|Year : 2015 | Volume
| Issue : 1 | Page : 42-46
Wakhloo Tulika, Aradhya Kiran
Department of Pedodontics and Preventive Dentistry, Dr. Syamala Reddy Dental College Hospital and Research Centre, Bengaluru, Karnataka, India
|Date of Web Publication||8-Apr-2015|
Department of Pedodontics and Preventive Dentistry, Dr. Syamala Reddy Dental College Hospital and Research Centre, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Ehlers-Danlos syndrome is a group of clinically and genetically heterogeneous inherited connective tissue disorders with widespread manifestations. The prevalence of this syndrome is 1:5000 worldwide without gender, racial or ethnic associations. This syndrome is characterized by joint hypermobility, dermal hyperelasticity and tissue fragility caused by mutations in genes encoding collagen type I, III, V and enzymes involved in the posttranslational modifications of collagen. The oral manifestations include increased mucosal fragility, delayed wound healing, early onset generalized periodontitis and temporomandibular joint hypermobility. Children presenting with this syndrome are often misdiagnosed for hematological problem as they present with bruising, malignancy and/or child abuse. A thorough assessment of the patient is, therefore, essential for early diagnosis and patient referral. This paper reviews current literature, oral manifestations, diagnostic investigations and effective dental management.
Keywords: Connective tissue disorders, Ehlers-Danlos syndrome, oral health
|How to cite this article:|
Tulika W, Kiran A. Ehlers-Danlos syndrome. J Dent Res Rev 2015;2:42-6
| Introduction|| |
Ehlers-Danlos syndrome (EDS) also known as tenascin X-Deficiency syndrome, Lysyl Hydroxylase Deficiency syndrome, Cutis Hyperelastica, Dystrophia Mesodermalis, Fibrodysplasia Elastic Generalisatica , is a group of clinically and genetically heterogeneous heritable disorder of connective tissue with specific oral manifestations. ,,, This syndrome is broadly characterized by joint hypermobility, dermal hyperelasticity and tissue fragility. ,,
The name and recognition of the syndrome are credited to Edward Ehlers, a Danish dermatologist and Henry Alexander Danlos, a French dermatologist, both of who reported cases in 1901 and 1908 respectively. In the mid-1930s, pertinent clinical features and associated phenotypes were described and the name EDS was assigned to the condition. ,,
In 1986 at Berlin, 10 EDS subtypes were classified by Roman numerals based on clinical manifestations and mode of inheritance. After years of nosologic confusion, a group of experts met at Villefranche in France in 1997 and identified six major EDS subtypes. The current taxonomy is based on online mendelian inheritance in man database that provides updated information on the clinical and molecular understanding of single gene (monogenic) disorders ,,,, [Table 1].
| Epidemiology|| |
Ehlers-Danlos syndrome demonstrates an equal prevalence amongst males and females of all racial and ethnic backgrounds. , Combined prevalence of all EDS subtypes is about 1/5000 ,,, with hypermobility and classic types of EDS accounting for 80% and 10% respectively. The prevalence of hypermobility type is 1/10,000-15,000 whereas classic and vascular types of EDS have a prevalence of 1/20,000-40,000 and 1/100,000 respectively. 
| Etiology|| |
Collagen is the most abundant protein in mammals and is secreted primarily by the connective tissue cells. About 20 identifiable forms of collagen have been found with types I, II, III, V, XI being present in the connective tissues.  Collagens make up the bulk of extracellular matrix in the orofacial structures (craniofacial skeleton and alveolar bone, temporomandibular joints (TMJs), teeth, and oral soft tissues). Therefore, alterations in the molecular structure of different types of collagen caused by mutation in the responsible genes result in altered mechanical properties of the connective tissues and abnormal phenotype depending upon the nature of the protein affected. Most EDS subtypes are caused by mutations in genes encoding collagen type I, III, V and enzymes involved in the posttranslational modifications of these collagens. , Three patterns of inheritance linked with various subtypes are: Autosomal dominant, autosomal recessive and X linked (rarest form). 
