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Ehlers-Danlos syndrome (EDS) is a rare inherited condition with disruption of the integrity of structural proteins in skin, ligaments, cartilage and blood vessels, leading to fragility of connective tissues.
Early literature quotes a 1/5,000 frequency of all types of EDS with EDS-hypermobility type (EDS-HT) accounting for about half of all registered cases. However, EDS-HT is an underdiagnosed condition. A frequency of 0.2-0.6% has been suggested for Caucasians, with a higher figure for Africans. Men have lower incidence of EDS-HT compared with women.
Some types of EDS have an autosomal dominant inheritance but some are recessive. Hypermobile EDS is considered to be an autosomal dominant trait with incomplete penetrance. Females are more commonly and possibly more seriously affected than males.
Abnormalities of collagen production result in:
- Bruising, bleeding from the gastrointestinal tract.
- Dissecting aortic aneurysm at an early age.
- Wide scars.
- Laxity of joints.
- Hyperelasticity of skin.
The first presentation may be premature rupture of the membranes.
Types of Ehlers-Danlos syndrome
There are many types of EDS based on different gene mutations affecting the structure or assembly of different collagens. Many syndromes overlap and it may be difficult to differentiate one from the other. All share common features of fragile skin and laxity of joints and ligaments, to a greater or lesser degree.
Hypermobile EDS (formerly known as type III)
- Is the most common type but often not diagnosed.
- It is not clear whether it is the same as, or a different condition from, joint hypermobility syndrome.
- Was considered for many years to be primarily a rheumatological condition. It is now known to have numerous systemic manifestations.
- Is characterised by generalised joint hypermobility, joint instability complications, widespread musculoskeletal pain and minor skin features.
- Common orthopaedic features include active joint hypermobility at the fingers, toes, elbows and knees and passive hyperextension at the great toe and heels.
- Structural changes due to joint instability include fixed subluxation of the distal ulna, asymptomatic fixed subluxation of the elbow,and fixed subluxation of the first metacarpal.
- Temporomandibular joint dysfunction may be a feature.
- Dermal changes include soft velvety skin but skin elasticity and scarring are less prominent features than other EDS types.
- Increased capillary fragility causes spontaneous ecchymoses.
- Increased or decreased activity of the sweat glands may represent a neurogenic feature of the condition.
- Dry mouth, dry eyes and vaginal dryness may be a reflection of autonomic abnormality.
- Increased mucosal fragility may result in nosebleeds, bleeding gums and gingivitis.
- Nervous system involvement is responsible for a significant amount of disability in this condition. Common features are chronic/recurrent pain, fatigue and headaches.
- Proprioceptive impairment can lead to reduced position sense with stumbling, clumsiness, increased tendency to falls and possible dyspraxia.
- Psychological symptoms such as anxiety and panic disorders are features of many types of EDS but are particularly common in the hypermobile type. Imaging studies suggest this may be associated with changes to brain structure.
- Cardiovascular involvement may include mild cardiac valve regurgitation and aortic root dilatation. Postural tachycardia may reflect a cardiac autonomic dysfunction.
- Connective tissue abnormalities of the lungs may lead to pulmonary complications such as persistent asthmatic symptoms, associated with increased lung volumes, impaired gas exchange and an increased tendency of both the lower and upper airways to collapse.
- Gastrointestinal symptoms, more common in patients with hypermobile EDS, include chronic (slow transit) constipation, hiatus hernia, Crohn's disease, faecal incontinence, rectal evacuatory dysfunction and functional gastrointestinal disorder.
- Gynaecological involvement may include irregular menses, menorrhagia, metrorrhagia, severe dysmenorrhea and pelvic prolapse.
Classic form (formerly known as types I and II)
- Major features are:
- Skin hyperextensibility (best tested by pulling the skin of the volar surface of the forearm until resistance is felt).
- Widened atrophic scars (a manifestation of skin fragility).
