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Ehlers-Danlos: about 664 cases

Statistical analysis of clinical signs from 644 patients with a Beighton scale ≥ 4/9

First international Symposium on the Ehlers-Danlos Syndrome. 8-11 september 2012, Ghent, Belgium.

Pr. Claude HAMONET, Pr. P. Ravaud, Dr. S. Villeneuve, Pr. A. Gompel, N. Serre, Pr. D. Fredy, Dr. D. Deparcy, Dr. G. Mazaltarine, Dr. J.D. Zeitoun, Dr. A. Métlaine, Pr. D. Léger, Pr. A. Benachi, Dr. A.G. Cordier, Pr. P. Césaro, Dr. C. Loche, Dr. N. Dantschev, M. Vienne, Dr. C. Séjourné, Pr. B. Gogly, Dr. MM Landru, Dr. S. Moussa Badran, Dr. Y. Raffray, Dr. G. Challe, Pr. L. Doursounian, J. Mohler.

- Faculty of Médicine of Créteil, University Paris-East Créteil, France & Department of Physical Médicine and Rehabilitation,  Hôtel-Dieu de Paris, France.
- Department of clinical Epidemiology & medical Statistics, Hôtel-Dieu, Paris, France.
- Department of Endocrinology-Gynecology Cochin-Port-Royal-Hôtel-Dieu Hospital,
- Association Tame EDS (ASED), Yerre, France.
- Department of Morphological & et Fonctiunal, Imagery (D.M.F.I.), Pr. JF Meder, Sainte-Anne Hospital, Paris, France.
- Department of Physical Medicine & Rehabilitation, Gustave Dron Hospital, Tourcoing France.
- Department of Physical Médicine & Réhabilitation,  Henri  Mondor-Albert Chenevier hospital, Créteil, France.
- Department of Gastroenterology, Henri Mondor-Albert Chenevier Hospital,  Créteil, France.
- French national Centre of reference for rare diseases of vigilance & sleep, Hôtel-Dieu Hospital, Paris, France
- Department of Genecology-Obstetrics, Antoine Béclère Hospital, Clamart, France.
- Department of Neurology, Henri Mondor-Albert Chenevier Hospital, Créteil, France.
- Department of Psychiatry, Hôtel-Dieu de Paris, France.
- IMAPe company, Nice, France.
- General practitioner, Marolles-en-Hurepoix, France.
- Department of Odontology, Henri Mondor-Albert Chenevier Hospital, Créteil, France.
- Department of Odontology,  Hospital of Amiens, France.
- Pain Center, Tenon Hospital, Paris, France.
- Department of Ophtalmology, Salpetrière Hospital, Paris, France.
- Department of Orthopaedic surgery, Saint-Antoine Hospital, Paris, France.

 

Introduction

"It is the combination of a bundle of symptoms in several patients who identifies disease. “ (Thomas Sydenham, founder of Clinical Epidemiology, famous for his aphorisms, nicknamed «the English Hippocrates 17th century. “)

Diagnosis criterions for Ehlers-Danlos syndrome are still debated and can change depending on the authors. This diagnosis uncertainty is detrimental to affected patients who are often subjects to a wandering medical, with increased risk of improper treatments and social exclusion.

In his thesis « Ehlers-Danlos syndrome », defended in Paris in 1933, Achille Miget (1) stated that the syndrome was likely to be more complex than believed but that cases were missing to allow a full description. «… This dystrophy is not a purely cutaneous disease».

We aimed to contribute to fill the gap by displaying the 664 first cases from a series of 1300 patients with EDS.

Inclusion criteria were chosen while taking into account the consensus among geneticists but also the spreading of connective tissues lesions.

We though came to identify new clinical manifestations that can also contribute to diagnosis. Most of them were infrequently related to EDS. However, they have functional consequences with sometimes severe situations of disability.

Thesis of Achille Miget MD (Syndrome d'Ehlers-Danlos, Paris, 1933). Introduction.

 

Objective

The objective of this clinical study is, beyond nosology debate, to propose a new description of the syndrome arising from data collected from patients themselves.

 

Material & methods

It is a prospective study. For the last 15 years, we have received at our consultation more than one thousand patients; many of them have been followed and treated.

They have often come after reading the description of the syndrome on our website. They were from France, Europe, the West Indies, Quebec, Argentina, USA and Brazil…

Gradually, supported by most consensual (2) criteria (joint hypermobility, skin fragility, pain, asthenia, easy bruising…), we have been able to establish a frame of symptoms analysis which allowed us to include novel debilitating manifestations: respiratory, gastrointestinal, oral, ophthalmological, bladder, gynaecological & obstetrical, neurovegetative, cardiovascular, thermoregulatory, and cognitive.

