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Background
This is a group of rare inheritable diseases all characterized by defects in collagen synthesis or structure. There are at least 14 genetically distinct forms of the disease with all patterns of inheritance.
CURRENT CLASSIFICATION
TYPE CLINICAL FEATURES INHERITANCE BIOCHEMICAL DEFECTS I Gravis Soft, hyperextensible skin
Easy bruising with thin atrophic scars
Hypermobile joints
Varicose veins
Prematurity of affected newbornsAD Mutations in proalpha1(V) or proalpha2 (V) chains of type V collagen II Mitis Similar to type I but less severe AD Same as EDS I III Familial hypermobility Soft skin
Large and small joint hypermobilityAD Unknown IV Arterial Thin translucent skin with visible veins
Easy bruising
Absence of skin and joint extensibility
Arterial, bowel and uterine ruptureAD Mutations in COL3A1
Abnormal type III collagen synthesis, secretion, or structureV X-linked Similar to EDS II XLR Unknown VI Soft skin muscle hypotonia
Scoliosis
Joint laxity
Hyperextensible skinAR Lysyl hydroxylase deficiency
Mutations in PLOD geneVII
Athrochalasia multiplexCongenital hip dislocation
Severe joint hypermobility
Soft skin with normal scarringAD Deletions of exons from type I collagen genes that encode the amino-terminal propeptide cleavage site of COL1A1 (type VIIA) or COL1A2 (type VIIB) Severe skin fragility, sagging redundant skin AR Recessive mutations in type I collagen N-peptidase VIII Periodontal Generalized periodontitis
Soft hyperextensible skin
Chronic purple-hued scarring over shinsAD Unknown X Similar to EDS II with abnormal clotting studies AR Proposed defect in fibronectin
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS EDS INCIDENCE 1/5000
DISEASE ASSOCIATIONS CHARACTERIZATION PREMATURE RUPTURE OF MEMBRANES
- Ehlers-Danlos-like dermal abnormalities in women with recurrent preterm premature rupture of fetal membranes.
Hermanns-Le T, Pierard G, Quatresooz P.
Department of Dermatopathology, University Hospital of Liege, Belgium.
Am J Dermatopathol. 2005 Oct;27(5):407-10. Abstract quote
Preterm premature rupture of membranes (PPROM) likely results from weakening of the constituent connective tissue. It is uncertain if the alterations are limited to the fetal membranes or are also present in other sites such as the skin.
The aim of the study was to compare the dermal structure of women suffering from recurrent PPROM with the dermis of both non-pregnant women and women with uneventful gestation. Skin biopsies were taken from 42 women who recently underwent PPROM, 33 women with uneventful gestation and 33 non-pregnant women.
Histochemistry, immunohistochemistry, and electron microscopy were performed on these specimens and analyzed blindly. Morphologic changes were found in the dermis of most (33 of 42 at optical microscopy and 40 of 42 at ultrastructure) of the women suffering from PPROM. They were reminiscent of those found in some types of Ehlers-Danlos Syndrome (EDS). However, there was no clinical evidence suggesting a recognized form of EDS.
We conclude that some cases of PPROM are a systemic connective tissue disorder representing a yet unidentified type of EDS.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General Tounge hypermobility Eyelid extensibility Lancet 2001;357:1500-1502
12 adults fulfilling criteria for type II or III
All had absent inferior labila frenulumTYPE III
- Type III Ehlers-Danlos syndrome: correlations among clinical signs, ultrasound, and histologic findings in a study of 35 cases.
Iurassich S, Rocco D, Aurilia A.
Department of Dermatology, Second University of Naples, Naples, Italy.
Int J Dermatol. 2001 Mar;40(3):175-8. Abstract quote
BACKGROUND: Patients with type III Ehlers-Danlos syndrome show hypermobile joints, luxation, and minimal atrophic scars. The disease has an incidence of 9-16% and the molecular defect that underlies this subtype is unknown. In order to widen diagnostic investigations in type III Ehlers-Danlos syndrome, skin and articular areas were studied by ultrasound (US) test.