- Joint hypermobility (both large and small joints).
- Minor features include:
- Smooth velvety skin.
- Molluscoid pseudotumours (rolled up skin around joints vulnerable to damage).
- Subcutaneous spheroids (nodules under the skin).
- Muscle hypotonia leading to delayed gross motor development.
- Multiple bruises, especially on the legs.
- Easy skin-splitting shows in childhood over the forehead, elbows, knees and chin.
- Manifestations of tissue extensibility - eg, hiatus hernia, childhood anal prolapse, cervical incompetence.
- Surgical complications - postoperative hernias.
Vascular type (formerly known as type IV)
- Appears as thin skin with venous patterns readily visible, ecchymoses over the knees and shins, premature ageing of the skin on the dorsum of the hands, feet and shins with a 'Madonna' face with large eyes, nasal thinning and small ear lobes.
- It is the most severe form of EDS.
- The main problem is spontaneous rupture of medium/large arteries at any age from mid-adolescence to late adult life. Arterial aneurysms are also common.
- Death results from arterial rupture but rupture of the sigmoid colon is also common.
- Recent studies showed that 15% of women who became pregnant died due to complications during pregnancy.
- Overall median lifespan is reduced to 48 years.
Kyphoscoliosis type (formerly known as type VI)
- Severe main features with spinal curvature, early progressive fibrosis and severe motor delay.
- Other features may include severe skin hyperelasticity and fragility, blue sclera, fragile eyeballs and microcornea.
Arthrochalasia type (formerly known as types VII A and B)
- Severe main features, short stature, hip dislocation, dentinogenesis imperfecta.
- Dysmorphic features such as micrognathia and sparse hair may be present but tend to improve as the child gets older.
Dermatosparaxis type (formerly known as type VII C)
- The condition is very rare. It is usually diagnosed by the age of 2.
- Anomalies during the first years of life include premature rupture of the membranes, extreme skin fragility and easy bruising, large fontanelles, blue sclerae, puffy eyelids, micrognathia, umbilical hernia and short fingers.
- Joint hypermobility becomes increasingly prominent with age.
- The most significant risk is rupture of internal organs.
- Orofacial features include micrognathia, a frontal open bite and gingival hyperplasia with varying degrees of hyperkeratosis. The appearance can be diagnostic.
- Dental complications are the most common features and include abnormal morphology of the deciduous molars, obliteration of the tooth pulp and severe enamel attrition. The main feature is variable, early tooth loss with severe periodontitis. The permanent dentition shows agenesis and microdontia of several teeth, with tooth discolouration, dysplastic roots and tooth pulp obliteration.
- Cutis laxa.
- Pseudoxanthoma elasticum .
- Other causes of joint hypermobility - eg, benign joint hypermobility syndrome, Marfan's syndrome, osteogenesis imperfecta.
- Diagnosis is normally made on the clinical presentation.
- Subcutaneous calcified spherules can be confirmed on X-rays.
- Molecular genetic testing is a relatively new technique that may assist in cases of diagnostic difficulty, although not all patients with the specific condition will demonstrate the associated mutation. The following associated mutations have been discovered:
- Hypermobility type - TNXB in some patients (autosomal dominant with incomplete penetrance).
- Classic type - COL5A1 and COL5A2 in more than 50% of families (autosomal dominant).
- Vascular type - COL3A1 (autosomal dominant).
- Kyphoscoliotic type - PLOD1 (autosomal recessive).
- Arthrochalasia type - COL1A1 or COL1A2 (autosomal dominant).
- Dermatosparaxis type - mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II and III (autosomal recessive).
- Assays of the various enzyme deficiencies resulting from the genetic mutations can also be performed. .
- There is no specific treatment.
- Celiprolol, a beta 1-adrenoceptor antagonist with a beta 2-adrenoceptor agonist action, has been used to prevent arterial dissections and ruptures in patients with vascular EDS. It is thought to act via a reduction in vascular haemodynamic stress with exercise and/or through a reduction in transforming growth factor-b. Vascular EDS patients may also benefit from the surgical treatment of complications.
