Ehlers-Danlos syndrome or disease?

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Citation: Hamonet C, Gompel A, Mazaltarine G, Brock I, Baeza-Velasco C, et al. Ehlers-Danlos Syndrome or Disease? J Syndromes. 2015;2(1): 5.
J Syndromes
July 2015 Vol.:2, Issue:1
© All rights are reserved by Hamonet et al.
Ehlers-Danlos Syndrome or
Disease?
Keywords: Ehlers-Danlos Syndrome; Joint hypermobility; Ehlers-
Danlos classication; Medical nosology; Denition of disease; Denition
of syndrome
Abstract
Although rst described in 1892 by Tschernogobow in Moscow, the
medical history of Ehlers-Danlos syndrome (EDS) begins with Edward
Ehlers’s description in 1900 in Copenhagen. Several avatars would
come to stymie its identication to this day, despite its frequency,
and foster confusion with other pathologies. The rst of these is the
description by Alexandre Danlos (1908), who particularly emphasized a
sign: excessively stretchable skin which would become solidly anchored
in the minds of doctors who, even today, use it to rule out the diagnosis
if it is not found. In 1933, in Paris, Achille Miget based his doctoral thesis
(Syndrome d’Ehlers-Danlos) in medicine on a new case, and expressed
doubts about the identity of Danlos’case. This case is, in fact, a
Pseudoxanthoma elasticum. The second avatar was the introduction
of identication and classication based on mutations of various
collagens, by associating one or several types of collagen with a set
of clinical manifestations. The clinical differences between the various
types are tenuous; excessive skin stretch ability and hypermobility are
found in both the classical form and hyper mobile forms, aneurysms,
can be found in every type of EDS. Rheumatologists rst addressed this
syndrome on the basis of hypermobility, describing it as benign. Prof.
Grahame was the rst to make a shift in the clinical perception of the
syndrome and progressively added other manifestations (i.e. pain).
They thus bridged the gap between joint hypermobility syndrome and
EDS-hyper mobile type. Now EDS appears as a reliable clinical entity,
characterized by patterns of easy-to-identify clinical symptoms, which
have very strong diagnostic value, when taken together with the
existence of similar cases in a patient’s family. We describe it from 644
of our rst patients (out of 2,213 patients). We have selected certain
signs which are particularly signicant in terms of their frequency
and because they agree with signs also described by other authors:
diffuse pains, fatigue and problems with vigilance, joint hypermobility,
fragility of skin, tendency to haemorrhages, proprioceptive
disturbances, dystonia, constipation, gastro-oesophagal reux,
dyspnea, sensations of respiratory blockage, dysautonomia, oral/
dental, ENT, visual symptoms, and cognitive difculties. It has been
proposed a discussion about the choice of syndrome or disease for
Ehlers-Danlos, the semiological anarchy may have originated in the
method for identifying diseases (the nosology) set up in the 18th century
by physicians who were also botanists (i.e. Boissier de Sauvages, 1771;
Cullen, 1769; Linnaeus, 1759). The syndrome is “a list of symptoms that
are not necessarily related to specic diseases” (Littré, 1875). The
usual medical culture perceives a disease as an entity that has an
etiological basis, which presents a characteristic clinical picture, and
which requires appropriate treatment. This is the case for Ehlers-Danlos
Disease, a term that should be preferred to that of EDS.
Birth and Evolution of the Concept of EDS
Although rst described in 1892 by Tschernogobow in Moscow
[1], the medical history of this syndrome only truly begins with its
rst and excellent description on December 15, 1900 by Edward
Ehlers in Copenhagen [2], based on the case of a law student, and
presented to the Danish Society of Dermatology and Syphiligraphy.
is observation, though brief, was very precise, and pointed out
several of the most important clinical signs that, even nowadays, allow
diagnosis: joint hypermobility, skin fragility, and haemorrhages.
Subsequently, several avatars would come to stymie its identication
to this day, despite its frequency, and foster confusion with other
pathologies with which it shares certain clinical manifestations.
e rst of these confusions is the description made in 1908,
by Alexandre Danlos to the French Society of Dermatology in Paris
[3], of “A case of cutis laxa with chronic contusions tumors of elbow
and knees (Pseudo-juvenile diabetic xanthoma) from MM Hallopeau
and Macé de l’Epinay”. Danlos particularly emphasized a sign which
would become solidly anchored in the minds of doctors who, even
today, use it to rule out the diagnosis if it is not found: excessively
stretchable skin, which he wrongly compared with rubber. Wrongly
so, because one of the principal factors leading to the symptoms of
Ehlers-Danlos Syndrome is precisely the reverse: it is the loss of the
connective tissues elasticity [4].