Clinical data from first 664 patients have been gathered on Excel software.

Severity index
A severity index with 5 levels of symptoms has been established thanks to the contribution of patients and following signs we have found:
0
None
1
Mild
2
Moderate
3
Important
4
Very important

 

Results

Characteristics of the population
664 patients, 543 women (82%) & 121 men (18%).
Mean age of women: 33 (2 to 79)
Mean age of men: 23 (2 to 65)
Mean age at diagnosis: 28
EDS type: the most common forms encountered in our medical practice, usually classified as classical type or hypermobility type (the vast majority), seem difficult to discriminate and functional consequences are often important in the classical type.

The seven most significant clinical data for EDS
1 - Pain (the whole body diagnosis is painful!):
joints (98%, grade 3-4 in 82%);
muscles (82%, grade 3-4 in 47%);
belly (77%, grade 3-4 in 53%);
chest (71%, grade 3-4 in 23%);
genital (75%, grade 3 -4 in 55%);
migrains (84%, grade 3-4 in 57%);
cutaneous hyperesthesia (39%).
2 - Asthenia (96%, grade 3-4 in 70%)
3 - Proprioceptive disorders (described by Ehlers (3) on December 1900): so-called sprains (86%, grade 3-4 in 55%); dislocations (90%, grade 3-4 in 39%)
4 - Hypermobility (97%) about 664 patients. 
5 - Skin modifications: thinness (91%); fragility (87%); stretch marks (64%); delayed healing (85%).
6 - Haemorrhages, described by Ehlers (3) on December 1900 (92%).
7 - Familial aggregation (including incomplete or mild forms): 97%.

Other relevant clinical manifestations
Digestive manifestations: GERD (80%), constipation (74%), bloating (70%).
Respiratory manifestations: dyspnea  (85%), respiratory crisis so called asthma (65%).
Oral manifestations: temporo-mandibular pains or dislocations (76%), gum alterations (80%), hyperosmia (69%).
Hearing and équilibration manifestations: hyperacousis (89%), hypoacousis or deafness (57%), tinnitus (69%), vertigos (80%).
Ophtalmological manifestations: visual fatigue (86%), myopia (56%).
Gynecological & obstétrical manifestations: menstrual bleeding (78%), difficult delivery (78%).
Neurovegetative and thermoregulatory manifestations: sensitive to cold (77%), profuse sweating (74%), Raynaud syndrome (74%), unexplained fever (52%), increased heart rate (66%).
Urinary manifestations: Dysuria (51%) pollakiuria, incontinence (63%).
Cognitive manifestations: memory alteration (69%), difficulty in attention (65%).

Other observed manifestations, frequent but not yet quantified
Gallstones, sometimes responsible for severe complications, studied with Dr. JD Zeitoun.
Ovarian pseudocysts, studied with Pr. A. Gompel.
Dystonia syndrome (studied with Pr. P. Césaro).
Peculiar alterations of polysomnography (Dr. Métlaine, Pr D. léger).
Encephalic lesions on MRI: corpus callosum, mamillary bodies … (Pr. D. Frédy).
No psychiatric symptoms (depression, bipolar state…) related to EDS. Studied with Dr. N. Dantcheff.

Evolution and factors affecting symptoms
The evolution is unpredictable. Acute episodes (crisis) are common, with worsening of symptoms.
Tow kinds of deteriorating factors have been identified:
Extrinsic : traumatism, climate.
Intrinsic : endocrinological, repeated movements.

 

Conclusions

Pending the availability of reliable genetic test, clinical examination remains the only tool for EDS diagnosis.

It is urgent to report it because EDS is no longer a rare disease. Most patients are misdiagnosed and at high risk of improper treatments. In addition, genetic information is missing.

It is now possible to relieve them with appropriate measures related most often to physical and rehabilitation medicine.

 

References

1 - Miget A., « Le syndrome d’Ehlers-Danlos », Thèse de Doctorat en Médecine, Faculté de Medecine de Paris, 1933.
2 - Beighton P, De Paepe A., Steinman B. & al, Ehlers-Danlos syndrome: revised nosology, Villefranche 1997, Am. J. Med, Genet, 1998, 77, 33-7.
3 - Ehlers E., Cutis laxa, tendance aux hémorragies de la peau, relâchement de plusieurs articulations (cas pour diagnostic), Société danoise de Dermatologie, 15 décembre 1899, m. Dermat. Woch. VIII, p. 173.

 

Contacts

Pr. Claude Hamonet, Service de Médecine Physique et Réadaptation, Hôtel-Dieu de Paris, 1 place du Parvis Notre-Dame, 75181 Paris Cedex 04, Tel. : 003314842348246 & 0033660687306. E-mail : >pr.hamonet@wanadoo.fr<