METHODS: Thirty-five patients, 20 women and 15 men, aged from 18 to 25 years, with type III Ehlers-Danlos syndrome were enrolled in this study. Patients showed hypermobile joints (35 cases), minimal atrophic wrinkled scars (35 cases), and a few ice-pick acne scars. Hypermobility of phalangeal joints was studied by means of the Beighton scoring system and by a US test (performed by Sonora Logic 400 MD unit with 10 MHz probe). The following US parameters were considered: the distance of the intra-articular space and the thicknesses of the extensor tendon and of the overhanging dermis and subcutis.
RESULT: US reports showed an increase in distance of the intra-articular space and a reduction in the thickness of the extensor tendon and of the dermis and subcutis covering it. The dermis showed high and homogeneous echogenicity with irregular hyperechogenic lines.
CONCLUSION: The Beighton scoring system, the US findings, and the aspect and diameter of the scars suggested that the disease can be divided into three different stages which allow the correlation, over progressive intervals of values, of the articular hypermobility and atrophic wrinkled scars. Our results showed that US test is able to confirm the clinical diagnosis and to evaluate the seriousness of hypermobile joints.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
- Abnormality of dermal collagen fibrils in Ehlers Danlos syndrome. Anticipation of the abnormality for the inherited hypermobile disorders.
Kobayasi T.
Laboratory for Ultrastructural Dermatopathology, Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, D-92 Bispebjerg Bakke 23, Kobenhavn NV DK-2400, Denmark.
Eur J Dermatol. 2004 Jul-Aug;14(4):221-9. Abstract quote
The abnormality of dermal collagen fibrils is the ultrastructural criterion of Ehlers-Danlos syndrome (EDS). This study evaluates the clinical significance of the abnormality. Besides 348 lax patients presenting the stigmata of EDS, skin specimens from 12 normal members in the pedigree of EDS, 98 randomly selected normal individuals, 7 Marfan syndrome and 4 osteogenesis inperfecta type I, were studied by electron microscopy. The abnormality was defined by thickness, array and shape of collagen fibrils.
Of 348 lax patients, 115 patients showed Beighton's score higher than 6 and constantly the abnormality (EDS). Variable numbers of the patients with scores 1 to 5 displayed the abnormality (forme fruste). The abnormality did not correspond with variation of laxity. Marfan syndrome and osteogenesis imperfecta were indistinguishable from EDS by the abnormality.
Some of the normal persons in the EDS pedigree and some controls also showed the abnormality. The abnormality expressed the disposition for heritably defected collagen fibril formation.
- Reduced skin thickness: a new minor diagnostic criterion for the classical and hypermobility types of Ehlers-Danlos syndrome.
Eisenbeiss C, Martinez A, Hagedorn-Greiwe M, Reinhardt DP, Batge B, Brinckmann J.
Department of Dermatology, University of Lubeck, 23538 Lubeck, Germany.
Br J Dermatol. 2003 Oct;149(4):850-2. Abstract quote
BACKGROUND: The diagnosis of Ehlers-Danlos syndrome (EDS) is mainly based on clinical criteria, although in some instances a sound molecular diagnosis is available. Clinical signs can be divided into two categories: one with high diagnostic specificity and the other with low specificity. Despite the fact that reduced skin thickness is one of the dermatological features in patients with EDS, this issue has not been analysed in greater detail.
OBJECTIVES: To determine skin thickness in patients with the classical and the hypermobility types of EDS.
METHODS: In 21 patients with classical type of EDS and in nine patients with hypermobility type of EDS, skin thickness was analysed at different body sites by cross-sectional b-mode scans obtained with a 20-MHz ultrasound system.
RESULTS: We found a significant decrease in skin thickness in both types of EDS, which was highest at the chest and at the distal part of the lower leg.