In 1933, in Paris, Achille Miget based his doctoral thesis in
medicine on a new case, giving it the name of the two rst doctors
to describe it. Ehlers-Danlos Syndrome (EDS) was born [5]. And yet,
Miget had doubts about the identity of Danlos’ case. He found the
patient and took a biopsy of his skin. He noted that the histopathology
of this case diered from the case described in his thesis. ese
ndings, together with the fact that the skin of Danlos’ patient was
highly stretchable, more so than is commonly found in this syndrome,
leads us to conclude that the case described by Danlos was in fact, a
Pseudoxanthoma elasticum [3]. Unfortunately, what many doctors
remember about the syndrome is the idea that signicant skin stretch
ability is a requisite for diagnosis, believing that its absence must rule
out the diagnosis. As a result, a very large number of patients were
and will continue to be deprived of diagnosis.
e second avatar was the introduction of genetics into its
history. e hereditary nature suspected in Ehlers’ initial diagnosis,
C. Hamonet1,2*, A. Gompel3, G. Mazaltarine4, I.
Brock1, C. Baeza-Velasco5, J.D Zeitoun6 and B.
Bienvenu7
1Consultation Ehlers-Danlos, Hôtel-Dieu de Paris, France
2Faculté de Médecine de Créteil, Université Paris-Est-Créteil,
Créteil, France
3Unité fonctionnelle: Endocrinologie Gynécologique, CHU Paris
Centre - Hôpital Cochin, Paris, France
4Service de Rééducation Neuro-orthopédique, Hôpital Henri
Mondor, Créteil, France
5Institut de Psychologie, Université Paris Descartes, Sorbonne
Paris Cité, Boulogne-Billancourt, France
6Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France
7Service de Médecine Interne, CHU de Caen, Hôpital de la Côte de
Nacre, Caen, France
*Address for Correspondence
C. Hamonet, Consultation Ehlers-Danlos, Hôtel-Dieu de Paris, France,
1 place du Parvis Notre-Dame, 75181, Paris Cedex 04, France, E-mail:
pr.hamonet@wanadoo.fr
Submission: 17 May 2015
Accepted: 21 July 2015
Published: 27 July 2015
Copyright: © 2015 Hamonet C, et al. This is an open access article
distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Review Article
Open Access
Journal of
Syndromes

Citation: Hamonet C, Gompel A, Mazaltarine G, Brock I, Baeza-Velasco C, et al. Ehlers-Danlos Syndrome or Disease? J Syndromes. 2015;2(1):
5.
J Syndromes 2(1): 5 (2015) Page - 02
was recognized early on. It led to attempts at identication and
classication based on mutations of various collagens, by associating
one or several types of collagen with a set of clinical manifestations.
ese classications have evolved over time. e most recent,
known as the Villefranche classication [6], distinguishes six forms:
classical type, hyper mobile type, vascular type, kyphoscoliosis
type, arthrochalasia type, and dermatosparaxis type. e clinical
dierences between these various types are tenuous; excessive skin
stretch ability and hypermobility are found in both the classical form
and the hyper mobile form. It is almost impossible to draw a clinical
distinction between the two in practice, and it makes no dierence,
either way; the consequences in terms of disability, precautions to be
taken, symptomatic treatment, prognosis, and genetic transmission
are the same. e terminology proposed at Villefranche [6], leads
to confusion because the hypermobility, that is the predominant
feature in both forms, may also be absent or have disappeared with
age [7], and retractions are possible as well [8]. In addition, the term,
“classical” leads one to believe that it is the most common form,
whereas those who continue to defend it as a separate form agree that
it is infrequent and that the usual form is the hyper mobile type [9].
As yet, however, no specic collagen mutation has been found to be
associated with it. Hypermobility, which was considered by many
geneticists to be an absolute prerequisite for the diagnosis of EDS,
is oen assessed using the 9-point Beighton score [10]. A Beighton
score equal to or greater than 4 is suggestive of hypermobility.
However this test is oen misleading or poorly applied; it considers
only a small number of joints [11], it does not take into account
pain or muscle contractures, and therefore wrongly rules out a large
number of patients. us a negative score is not incompatible with a
positive diagnosis, especially in adults [7]. Although less numerous,
studies in children oen use the Beighton score. A recent study using
this method, found that hyper mobile children had three times higher
risk of developing joint pain in adolescence [12].