Ehlers-Danlos syndrome type I and II, classic variety, involve COL5A1, COL5A2, and tenasin-X genes. Type IV is characterized by a mutant COL3A1 gene resulting in decreased amount of type III collagen. Type V and VI characterized by defect in PLOD1 gene result in deficiency of enzymes lysl oxidase and hydroxylase. Type VII is associated with mutation in ADAMTS2 gene that encodes for an amino terminal procollagen peptidase. Type IX has abnormal copper metabolism and type X has a nonfunctioning plasma fibronectin. COL1A1, COL1A2 genes encode type I collagen. ,,,, [Table 2].
| Clinical Manifestations|| |
The patients suffering from EDS have distinctive facies with sparse hair, hypertelorism, wide nasal bridge, epicanthic folds, protruding ears and frontal bossing. They also exhibit freely movable subcutaneous nodules that appear as fibrosis lobules of fat. , Also, patients suffering from vascular type IV EDS display prominent eyes, pinched nose, small lips, hollow cheeks and lobeless ears due to lack of subcutaneous adipose tissue. Excessive wrinkling and thinness of skin over hands and feet produces an acrogeric or an old looking appearance. , Joint hypermobility is a dominant manifestation particularly in classical type EDS affecting both large and small joints. This feature usually comes to attention when the child starts to walk.  The shoulder, knee, and TMJs are particularly susceptible to dislocation. It can be assessed using the 'thumb-abduction test' or passive apposition of the thumbs to the flexor aspect of the forearm  [Figure 1]a. These patients present with characteristic dermal hyperextensibility. The skin extends easily and snaps back after release.
|Figure 1: Cardinal features of Ehlers-Danlos syndromes: (a) Joint hypermobility (b) skin hyperextensibility (c) increased tissue fragility with extensive scarring|
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It is recommended to test this feature clinically at a neutral site that is not subjected to mechanical forces e.g.: Volar surface of the forearm and is measured by pulling up the skin (>1.5 cm) till resistance is felt , [Figure 1]b.
In addition, wide atrophic scarring due to tissue fragility is frequently encountered. It occurs mainly over knees, shin, forehead, and chin. The skin splits easily and heals slowly leaving scars that have a papyraceous or "cigarette paper-like" quality ,,, [Figure 1]c. In areas of repetitive trauma, hemosiderin deposition may lead to dark and unaesthetic discoloration of the skin. Capillary fragility leads to spontaneous intramuscular and subcutaneous hematomas. Also, minor wound healing defects may present as nonpapyraceous scars. 
Increased mucosal fragility is a dominant finding in all EDS subtypes [Figure 2]a. This feature is attributed to the structural alterations in collagen type I, III and V present in the lamina propria that supports the oral epithelium. This accounts for decreased shear resistance of the epithelium resulting in frequent tearing of the mucosal tissues. The most prevalent initiating factor being mastication, brushing of teeth and a combination of both. ,,
Increased mucosal fragility is also accompanied by the presence of bruises and grazes in the oral epithelium due to extravasation of blood that present as dark colored mucosal swellings and small red points respectively. In addition, circumscribed spots of white or gray color with a pale outline called Regenerative patches are a common feature. It represents recent bruising with deficient wound healing and should be distinguished from white lesions occurring in the oral mucous membrane. 
