Hypermobile SED / Hypermobility Spectrum Disorders (HSD)

Thanks to Prof. Claude Hamonet, let's review the history of this (clinical) syndrome or disease (of the connective tissue):

I - Introduction: the historical weight of the label of strangeness, monstrosity.

Ehlers-Danlos is a disease that has met a paradoxical fate. Clinically identified 125 years ago (Chernogobow)), easy to recognize and diagnose, it is unknown to almost all doctors who never diagnose it (Rodney Grahame). Those who know her name, in their great majority, consider her rather as a curiosity because of very mobile joints immediately evoking the contortionist or a very stretchy skin like the Spanish sailor, Georgius Albes, aged 23, presented by the Dutch surgeon of Amsterdam, Job van Meek'ren at the Leiden Academy in 1657.

This context leads physicians to consider Ehlers-Danlos syndrome as a "minor illness", an illness that is not "serious", in short a "negligible" illness (Rodney Grahame). Some even conclude their consultation by saying: "you should work in a circus", seeing only the two signs that have marked, from the beginning of its history, its identification and neglecting the multiplicity of symptoms that accompany this systemic disease that concerns the very framework of what constitutes our body: the collagen tissue.

Beyond the carelessness and misunderstanding, there is the contempt and suspicion of which these patients are very often victims, the discrepancy between the "normal" appearance of their limbs, the seat of often excruciating pain and uncontrollable clumsiness. The "invisible" side of their illness exposes them to inappropriate and violent reactions from doctors, which are echoed by those around them, both of whom "do not understand".

II - Initially, it's a matter of skin and joints that are too mobile...

The most apparent manifestations naturally attracted the attention of one of the first medical specialties to identify and structure itself: dermatology. The first known descriptors are dermatologists (Tschernogobow, Ehlers, Danlos) who introduced the two signs that have marked the history of this disease until now: the stretchability of tissues, of the skin in particular, and an excessive mobility of the joints. The importance attached to these two signs will have unfortunate consequences for the patients concerned since, in their absence, on the one hand, 'genuine' cases of Ehlers-Danlos disease will be eliminated and, on the other hand, other signs which make up the severity of this disease, which today appears to be a frequent cause of disability, will be minimised or ruled out. The first and most complete description of the disease was given by a Dane, Edvard Lauritz Ehlers (1863-1937), son of the mayor of his town, who studied medicine in Berlin and Paris.

This description follows that of the Russian dermatologist Alexander Nicolaiev Tschernogobow (otherwise spelled Chernogobow or Csernogobov) who, in 1892, presented two patients (a 17-year-old man and a 50-year-old woman) to the Moscow Society of Dermatology and Venereology. 

A case later recognized by Weber (1936) was presented by Sir Malcolm Morris in 1900 to the Dermatological Society of London.

In 1907, Cohn presented a case "of a patient with rubber skin (cutis laxa)" at the IXth Congress of the German Dermatological Societies, this publication went unnoticed.

In 1908, Henri Alexandre Danlos, physicist and dermatologist (the first to have introduced Radium needles into skin cancers), associated with Mr. Pautrier for histology, presented to the French Society of Dermatology and Syphiligraphy of Paris "a case of cutis laxa with tumors by chronic contusion of the elbows and knees". He insists on two signs: "the abnormal thinness" and "the extraordinary elasticity" of the skin which he compares to that of "a thin rubber blade". In fact, Danlos had examined a patient whom François Hallopeau and Macé de Lépinay had already presented in 1906 to the French Society of Dermatology with the title of pseudo-diabetic juvenile xanthoma. This emphasis on cutaneous hypersensitivity will have serious consequences in the face of this syndrome on the attitude of doctors who expect it to be "extraordinary" whereas it is modest in the SED and sometimes absent. Many still wrongly consider its absence as a cause for exclusion from this diagnosis.

III - Parallel Navigation of the SED in Rheumatology and Genetics

The rest of the history of Ehlers-Danlos syndrome is marked by the involvement of two medical disciplines in its description and identification tests: rheumatology with Grahame and genetics with Beighton. The benign nature of the disease has been dramatically emphasized as Rodney Grahame points out with regard to the "Hypermobility Joint Syndrome", the name rheumatologists give to this disease: In 1967 is published in Annals of rheumatology diseases.an article on the generalized musculoskeletal hypermobility syndrome in people considered "otherwise normal", i.e. that these people are not sick at all, that they are healthy with a particular aspect of normality.
Grahame and Bravo have considerably evolved its clinical description among rheumatologists, enriching it progressively: pain, fatigue, digestive disorders, dysautonomy, situations of handicap...). Grahame developed the so-called Brighton diagnostic criteria for the hypermobility of joints syndrome, which include two main criteria: a Beighton's hypermobility test greater than 4 at the time of the examination or previously and joint pain for more than three months in four or more joints and minor criteria such as stretch marks, epicondylitis, dislocations, etc. Finally, this is in line with historical descriptions and is close to the observations that will be made by geneticists.