Methodological aspects, such limits of Beighton score, have
introduced a considerable amount of confusion into the clinical
diagnosis of EDS, with the result that even today this very common
pathology continues to be considered, against all odds, to be rare.
Indeed, it is almost never mentioned and it is constantly confused
with other diagnoses that impose aggressive medical or surgical
treatments on patients whose primary characteristic is their fragility
in case of aggressive surgical and medical treatment.
is semantic confusion was further exacerbated with the recent
emphasis [13], on the so-called vascular forms (EDS-vascular), in
which aneurysms and arterial dissection are particularly frequent.
ese forms can be genetically identied by the frequent mutation
of the COL3 A1 gene. eir clinical description overlaps with many
manifestations found in other forms of EDS: thinness of the skin,
intestinal and uterine fragility, easy bruising, smooth facial appearance
(the so-called “portrait of the Madonna”) which is very oen found in
the other forms, in which a person may have no wrinkles, giving the
impression that they are, on average, ten years younger than they really
are. Similarly, aneurysms may occur in all forms of the syndrome,
and should be systematically screened for, with sonography, with, if
necessary, an artery scan or brain MRI. Fortunately, these so-called
“lethal” forms by those that described them [13] are exceptionally
rare. eir diagnosis though is oen a source of stress for both
patients and doctors who are basing their conclusions on signs which
exist in all the ordinary forms of the syndrome (e.g. the tendency to
haemorrhage). is emphasis on the severity of certain manifestations
of EDS and the multiplicity of publications on the subject have led
many doctors to focus only on these more severe but very rare forms,
and to neglect the more frequent forms, believing that they have few,
if any, functional consequences. is attitude has led to a lack of
interest and to the denial of the more frequent forms of EDS, which
may nonetheless cause serious disability. EDS patients have been
abandoned, even ostracized, by much of the medical community.
eir symptoms are labeled psychosomatic or even imputed to severe
mental illness, sometimes leading to powerful psychiatric treatment,
resulting in destructive iatrogenic and social eects. Grahame stated
“to my knowledge, there is no other illness that has been so neglected--
the patients are much more familiar with it than their doctors” [14].
Rheumatologists rst addressed this syndrome on the basis of
hypermobility. Grahame, Gazit, Bravo and Bulbena were among
the rst to make a shi in the clinical perception of the syndrome
and progressively added other manifestations (such as pain,
dysautonomia, pathological anxiety and digestive disturbances)
and found functional limitations which were the cause of disability
[11,15-17]. ey thus bridged the gap between joint hypermobility
syndrome and EDS-hyper mobile type [18], resulting in a reliable
clinical entity, characterized by patterns of easy-to-identify clinical
symptoms which have very strong diagnostic value on their own and
when taken together with the existence of similar cases in a patient’s
family.
Clinical practice reveals a high frequency of EDS, but heterogeneity
of evaluation systems does not allow knowing the prevalence of the
syndrome. However some interesting data are available. Grahame and
Hakim reported a prevalence of 45% in patients from a rheumatologic
clinic in England [19]. Bravo and Wol observed a prevalence of 39%
in Chile, and we estimated that 1 million people are aected in France
[16,20].
Up-to-date Clinical Practice for EDS
Based on a statistical analysis of 644 of our rst patients (out
of 2,213 patients in 16 years) [21], we have selected certain signs
which are particularly signicant, both in terms of their frequency
and because they agree with signs that have been described by other
authors [22,23]. EDS is a collagen disorder that aects all of a person’s
connective tissue. It causes these tissues to be less resistant (e.g. skin
fragility, fragility of small vessels, easy bruising, and osteopenia)
and lose their elasticity, thereby disrupting the signals sent by
receptors situated in connective tissue (such as pain, proprioceptive
dysfunction, dysautonomia, and dystonia) [24]. Concerning pain,
it is well known that the pain experience may be modulated by
psychological factors (e.g. emotional, cognitive) [25]. In this regard,
patients with hereditary disorders of the connective tissue, especially
Ehlers-Danlos syndrome hypermobility type, have a tendency to
suer from pathological anxiety and other negative emotions, as well
as enhanced interoception and somatosensory amplication [26].
ese aspects may contribute to increase the painful experience.
It is necessary to understand this mechanism in order to grasp
the symptomatology and determine appropriate treatment. e
specic nature of the connective tissue explains the wide diversity of

Citation: Hamonet C, Gompel A, Mazaltarine G, Brock I, Baeza-Velasco C, et al. Ehlers-Danlos Syndrome or Disease? J Syndromes. 2015;2(1):
5.