|Figure 2: Intra oral manifestations: (a) Increased mucosal fragility on the frontal slope of palate (b) Gorlin's sign (c) lingual frenum agenesis|
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Hypermobility of the TMJ with recurrent subluxation and dislocation of the joint is pathognomic for EDS  and in particular for EDS types II, IV, V, and VI. This can occur in association with joint noises, myofascial pain, arthralgia, and parafunctional habits. The fibrocartilagenous structure, supporting ligaments and the retrodiscal tissue are composed of mainly type I, III and V collagen. The presence of defective collagen in this syndrome leads to joint laxity with internal joint derangement and dislocation. Reduction of TMJ dislocation can cause intracapsular hemorrhage and extensive scar formation leading to hemarthrosis. ,
Early onset generalized periodontitis, the main clinical finding in EDS type VIII ,, has dominant transmission and a very high penetrance. This leads to premature loss of deciduous and permanent teeth.  Repeated gingival damage due to increased mucosal fragility may present as recurrent gingival inflammations/infections.  Loss of gingival attachment  and pathological migration of teeth is also a frequent finding in such patients.  Impaired oral hygiene due to increased gingival bleeding, mucosal fragility and restraint of wrist mobility is commonly encountered.  This is reflected by high decayed, missing, filled/decayed, missing, and filled teeth and plaque scores in these patients. Patients brush their teeth less frequently and need to adopt special brushing techniques.
Hypodontia, abnormal pulp shape and moderate generalized pulp calcification (pulp stones) are frequent findings. , Abnormal dentin structure due to aberrant collagenous matrix can lead to unusual crown anatomy, e.g. crenulated incisors.  Lack of normal scalloping of the dentino enamel junction,  stunted roots or dilacerations, congenital absence of teeth  and supernumerary teeth have also been reported.  The patients suffering from this syndrome can touch the end of their nose with their tongue (Gorlin's sign) [Figure 2]b. They also exhibit absence of labial and lingual frena [Figure 2]c and high arch palate. ,,
| Diagnostic Investigations|| |
Biochemical testing includes analysis by sodium do decyl sulfate - polyacrylamide gel electrophoresis of radioactively labeled collagens extracted from skin fibroblast cultures. This analysis identifies >95% individuals harboring a defect of type III collagen.  Molecular (DNA based) testing is available for EDS type IV and VII. A diagnostic assay of urine pyridinoline cross-links identifies EDS type VI. Hematological studies including evaluation of clotting factors, platelet aggregation and bleeding time are usually normal except for the hess test (Rumple-Leed test) indicating capillary fragility.  Imaging studies in the form of computed tomography scanning, magnetic resonance imaging, ultrasonography and angiography reveal arterial aneurysms, arterial dissections in vascular type IV EDS. Skin biopsy or histopathology of skin and connective tissue fails to reveal any diagnostic abnormality. 
| Dental Management|| |
Surgical interventions are generally discouraged  because of increased vascular fragility, impaired healing and increased likelihood of scarring. Mucoperiosteal flaps should be raised with great care because of easy tearing of the gingiva. Sutures should be tied under slight tension to a larger than normal section of tissue and left in place twice as long as usual. A prefabricated acrylic splint/plate is placed over the surgical site as sutures do not hold well. ,,
The dentist may encounter prolonged, recurrent bleeding from the socket following a tooth extraction. , Hemostatic therapy in the form of 1 Deamino 8-D-Arginine Vasopressin (DDAVP), a vasopressin analog injected or administered intranasally, tranexamic acid and recombinant factor VIIa has been used in patients with massive hemorrhagia and prolonged bleeding time. ,
Cardiovascular involvement is a feature of many hereditary connective tissue disorders. Mitral valve prolapse and regurgitation is reported to be around 25% in classic EDS. Therefore, these patients require antibiotic prophylaxis against bacterial endocarditis before any surgical procedure is planned. ,,
Local anesthesia may have reduced or no effect in some EDS patients  as a result of tissue scarring resulting in decreased spread of local anesthetic and subsequent block failure. This includes failure of the eutectic mixture of local anesthetic cream that is especially used in pediatric patients for pain reduction during venous puncture. Inferior alveolar nerve block should be given with great care to avoid causing hematomas. 