The second medical discipline that became involved in this syndrome was genetics from 1949 onwards. The family character evoked by Achille Miget in his thesis is demonstrated by Johnson and Falls who prove the dominant hereditary character of the syndrome from a family tree of 123 people over 6 generations. Jansen (21), in 1955, shows that the intertwining of collagen fibres is less tight in the skin of a subject with Ehlers-Danlos syndrome than in the skin of a control subject and explains the clinical manifestations in this way.

In 1968, an X-linked transmission is highlighted by Beighton. In 1969, Beighton, based on the observation of 100 patients, proposed five distinct, clinically detectable forms: the acute type or type I, the mitis type or type II, the hypermobile type or type III, the ecchymotic type or type IV corresponding to Barabas' arterial type, and the X-linked syndrome to type V.

Beighton gave his name to a 9-point hypermobility test, an application of a test used to compare the joint mobility of Blacks and Whites in South Africa. It will become a reference for many clinicians. However, it is imperfect, variable, often misapplied and misinterpreted, and, like stretching, is too frequently used to eliminate a diagnosis that is obvious when other equally significant symptoms are present. Around Beighton and his school, a classification based on collagen mutations was developed. This classification, which started with eleven types in Berlin, is reduced in the latest version in Villefranche to six and, in current practice, to three (classic, hypermobile, vascular). It is of great concern to patients who fear that they may be affected by the vascular SED, which has been described as early (40 years) lethal with the risk of aneurysm rupture and serious organ tears ("bursting" of the uterus for example). Fortunately, this picture is extremely rare, but it continues to make a difference and many women in labour today are threatened with the authority of a Caesarean section if their obstetrician learns they have SED. Villefranche's classification criteria lack most of the symptoms of SED as currently described, which is a barrier to its diagnostic use and creates a lot of confusion that is detrimental to patients. It is clear, as Tinkle indicates, that rheumatologists' hypermobility of joints and geneticists' hypermobile Ehlers-Danlos syndrome are one and the same clinical entity that falls under the same prevention and contraindications in the face of the risks (especially iatrogenic) and the same treatments of the proprioceptive syndrome.

IV - Cognitive and psychopathological aspects. Autism and Ehlers-Danlos Syndrome.

One aspect of SED semiology that has been neglected is the cognitive aspect and psychopathology. Antonio Bulbena (Barcelona) and his team, in 1988, highlighted the correlation between joint hypermobility and anxiety in patients followed in ambulatory care by the rheumatology department at the Hospital del Mar in Barcelona: 70% of hypermobile patients present a psychopathological disorder compared to 22% of controls. This relationship between anxiety, depression and eating disorders is the subject of studies and publications. Several leads can be evoked: difficulties in managing a permanent disabling syndrome favour pathological anxiety in patients with Ehlers-Danlos SED. The presence of cognitive disorders (memory, attention, concentration, orientation) can also create significant psycho-affective disturbances.

A special case is autism for which associations with SED exist, associating in the same family of cases Ehlers-Danlos syndrome and autism, as we have observed. This diagnosis of autism is sometimes over-diagnosed.

V - Other events

Other manifestations have recently been linked to Ehlers-Danlos disease: Alterations of mast cells with a fragility observed in our patients in the face of infections, attached marrow, Arnold-Chiari, the frequency of cysts (cutaneous, ovarian, hepatic, renal, suggesting polycystosis, pancreatic, pituitary ...), MRI images with diffusion tensor, the arched bundle in particular.

VI - For a radical change in the medical and social vision of Ehlers-Danlos disease.
It is a frequent disease (prevalence based on the number of cases detected by general practitioners trained in diagnosis: one million people in France) which should no longer be confined within the narrow framework of rare and orphan diseases.

It is a hereditary, autosomal, widely transmissible disease: careful observation of the families of our patients tells us that, in almost all cases, all the children in a family are affected if one of the parents is affected. Sometimes it is both parents who are affected, showing the frequency of the disease.

Women are more numerous in our consultations (80%) because the clinical manifestations are more severe in them, due to the hormonal factor that punctuates the course of their disease (puberty, cycle, pregnancy, childbirth, menopause).
She is not or very late (23 years late on average in our cohort) diagnosed, which exposes her to medical wandering with the iatrogenic risks induced by the treatments (surgical, medicinal, osteopathic, psychiatric with abusive internments...). The generalized medical ignorance or the underestimation of the symptoms very often direct, because of the frequent pains and the diffuse hyperesthesia, towards the diagnosis of fibromyalgia, which must be systematically discussed in the case of Ehlers-Danlos. Treatments applied in this pathology, in particular antidepressants, aggravate the symptoms of Ehlers-Danlos disease.