J Syndromes 2(1): 5 (2015) Page - 03
symptoms, which, when taken together, are suciently evocative of
the syndrome. is approach is contrary to that which many doctors
still use, as a result of their medical training, which is to address
disease in one organ at a time. ey have great diculty in taking
a systemic and holistic approach, and in making a diagnosis on the
basis of clinical symptoms alone. e contribution of genetics, with
the exception of the forms involving multiple aneurysms, remains
very limited and, indeed, is useless in the diagnosis of the forms most
commonly found.
Main symptoms observed in 644 of our patients:
- Diuse joint pain (98%), pain in muscles (80%), skin, and
abdomen (77%), thoracic pain (66%), genital pain and
migraines (87%) which may be variable and oen resist
analgesic medicines, even powerful ones.
- Fatigue and problems with vigilance (98%) with spells of
sleepiness and feelings of exhaustion, even upon waking.
- Joint hypermobility (96%) which is not always spectacular
and which diminishes with age (Beighton score equal to or
greater than 4/9).
- Skin fragility (97%) which may take several forms: frequent
excoriation of the skin (83 %), slow and dicult wound
healing (73%), early and/or abundant stretch marks (74 %),
so, velvety skin (74%).
- Highly stretchable skin is absent in 31% of cases. ere is less
resistance to transmission of electricity, and patients may feel
electric shocks upon contact with metal objects (we call it “the
car door sign” as patients very oen and even in summer get a
small electric shock when opening the car door).
- Tendency to haemorrhages (91%). is is due to the weakness
of the blood vessel walls and is expressed by the seemingly
spontaneous appearance of bruises and hematomas, bleeding
of the gums, nosebleeds, very abundant menstrual bleeding,
bronchial bleeding, or digestive bleeding, which, in addition
with the organ’s wall weakness make patients vulnerable to
accidents during endoscopies.
- Proprioceptive disturbances (98%), with diculty in
perceiving the body and in controlling movements, and
which are evidenced by subluxations, sometimes confused
with sprains, missteps, legs giving way when walking,
bumping into things or people (such as doorframes, in
particular: “the door sign”), falling down, clumsiness
(dropping things), and pseudo-paralytic presentations and/
or a complete lack of sensation in a part of the body. We have
also observed dystonic-type movements (involuntary startle
movements, clonic movements, trembling, and sometimes
intense pseudo-epileptic contractions), which resolve with
antiparkinson treatment.
- Constipation (72%), which may be severe, and lead to
occlusions, which in turn may lead to medical intervention.
It may alternate with diarrhea.
- Gastro-oesophagal reux (76%) with multiple concomitant
complications aecting the airways.
- Dyspnea (83%) arising as a result of insignicant eort (“the
staircase sign”).
- Frequent sensations of respiratory blockage with inspiration,
bradypnea occurring at random.
- Dysautonomia is frequent, with feelings of cold extremities
(“the sock sign”), low blood pressure, sweating (as described
by Ehlers), changes in heart rate (bradycardia at rest, stressful
episodes of tachycardia).
- Oral/dental, ENT, and visual manifestations are frequent as
well.
- Cognitive diculties (e.g., diculties with working memory,
attention, concentration, and orientation) are frequently
associated, as well as sleep disturbances.
Onset of these manifestations oen takes place in childhood, in
a dierent order for each patient, and with variable intensity. Most
oen, there are acute episodes arising out of a background of chronic
discomfort. Certain factors cause symptoms to signicantly worsen:
trauma, hormonal uctuations (80% of our patients are women),
variations in the weather (especially cold and humid weather), and
insucient physical exercise.
Ehlers-Danlos: A Syndrome or a Disease? A challenge
for Medical Semiotics Arising from Botany
ere is currently some confusion about the terms “disease”
or “syndrome” in both medical usage as well as the vernacular. For
instance, bromyalgia is spoken of as a disease, whereas it consists
of symptoms involving pain in muscles and tendons. e terms
“disease” or “syndrome” are interchangeable in the case of “restless
legs”, and the diagnosis of “chronic fatigue” needs no qualier.
