to 'twist'.

 

Cognition and Ehlers-Danlos syndrome

Cognitive disorders can affect attention and memory. There is also an important perturbation in the perception of the corporal pattern, which is expressed by episodes of sensorimotor disconnections that may concern a more or less important part of the body (one or two limbs for example), responsible for falls by stunting, of pseudo-paralytic syndromes (they disconcert neurologists greatly when they find that scanners and MRI are mute), of "clumsiness" with falls of objects and difficulty of execution of simple tasks, of obstacles clashes such as knocking the doorframe at the passage of a door. These manifestations can extend to all the nearby environment which is badly perceived, badly integrated, and at the origin of difficulties of locating (to park a car for example, to find the location of familiar objects).

With the pain and fatigue, this transformation of the corporal pattern is at the origin of most situations of handicap encountered in people with Ehlers-Danlos syndrome. There is a real dissociation between the brain that knows what to do and a rebellious body that "does not obey", and sometimes even perceived as an "external object" or even a "robot".

Mental functions and academic performance are often remarkable, despite absences and difficulties related to fatigue and pain. The imagination and creativity of thought are often marked, which makes the dialogue with these people very rich and very constructive.

Sleep can be disturbed, despite the fatigue of the day, with difficulties of falling asleep, as if the brain and thus thought, freed from bodily constraints, continued their activity, forgetting the need for rest of the organism.

 

Respiratory symptoms

Respiratory manifestations of Ehlers-Danlos syndrome are practically ignored, unknown or little known to pneumologists.

The notion of an asthma attack is frequently noted.

 

We also find:

- Variable shortness of breath and not always with the importance of the effort involved;

- Very unpleasant respiratory "blockages" with the sensation of not being able to penetrate the air;

- Bronchitis is frequent;

- Inflammation of the upper airways: rhinitis, tracheitis, cough. The disturbances of the voice can be related to those troubles.

- Low chest pain evokes diaphragmatic pain, partly explaining discomfort to inspiration.

 

The "neurovegetative" disorders, chilliness

Thermoregulation disorders: chilliness is very frequent, coldness of the extremities (feet and hands sometimes frozen), Raynaud's syndrome. More rarely it is intolerance to a high temperature with sweating. Also, venous disorders with edema, dry eyes, palpitations, changes in heart rhythm (bradycardia, episodes of tachycardia), decreases in blood pressure, dizziness or postprandial reactions.

 

 

What does not occur

There is no paralysis but the muscles work under poor conditions due to elasticity of the tendons, intermuscular partitions, excessive mobility and proprioceptive disorders which make movement uncertain and expensive in energy consumption at muscular level. The superficial nerves, badly protected by the soft parts, "too soft", are threatened with compressions responsible for paralysis mostly incomplete, in any case transient.

The nervous system is preserved in the Ehlers-Danlos syndrome, in any case it is not the place of primitive attacks due to the process of the disease. Vascular involvement alone may be responsible for neurological damage. With the proviso that small-fiber neuropathy (SFN) is a common feature in patients with Ehlers-Danlos syndrome. In the SFN, diagnosed by a skin biopsy, the neurological examination and the standard electromyogram are normal.

The bone system is preserved in Ehlers-Danlos syndrome. Fractures are exceptional. A reserve should be made for the cartilage which is connective tissue rich in collagen, which can play a role in chest pain and respiratory discomfort. Osteoarthritis is mostly absent.

 

Discussion

● It is a diagnosis that is often difficult, especially in the crude forms presenting appearances of banal appearance such as diffuse pain, fatigue, constipation ...

● The diagnosis is often made only in adolescence or adulthood, 20 to 30 years, after, for example, the failure of ligamentous surgery.

● It should be noted that some manifestations present in childhood may have disappeared or been greatly reduced. Examples are hypermobility, sprains, falls, bruises, pseudo asthma attacks. Conversely, other manifestations appear later in adolescence or adulthood, sometimes after physical trauma. The role of psychic trauma is not easy to assert. What should be retained for the diagnosis is that the sign has existed at a given moment. Its attenuation or disappearance must not cause the diagnosis to be eliminated.

● It should also be noted that the symptomatology varies by "crises" rather than "outbreaks" (it is not a degenerative disease), under the influence of exogenous factors (climatic, traumatic) or endogenous factors (hormonal factors explaining the increase in symptoms at puberty and after childbirth, while pregnancy and lactation can be accompanied by significant sedation of clinical manifestations, as well as the influence of the hormonal cycle). Crises persist for several days or more. It is the regrouping of the symptoms and precisely this evolution, apparently "chaotic" which is particularly evocative. Some describe these patients as "intermittent of disability".