In the absence of a biological marker, the diagnosis is based solely on the clinic's ability to group together manifestations expressing multiple localisations (cutaneous, oral, musculo-articular, vascular, respiratory, digestive, urinary, ENT, ophthalmological, vestibular, gynaecological - with sometimes severe consequences on pregnancy and childbirth -, neuro-vegetative, dystonic, cognitive, affective and behavioural. This multiplicity should not be surprising and should not lead to a "psychosomatic" origin, as we very often observe.
The Munschausen Syndrome is often mentioned, even by the most reputable clinicians, as medical prejudices are so important and mistrust of the patient is too often rooted in the mind of the doctor.

The clinical manifestations can be expressed from birth (hip dislocation, club foot) or begin in the first months of life (constipation, reflux, ecchymosis, ear infections), in the first years (hypermobility, thin and fragile skin, significant fatigue, instability when walking with falls, violent abdominal pain, bloating, generalized musculo-articular pain, painful instability with the obligation to move, to get up incompatible with class, migraines, bronchitis, so-called asthmatiform respiratory blockages sometimes due to costal pain, sprains, dislocations, cold extremities, swallowing disorders, visual fatigue, myopia, hyperacusis, hyperosmia, anarchic dental flares, retrognatism, ogival palate, Gorlin's sign in which it is possible to touch the nose with the tip of the tongue). During childhood, a tendency to hyperactivity with attention difficulties can be observed. On the other hand, intelligence is lively, with very good school performances, despite (or thanks to) hypermobility, sports performances (dance, gymnastics, combat sports) are often excellent.
During adolescence, everything changes, school performance persists, sports performance collapses, pain becomes more and more intense, causing the cessation of sports activity, but also asthenia sets in, accompanied by migraines, significant sleep disturbances, seriously disrupting school and social life. Dysautonomy manifests itself more with hypotension, diffuse malaise (POTS), tachycardia attacks, chills, excessive sweating. The impact on educational and vocational guidance is strong, sometimes constraining.

Elsewhere, the first manifestations that lead to seeking medical advice are later. They may occur at the time of a violent trauma (road accident, sports accident), posing the problems of compensation for bodily injury that one imagines when faced with the ignorance of the syndrome on the part of the medical advisors. Age does not appear to be a systematic aggravating factor.

The practical conduct of the diagnosis requires a list of evocative symptoms and the measurement of their severity on an analogical scale from 0 to 4 (Lickert). The one presented here has been the subject of an initial validation with a control group of patients without Ehlers-Danlos disease.

Grouping of clinical manifestations of Ehlers-Danlos disease contributing to its diagnosis (44).
Pain (45), the whole body is in pain. They are: articular and periarticular (98%, very intense in 82% of cases), muscular (82%), abdominal (77%), thoracic (71%), genital (75%), migraines (84%), cutaneous hypersensitivity (39%). Proprioceptive and movement control disorders: pseudo sprains (86%), dislocations (90%), hypermobility (97%). Skin alterations: thinness (91%), fragility (87%), stretch marks (64%), delayed healing (85%). Haemorrhages (92%). Gastrointestinal manifestations: gastro-esophageal reflux (80%),(85%), respiratory "blockages" with a feeling of suffocation (65%). Oral manifestations (71%). Ear, nose and throat: hyperacusis (89%), hearing loss or deafness (57%), tinnitus (69%), hyperosmia (69%), dizziness (80%). Ophthalmological manifestations: visual fatigue (86%), myopia (56%). Gynaecological and obstetrical manifestations: heavy menstruation (78%), difficult childbirth (78%). Dysautonomy: chills (77%), abundant sweating (74%), pseudo Raynaud's syndrome (74%), accelerated heart rate (66%), vesico-sphincterial manifestations: difficulty to urinate, urgent cravings. Cognitive manifestations: impaired working memory, attention, orientation. In addition, there are sometimes manifestations of dystonia (sometimes alternating involuntary movements, tremors, deceptive diffuse attacks generalized to a hemicorps, or to the extremities, contractures etc.).

Familial character (including frustrated, incomplete or partial forms) is a major contributor to the diagnosis of hereditary disease in the current absence of genetic testing, unnecessary when four out of four children and their mothers are affected.

A recent physiopathological contribution that revolutionizes the semiological and therapeutic approach to Ehlers-Danlos disease: the major alteration of proprioception and body image.

It is based on the knowledge of the role of collagen tissue in the resistance of tissues and as a support for sensors that provide conscious, automatic and vegetative regulation centres with the information necessary for the proper regulation of our human economy. This perception, called by Sherrington proprioception, a true sixth sense, constantly informs us about what is happening in our body (inside and outside) and about the relationship between our body and its immediate environment. Ehlers-Danlos disease is therefore a disease of proprioception, which makes it possible to interpret its manifestations and to give a line of action to its treatments, which will be specific. Their effectiveness is a therapeutic argument for the diagnosis.

Regarding the New York 2017 criteria and for the Beighton score, and regarding skin biopsy in Belgium (we are one of the few countries in Europe with a huge experience in skin biopsy in the SED as well as for other connective tissue pathologies (at the dermatopathology department of the CHU Sart Tillman de Liège):

See our "BIOPSY"page