CONCLUSIONS: We propose that the reduced thickness of the dermis as determined by high-resolution 20-MHz ultrasound can be used as a new minor criterion in the diagnosis of the classical and the hypermobility types of EDS.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE FACTOR XIIa
- Factor XIIIa-positive dendrocyte rarefaction in Ehlers-Danlos syndrome, classic type.
Hermanns-Le T, Pierard GE.
Department of Dermatopathology, University Medical Center Sart Tilman, Liege, Belgium.
Am J Dermatopathol. 2001 Oct;23(5):427-30. Abstract quote
The Ehlers-Danlos syndrome (EDS) represents a heterogeneous group of connective tissue disorders recognized by distinct clinical, microscopic, and biochemical aspects. In particular, some histologic and ultrastructural clues have been reported in the literature.
We present a novel immunohistochemical aid to the diagnosis of the most frequent type of EDS. Factor XIIIa-positive dendrocytes are almost absent in the reticular dermis and markedly reduced in number and size in the adventitial dermis. By contrast, the densities of vimentin-positive cells and CD34-positive cells were unremarkable.
The biologic significance of this finding is unknown. However, at least a subset of dermal dendrocytes interacts with fibroblasts. This mechanism could be affected in the classic form of EDS.ELECTRON MICROSCOPY
- The ultrastructural and histophotometric study of elastic and collagen fibers in type II Ehlers-Danlos syndrome and subclinical forms.
de Moraes AM, Cintra ML, Sampaio S de A, Sotto MN, Sesso A.
Dermatology Division, Faculty of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Sao Paulo, Brazil.
Ultrastruct Pathol. 2000 May-Jun;24(3):129-34. Abstract quote
Skin disorders in type II Ehlers-Danlos Syndrome (EDS) are characterized by signs of cutaneous hyperdistensibility, skin and vascular fragility, atrophic scars, and articular hypermobility. These features may have less important clinical presentation in the intermediate forms of type II EDS. The authors studied the ultrastructural and quantitative aspects of elastic and collagen fibers in the skin of individuals with subclinical signs of type II of Ehlers-Danlos Syndrome.
A group of 27 individuals (Group I) with large atrophic scars, articular hypermobility of the hands, and cutaneous and vascular fragility were compared with 10 healthy individuals. The subjects from both groups were volunteers from Hospital das Clinicas da Universidade de Sao Paulo.
The elastic fibers did not show alterations but collagen ultrastructural abnormalities were seen in diameter and curvature, such as torsion, collagen flower-like aspect and discrete mass enlargement by histophotometry
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
PROGNOSIS CHARACTERIZATION
- The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience.
Oderich GS, Panneton JM, Bower TC, Lindor NM, Cherry KJ, Noel AA, Kalra M, Sullivan T, Gloviczki P.
Division of Vascular Surgery and Department of Medical Genetics, Mayo Clinic, USA.
J Vasc Surg. 2005 Jul;42(1):98-106 Abstract quote
PURPOSE: Ehlers-Danlos syndrome type IV (EDS-IV) results from abnormal procollagen III synthesis and leads to arterial, intestinal, and uterine rupture. The purpose of this study was to review the spectrum, management, and clinical outcome of EDS-IV patients.
METHODS: We retrospectively reviewed the clinical data of 31 patients (15 male and 16 female) with a clinical diagnosis of EDS-IV treated over a 30-year period (1971 to 2001). Biochemical confirmation was obtained in 24 patients, and mutation of the COL3A1 gene was confirmed in 11 patients. The study excluded patients with other connective tissue dysplasias.
