Dr Nigel Burrows MD FRCP, Addenbrooke's NHS Trust, Cambridge
The Ehlers-Danlos syndrome (EDS) is one of the many inherited disorders of connective tissue. These disorders are a diverse group of conditions with features ranging from minor symptoms to life- threatening complications. All share varying degrees of abnormality in structural proteins resulting in joint hypermobility (laxity) and fragility of connective tissue possibly leading to internal blood vessel weakness.
Joint hypermobility (laxity) refers to joints that easily move beyond the normal range. This occurs most significantly in the Joint Hypermobility syndrome (JHS previously known as Benign joint hypermobility syndrome (BJHS)), hypermobile EDS, osteogenesis imperfecta (OI) and Marfan syndrome (MFS) but is also seen in Stickler syndrome (SS).
The development of aneurysms (enlarged blood vessels that can rupture) is specific to certain conditions and is seen most commonly in vascular EDS, Loeys-Dietz syndrome and MFS. This information sheet brieﬂy outlines these different syndromes.
Joint Hypermobility syndrome (JHS)
Whilst some degree of joint hypermobility is present in most of the inherited disorders of connective tissue it is most pronounced in JHS and hypermobile (type III) EDS. Both JHS and hypermobile EDS are characterised by laxity affecting many joints and variable skin involvement. Most experts therefore feel they are probably one and the same condition.
A study of a small number of patients with hypermobility suggested that hypermobile EDS patients were more likely to show resistance to the effects of local anaesthetic (LA) injections compared to JHS patients. The authors proposed this could be a useful discriminator between the two groups. Interestingly, this study has not been replicated and the criteria used to differentiate EDS from JHS individuals were not clear. It is my experience that many patients with hypermobility have some impairment of response to LA and this is not confined solely to any one group.
The reason that we cannot be dogmatic about separating these two conditions is the lack of understanding of the cause. It is very likely that many genetic faults lie behind these conditions leading to the spectrum of variable features seen. To date, the only consistent abnormality detected is reduction of a protein called tenascin-X. This accounts for only about 10% of hypermobile individuals and occurs in females only.
It is important to note that whilst JHS and hypermobile EDS cause troublesome and often painful joints, vital organs are not affected and there is therefore no serious threat to life. However autonomic nervous system-related symptoms such as giddiness, palpitations and easy fatigue occur more commonly in hypermobile patients.
Osteogenesis imperfecta (brittle bones)
Osteogenesis imperfecta (OI) is a congenital disorder of bone fragility leading to multiple fractures. It is caused by mutations in the genes (COL1A1 and COL1A2) that code for type I procollagen. The brittle bone changes can vary according to the type of OI from very mild to lethal forms. The sclerae (whites of the eyes) are often blue and there is joint hypermobility and short stature. It is now recognised that a reduction in bone density can occur in some individuals with EDS (and MFS) although this does not usually cause any obvious symptoms. However, some individuals, particularly with arthrochalasia type VII EDS, have been noted to fracture more easily and therefore genuinely overlap with OI.
Stickler syndrome (SS, progressive hereditary arthroophthalmopathy)
This syndrome is named after Dr Gunnar B Stickler. It is caused by abnormalities in collagen II and XI genes that are important in eye and joint development and function. Many, but not all, have hypermobility in addition to the potentially serious eye problems; short-sight (myopia) retinal detachments, cataracts or glaucoma. These eye features overlap with some of the eye abnormalities present in kyphoscoliotic type VI EDS. But the more marked joint hypermobility and skin fragility in individuals with EDS mean the two groups of disorders can be distinguished clinically. Furthermore, individuals with SS often have facial changes including a ﬂat nose and cleft palate.
Marfan syndrome (MFS)
A typical individual with classical MFS is distinct from EDS. MFS is characterized mainly by widening of the aorta (major blood vessel that leaves the heart), lens dislocation in the eye, tall stature with long limbs and fingers, and mild to moderate joint hypermobility. However a similar, but not so striking (Marfanoid) body shape can be seen in individuals with hypermobile EDS and BJHMS and it is important to differentiate these people from MFS.
Loeys-Dietz syndrome (LDS)
In 2005, a new autosomal dominant disorder, Loeys-Dietz syndrome, was described. It overlaps clinically with MFS both in the resulting physical appearance but also the development of aortic aneurysms. Type I LDS patients may also have a cleft palate, craniosynostosis (abnormal head shape) or hypertelorism (widespaced eyes). By contrast another group of Loeys-Dietz syndrome patients [type II] may have features that overlap with the vascular EDS physical traits, namely: easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy. In addition type II LDS individuals may have a divided (bifid) uvula. Joint laxity is more prominent in LDS than in vascular EDS. The median overall survival of type II LDS patients is 37 years compared to 48 years for vascular EDS patients. However the survival during or immediately after vascular surgery is dramatically lower in LDS patients compared to vascular EDS patients (4.8% versus 45% respectively). This illustrates one of the important reasons for accurate genetic diagnosis (genotyping) in such patients.
The views expressed are those of the author(s) and should not be construed to represent the opinions or policy of the Ehlers-Danlos Support UK or its Trustees.