is lack of precision in the medical vocabulary led the celebrated
French semiologist Roland Barthes, to speak quite harshly of medical
semiology, stating that it was not semiology and that he could not
understand medical descriptions [27]. is brutal conclusion requires
that we take another look at medical practice and the way we use
words and concepts to create a special doctor/patient relationship
in order to, together, arrive at a diagnosis. A new way on how we
establish proper doctor patient communication, a constructive
dialogue expressing the patient’s experience (the symptoms) and the
doctor’s interpretation is needed. Signs can then be re-interpreted
and when taken together, will permit the identication of a clinical
entity (disease or syndrome), which will result in the oer of
appropriate treatment. is apparent semiological anarchy may have
originated in the method for identifying diseases (the nosology) set
up in the 18th century by doctors who were also botanists (Linnaeus
in Sweden, Boissier de Sauvages in France and Cullen in England).
e “Methodical nosology, in which Disease are Sorted by Categories,
Following Sydenham’s System, as well as that of Botanists” (1756 in
latin, 1771, in French) [28]. Within “Boissier’s tables” or tableaux,
(thus giving rise to the expression, “clinical picture”) for each class,
there are subsets (orders) which are really clinical forms, but which
are closer to certain classes (class VII, Pain) in the representation
of a syndrome. e term “syndrome” does not, however, appear in
Boissier’s writings and commentary. ere is continuity between
Boissier’s Classication and the current classication of diseases
used by the WHO [29]. e principle of classications remains

Citation: Hamonet C, Gompel A, Mazaltarine G, Brock I, Baeza-Velasco C, et al. Ehlers-Danlos Syndrome or Disease? J Syndromes. 2015;2(1):
5.
J Syndromes 2(1): 5 (2015) Page - 04
omnipresent in the description of diseases. EDS is an example when
seen in the light of the classications made by geneticists and used
as a diagnostic tool. e word “syndrome” comes from the Greek:
sun dromein, meaning, “to go or race together”. It applies well to the
denition given to it by Emile Littré, who was trained as a physician:
“the name that the ancient Greeks gave to lists of symptoms that are
not necessarily related to specic diseases” [30]. erefore, it is the
notion of a etiology that distinguishes a syndrome from a disease.
Paradoxically, certain aspects that are specic to the vascular form
of EDS were connected to the term, “the Ehlers-Danlos Syndromes”.
e denition of disease is relative “In order to precisely dene
disease in general, one must rst know what health is” [30], “Changes
in health” [31]. is is an important point in EDS because the
presenting symptoms are banal and are part of daily life: fatigue,
sleep disturbances, dizziness, pain, digestive diculties, clumsiness,
etc. Such symptoms are all too oen dismissed or not believed by
doctors. It is their intensity, the fact that they exist together, and their
persistence that should retain one’s attention and lead to a diagnosis,
thereby distinguishing what is normal from what is pathological.
One aspect should be borne in mind, which is how the terms utilized
resonate in the mind: the concept of “syndrome” remains vague in the
minds of most people, and does not contribute to consolidating the
reality of a pathology which is disabling and which disrupts day-to-
day life, oen requiring drastic precautions to be taken. In general,
the medical culture perceives a disease as an entity that has an
etiological basis, which presents a characteristic clinical picture, and
which requires appropriate treatment. Ehlers-Danlos exactly fulls
these conditions, and therefore should be considered as a disease: it
is familial in nature it is transmissible, it has a clearly-dened clinical
picture, and enables diagnoses to be made with a very high degree of
certainty, appropriate treatments do exist, and there are also precise
precautions and contraindications. e nosologic problems that arise
when an actual disease is called a syndrome can well be exemplied
by Ehlers-Danlos Syndrome.
Conclusion
Ehlers-Danlos is a familial, transmissible pathology of connective
tissue, resulting from defective protein synthesis [32]. ese
alterations are responsible for numerous clinical manifestations (e.g.,
pain, joint disorders, fatigue, skin fragility, haemorrhages, digestive
problems, ENT problems, respiratory problems, dysautonomia,
dystonia, bladder and sphincter problems, oral and dental problems,
and cognitive disturbances). In addition, it does not appear to be a
rare disease; instead, it is actually frequent, despite the fact that many
doctors are highly unfamiliar with it, thereby causing numerous
iatrogenic complications. Physicians’ lack of knowledge about
Ehlers-Danlos syndrome is the result of random and incomplete
descriptions, which, fortunately, are beginning to be corrected in the
international medical literature. Although it is known as a syndrome,
it is in fact a disease whose diagnosis may be made with certainty on
the basis of a set of clinical manifestations alone. Genetic tests are
most oen inconclusive as regards to the types of cases most oen
seen in clinical practice. Signicant eorts have yet to be made on the
international level, in order to build awareness to the disease and its
treatments, and to help aected families who are all too oen rejected
and excluded.
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