RESULTS: The mean age at the time of diagnosis was 28.5 +/- 11 years (range, 10 to 53 years). Twenty-four patients developed 132 vascular complications; of these, 85 were present either before or at the time of the initial evaluation, and 47 complications occurred during a median follow-up of 6.3 years (range, 0.5 to 26 years). Survival free of vascular complications was 90% at age 20 years, 39% at 40 years, and 20% at age 60 years. Fifteen patients underwent 30 operative interventions for vascular complications, including arterial reconstruction (n = 15), simple repair or ligation (n = 4), coil embolization (n = 3), splenectomy (n = 2), and abdominal decompression, nephrectomy, graft thrombectomy, vein stripping and thoracoscopy (n = 1 each). Three hospital deaths occurred from exsanguinating hemorrhage: two after operative interventions and one because of a ruptured splenic artery. Procedure-related morbidity was 46%, including a 37% incidence of postoperative bleeding and a 20% need for re-exploration. The incidence of late graft-related complications was 40% of arterial reconstructions, including 4 anastomotic aneurysms, 1 fatal anastomotic disruption, and 1 graft thrombosis. Patient survival was 68% at age 50 years and 35% at age 80 years. Of the 12 deaths during the study period, 11 were associated with vascular or graft-related complications.
CONCLUSION: Operative mortality in patients with vascular complications of EDS-IV was not excessively high, but the incidence of postoperative bleeding complications and late graft-related problems was significant. Despite successful repair of vascular complications, survival was shortened because of secondary vascular or graft-related complications.MORTALITY
- Death due to Ehlers-Danlos syndrome type IV.
Prahlow JA, Wagner SA.
South Bend Medical Foundation and Indiana University School of Medicine, South Bend Center for Medical Education at the University of Notre Dame, South Bend, IN 46601, USA.
Am J Forensic Med Pathol. 2005 Mar;26(1):78-82. Abstract quote
Ehlers-Danlos syndrome (EDS) represents a group of collagen connective tissue disorders characterized by joint laxity, easy bruising, and various skin manifestations. Persons with type IV EDS are at risk for gastrointestinal, uterine, and arterial rupture. Mutations in the COL3A1 gene that encodes for type III procollagen underlie the pathologic abnormalities.
Forensic pathologists must be aware of this rare, autosomal-dominant connective tissue disorder. Postmortem diagnosis is possible but requires specialized testing (fibroblast culture and subsequent biochemical assays, with or without molecular studies).
When the condition is diagnosed or suspected at autopsy, it is important for forensic pathologists to notify family members of this potentially lethal disorder. Three cases of type IV EDS diagnosed by forensic pathologists are presented, followed by a discussion of the disorder.
TREATMENT CHARACTERIZATION GENERAL DENTAL
- Oral health in prevalent types of Ehlers-Danlos syndromes.
De Coster PJ, Martens LC, De Paepe A.
Department of Paediatric Dentistry, Centre for Special Care, Paecamed Research, Ghent University, B-9000 Ghent, Belgium.
J Oral Pathol Med. 2005 May;34(5):298-307. Abstract quote
BACKGROUND: The Ehlers-Danlos syndromes (EDS) comprise a heterogenous group of heritable disorders of connective tissue, characterized by joint hypermobility, skin hyperextensibility and tissue fragility. Most EDS types are caused by mutations in genes encoding different types of collagen or enzymes, essential for normal processing of collagen.
METHODS: Oral health was assessed in 31 subjects with EDS (16 with hypermobility EDS, nine with classical EDS and six with vascular EDS), including signs and symptoms of temporomandibular disorders (TMD), alterations of dental hard tissues, oral mucosa and periodontium, and was compared with matched controls.
RESULTS: All EDS subjects were symptomatic for TMD and reported recurrent temporomandibular joint (TMJ) dislocations. Abnormal pulp shape (13%) and pulp calcification (78%) were observed in subjects affected with classical EDS. Caries experience was higher in EDS compared with controls and was related to poor oral hygiene, influenced by increased mucosal fragility and restraint of (wrist) joint mobility. The overall periodontal status in EDS was poor, with 62% of EDS subjects presenting high periodontal treatment needs (community periodontal index for treatment need, CPITN = II).
CONCLUSION: Oral health may be severely compromised in EDS as a result of specific alterations of collagen in orofacial structures. When considering dental treatment in EDS, a number of tissue responses (mucosa, periodontium, pulp) and precautions (TMJ dislocation) should be anticipated.Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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