● This syndrome is too often relegated, in the minds of physicians, to the musculoskeletal system when it is a diffuse disease of the connective tissue.

● The association of locomotor manifestations, pain, fatigue and digestive, cutaneous, hemorrhagic, cognitive, respiratory or urinary manifestations should be a diagnostic guideline. In the end, there are too many manifestations for them not to have a single cause.

● Emphasize that diagnosis is relatively easy if it is part of a family context, one or more other cases in the family.

● Finally, in the vast majority of cases, the prognosis of this syndrome is compatible with a life expectancy identical to that of the general population, with the reserve of the forms qualified as "vascular" with the notion of arterial complications (which must be systematically detected), but which should not unnecessarily cloud the prognosis of this syndrome.

 

Some clinical entities may be confusing : differential diagnosis

1- Isolated hypermobility syndrome is quite common among people from Black Africa, the Maghreb or the Indian Ocean, but also among Europeans. If it is associated with other clinical features of Ehlers-Danlos syndrome, then these may be crude forms of the syndrome which appear rather as a morphological feature without pathological consequence.

One particular case is that of a recurrent dislocation of the hip at birth, which should evoke the Ehlers-Danlos syndrome with implications for the choice of therapeutics. This is not easy.

2- The Marfan syndrome and the imperfect osteogenesis present affinities with the Ehlers-Danlos syndrome. They have in common ligament hyperlaxity. The first is also a genetic disease of the connective tissue which, besides hyperlaxity, is responsible for changes in the heart (heart valves) and large vessels (especially the aorta), dysmorphy with particularly long limbs, fingers and toes abnormally long and slender (arachnodactyly), and the sternum in recess or protrusion.

The second is characterized by frequent fractures for minor trauma, which has earned this syndrome the nickname of "glass bone disease", whereas in Ehlers-Danlos syndrome fractures are very rare despite the frequency of falls.

3- The syndrome of battered children or battered women could be mistakenly mentioned in front of a young child with articular dislocations or especially bruises and multiple hematomas.

4- Fibromyalgia which the resemblances of the symptomatology justify to verify always whether it is, in fact, an authentic syndrome of Ehlers-Danlos.

5- Small-fiber neuropathy (SFN) is a recognized cause of generalized chronic pain for which there are objective tests and treatments. It has several symptoms in common with Ehlers-Danlos syndrome as well as fibromyalgia. In fact, SFN is a common feature in patients with Ehlers-Danlos syndrome and with fibromyalgia. In addition to the fact that SFN can cause pain of all kinds and extreme sensitivity to touch, there are also the same neurovegetative disorders - bladder, digestive, vasomotor, and cognitive and sexual disorders - which encountered both in Ehlers-Danlos syndrome and in fibromyalgia. It should be noted that approximately 60% of patients suffering from fibromyalgia have a small-fiber neuropathy, objective evidence of a mechanism causing fibromyalgia. Thus, a number of patients suffering from chronic pain labeled as fibromyalgia actually have unknown SFN or Ehlers-Danlos syndrome. They are frequently confused. The cutaneous biopsy makes the diagnosis of SFN. It could be considered as an additional diagnostic tool to investigate pain manifestations in Ehlers-Danlos syndrome.

6- Multiple sclerosis is sometimes mistakenly diagnosed as Ehlers-Danlos syndrome.

7- Hypothyroidism can be confusing facing fatigue, cognitive and sleep disorders, disorders of menstruation, chilliness, cold extremities, easy bruising, constipation, dysuria. Muscular and articular pains fit perfectly into the clinical picture of hypothyroidism, with biological iron-deficiency anemia, not due to bruises, whereas in Ehlers-Danlos syndrome it is related to hemorrhages. The thyroid hormone administration cures the problem. But it is possible to suffer from both Ehlers-Danlos syndrome and hypothyroidism.

8- Miscellaneous conditions, as spinal cord injury with hyperalgic radiculitis, as muscular dystrophy (myopathy), as Lyme disease.

 

Conclusion

The diagnosis of Ehlers-Danlos syndrome is clinical based on the history and physical examination. Ehlers-Danlos syndrome is not a progressive disease. It is a connective tissue disease which results in painful and/or disabling manifestations. Hypermobility is reduced with age.

Due to the lack of knowledge of this syndrome, it is considered benign. However intolerable sufferings frequently occur, and are seldom relieved by powerful analgesics. There is therefore a gap between the knowledge and the medical perception of the syndrome and the daily suffering of the patients.

The symptoms of Ehlers-Danlos syndrome can be alleviated. There are treatments that are mainly in Physical Medicine. Others, immunostimulating drugs, allow to relieve the chronic pain and to improve the functional state.

norkurld@zahav.net.il
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