- Trauma should be minimised and protective clothing and padding may help. For patients with skin and soft tissue fragility, extra care (eg, non-tension sutures to skin, deep double sutures to other wounds, leaving stitches in for twice the normal time) should be taken when repairing injuries.
- Children with hypotonia and delay in motor development should receive physiotherapy.
- Physiotherapy will also be useful for adult patients with joint hypermobility problems. Anti-inflammatory tablets and analgesics may be required to control pain.
- Ascorbic acid is sometimes recommended to lessen the risk of spontaneous bruising.
- Genetic counselling should be provided.
- In patients with tissue fragility and bleeding disorders, pregnancy may be very dangerous. Obstetric complications include risk of uterine rupture during labour, damage to the vagina and perineum, bleeding and rupture of blood vessels and the colon during the puerperium.
- Abnormal bleeding may cause extreme difficulty with any surgical operation.
- Lifespan is usually normal unless there is marked vascular fragility.
- A high prevalence of severe complications occurs in a minority of families.
Further reading & references
- Ehlers-Danlos Syndrome, Type 1; Online Mendelian Inheritance in Man (OMIM)
- Gawthrop F, Mould R, Sperritt A, et al; Ehlers-Danlos syndrome. BMJ. 2007 Sep 1;335(7617):448-50.
- Ehlers-Danlos Support UK
- Castori M; Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatol. 2012;2012:751768. doi: 10.5402/2012/751768. Epub 2012 Nov 22.
- Ehlers-Danlos Syndrome, Autosomal Dominant, Type Unspecified; Online Mendelian Inheritance in Man (OMIM)
- Malfait F et al; Ehlers-Danlos Syndrome, Classic Type, Gene Reviews, 2014
- Watanabe A, Shimada T; Vascular type of Ehlers-Danlos syndrome. J Nippon Med Sch. 2008 Oct;75(5):254-61.
- Sadakata R, Hatamochi A, Kodama K, et al; Ehlers-Danlos syndrome type IV, vascular type, which demonstrated a novel point mutation in the COL3A1 gene. Intern Med. 2010;49(16):1797-800. Epub 2010 Aug 13.
- Rohrbach M, Vandersteen A, Yis U, et al; Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. Orphanet J Rare Dis. 2011 Jun 23;6:46. doi: 10.1186/1750-1172-6-46.
- Klaassens M, Reinstein E, Hilhorst-Hofstee Y, et al; Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood. Clin Genet. 2012 Aug;82(2):121-30. doi: 10.1111/j.1399-0004.2011.01758.x. Epub 2011 Aug 24.
- Malfait F, De Coster P, Hausser I, et al; The natural history, including orofacial features of three patients with Ehlers-Danlos syndrome, dermatosparaxis type (EDS type VIIC). Am J Med Genet A. 2004 Nov 15;131(1):18-28.
- Malfait F, Hakim AJ, De Paepe A, et al; The genetic basis of the joint hypermobility syndromes. Rheumatology (Oxford). 2006 May;45(5):502-7. Epub 2006 Jan 17.
- Colige A, Nuytinck L, Hausser I, et al; Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene. J Invest Dermatol. 2004 Oct;123(4):656-63.
- Beridze N, Frishman WH; Vascular Ehlers-Danlos syndrome: pathophysiology, diagnosis, and prevention and treatment of its complications. Cardiol Rev. 2012 Jan-Feb;20(1):4-7. doi: 10.1097/CRD.0b013e3182342316.
- Erez Y, Ezra Y, Rojansky N; Ehlers-Danlos type IV in pregnancy. A case report and a literature review. Fetal Diagn Ther. 2008;23(1):7-9. Epub 2007 Oct 9.
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Dr Colin Tidy
Dr Laurence Knott
Dr John Cox