General anesthesia can be performed as balanced anesthesia with nitrous oxide or as total intravenous anesthesia. Intraoperative positioning of the patient should focus on optimal padding of the patient in order to decrease shear forces. Careful mask ventilation is advised to avoid TMJ subluxation and using small endotracheal tubes for intubation reduces the risk of mucosal damage to the trachea. 
Orthodontic and temporomandibular joint considerations
For a given moment to force ratio applied for tooth movement, the periodontal ligament of an EDS patient shows larger strain than a normal child. Rapid migration and greater tooth mobility during orthodontic treatment is, therefore, an important consideration.  Various immunohistochemical studies have documented altered levels of Prostaglandin E2 and c-AMP in the tissue sites that signal osteocytic differentiation. Osteocytes in turn produce lactic acid and pro collagenase, which resorb the bone and result in rapid tooth movement.  The retention phase after orthodontic treatment is prolonged due to slow repair of periodontal fibers. ,,
In order to avoid TMJ subluxation, children with EDS should avoid contact sports and heavy weight exercises that place increased stress on premorbid lax joints. , Children with pronounced skin fragility should wear protective pads or bandages over forehead and knees.  Prolotherapy, a procedure in which saline/other irritants are injected into the tendons and surrounding tissues to produce inflammation and subsequent scar formation. This can be used to create increased soft tissue stability around the TMJ. 
Anesthetic and anti-inflammatory medications can be injected around joints to address acute, localized episodes of pain and inflammation.  Arthroscopic debridement, tendon relocation, capsulorrhaphy, and arthroplasty produce less satisfactory results than in individuals without EDS. 
| Endodontic considerations|| |
Pulp stones, pulp calcifications and abnormal root morphologies in EDS patients may present significant challenge in the root canal treatment. Consideration should be given to frequent resting of the TMJ during lengthy dental procedures in anticipation of subluxation. ,
The major challenge in contemporary periodontal therapy is the re-establishment of the soft tissue attachment due to defective interdigitation of newly assembled (abnormal) collagen fibers on the root surface. This occurs because the collagens become more soluble, ratios of collagen types are altered with increased type V collagen.  The regenerative capacity of the connective tissues is decreased due to deficient processing of new collagen.  Further, immunophenotyping studies reveal lymphocytopenia and a slightly raised CD4-CD8 ratio with normal T-cell activation. Natural killer cell count was found to be at the lower end of the reference range. 
High dose Vitamin C supplementation (1-4 g/day)  is recommended in EDS patients against a normal dose of 35-100 mg/day. Ascorbic acid that is a co factor for cross-linking of collagen fibers promotes wound healing and improves bleeding time and muscle strength.  Nonsteroidal anti-inflammatory drugs, muscle relaxants, and glucosamine, are prescribed for pain relief, myofacial spasms and osteoarthritis respectively. , In vascular type IV EDS, prophylactic use of beta adrenergic blockers is under research. These drugs slow the rate of aortic dilatation and reduce aortic complications. Anti-coagulants and drugs, e.g. Acetylsalicylic acid that interfere with platelet function are contraindicated. 
| Differential Diagnosis|| |
Conditions that mimic EDS include Marfans Syndrome, Loeys-Dietz Syndrome, Stickler Syndrome, Achondroplasia and Osteogenesis Imperfecta. However, final diagnosis is based on the clinical, radiographic findings and on confirmation with laboratory investigations. ,,
| Conclusion|| |
Ehlers-Danlos syndrome is a group of hereditary connective tissue disorders that has widespread oral manifestations. Children with this syndrome are often misdiagnosed for child abuse, hematological problems, and malignancy. Final diagnosis is, however, dependent on confirmation with laboratory investigations. A thorough assessment of the patients by a pediatric dentist is, therefore, essential for early diagnosis and referral. With suitable understanding of the disease manifestations and appropriate precautions, dental treatment can be instituted with minimal untoward effects. This paper highlights the impact of collagen deficiency on oral health and treatment considerations for effective dental management of EDS patients.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]
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