Ehlers-Danlos Syndrome and Marfan Syndrome

Ehlers-Danlos syndrome and Marfan syndrome are two distinct groups of heritable connective tissue disorders with some overlapping features. They result from mutations affecting structural connective tissue proteins: predominantly collagen in Ehlers-Danlos syndrome and fibrillin-1 in Marfan syndrome.

Each produces a characteristic constellation of musculoskeletal, cutaneous and, most importantly, cardiovascular manifestations.

Accurate diagnosis and classification into the specific subtype within each condition has direct implications for prognosis and for the targeted surveillance and management required.

This matters because Marfan syndrome and the vascular subtype of Ehlers-Danlos syndrome carry a substantial, well established risk of life-threatening aortic and other vascular complications.

Classification and pathophysiology

• Ehlers-Danlos syndrome encompasses a heterogeneous group of at least thirteen recognised subtypes. Each results from a distinct genetic defect affecting collagen structure or processing.
• The hypermobile subtype is the commonest and generally milder. It is characterised predominantly by joint hypermobility and its musculoskeletal consequences.
• The classical subtype adds skin hyperextensibility and fragility.
• The vascular subtype is substantially rarer than the other subtypes but carries by far the most serious prognosis. It reflects a defect in type III collagen production and brings a substantially elevated risk of spontaneous arterial rupture, bowel perforation, and uterine rupture during pregnancy.
• Marfan syndrome is an autosomal dominant condition caused by mutations in the FBN1 gene, which encodes fibrillin-1. Fibrillin-1 is an essential structural component of the extracellular matrix microfibrils, which provide structural support and regulate transforming growth factor beta signalling.
• These microfibrils are widely distributed in connective tissue, so Marfan syndrome produces skeletal, ocular, and cardiovascular manifestations.
• The principal, life-threatening concern is cardiovascular: progressive aortic root dilation with risk of aortic dissection. It requires proactive, structured lifelong surveillance and, where indicated, prophylactic surgical intervention.
• Loeys-Dietz syndrome is a related but genetically and clinically distinct condition, caused by mutations affecting the transforming growth factor beta signalling pathway. It shares features with Marfan syndrome, including aortic root dilation.
• Its vascular phenotype is generally more aggressive and rapidly progressive. Additional characteristic features include hypertelorism, bifid uvula, and arterial tortuosity.
• Consider Loeys-Dietz syndrome as a differential diagnosis in any patient with a Marfan-like phenotype.

• Ehlers-Danlos syndrome, particularly the hypermobile subtype, presents with generalised joint hypermobility (formally assessed using the Beighton scoring system). Recurrent joint subluxation and dislocation and chronic musculoskeletal pain accompany it.
• In a substantial proportion of affected individuals there is also easy bruising and soft, velvety skin texture.
• There is a recognised, significant association with dysautonomia (including postural orthostatic tachycardia syndrome) and functional gastrointestinal disorders. These are often a significant part of the overall symptom burden.
• Classical Ehlers-Danlos syndrome adds skin hyperextensibility, fragility, and easy bruising to the joint hypermobility shared with the hypermobile subtype. Wounds heal poorly and frequently leave characteristic, widened "cigarette paper" scars.
• Vascular Ehlers-Danlos syndrome presents with thin, translucent skin with visible underlying vasculature. Characteristic facial features include a thin nose, thin lips, and prominent eyes.
• The critical risks are spontaneous, catastrophic arterial rupture, bowel perforation (particularly of the sigmoid colon), and uterine rupture during pregnancy. These are life-threatening emergencies that can occur without significant preceding trauma or warning. Identifying this rarer subtype accurately is therefore important.
• Marfan syndrome presents with characteristic skeletal features: tall stature with disproportionately long limbs (dolichostenomelia), arachnodactyly (long, slender fingers), pectus deformity (either excavatum or carinatum), scoliosis, and a high-arched palate.
• Characteristic ocular features include lens dislocation (ectopia lentis), which is a highly specific and important diagnostic feature when present.
• Of greatest clinical significance is progressive aortic root dilation, with risk of aortic dissection and rupture. Mitral valve prolapse and an increased risk of spontaneous pneumothorax also occur.
• Aortic dissection in Marfan syndrome and the related connective tissue disorders can occur at a substantially younger age and at a smaller absolute aortic diameter than in the general population.
• It can present with the classical, severe, tearing chest or back pain of aortic dissection, but may occasionally present more insidiously.
• Proactive, structured surveillance imaging is therefore essential. Do not rely on symptoms alone to identify progressive, high-risk aortic dilation before dissection occurs.

• Diagnosis of Ehlers-Danlos syndrome, particularly the hypermobile subtype, is clinical. It uses formal diagnostic criteria incorporating the Beighton hypermobility score and a range of additional systemic features, because no specific genetic marker is currently identified for this subtype.
• In the classical and vascular subtypes, genetic testing targeting the specific collagen gene mutations is available and supports definitive confirmation.
• Marfan syndrome is diagnosed using the revised Ghent criteria. They combine specific skeletal, ocular, and cardiovascular features with, where available, genetic testing for FBN1 mutations.
• Within the criteria, aortic root dilation and ectopia lentis carry particular diagnostic weight because of their specificity and clinical significance.
• Cardiovascular assessment, including echocardiography to assess aortic root diameter, is a standard part of the initial evaluation for Marfan syndrome and any suspected connective tissue disorder with cardiovascular involvement.
• Formal ophthalmological assessment, screening for ectopia lentis and myopia, is also essential in suspected Marfan syndrome.
• Genetic testing, where available and clinically indicated, supports definitive molecular diagnosis across this group of conditions.
• It is particularly important for confirming the Ehlers-Danlos subtype, because prognostic and management implications differ substantially between subtypes.
• It also supports family cascade screening, given the autosomal dominant inheritance of Marfan syndrome and the majority of Ehlers-Danlos syndrome subtypes.

• Marfan syndrome cardiovascular management centres on regular echocardiographic surveillance of aortic root diameter.
• Treat with beta blockade or, as an increasingly used alternative or adjunct, angiotensin receptor blockade. Both have evidence of reducing the rate of aortic root dilation.
• Recommend prophylactic surgical aortic root replacement once the aortic diameter reaches an established threshold, generally around 4.5 to 5 centimetres.
• Individualise the threshold according to family history of dissection at a smaller diameter, rate of growth, and any additional risk factor.
• Elective, planned repair carries a substantially lower risk than emergency repair after dissection.
• Advise activity modification, generally avoiding high-intensity isometric exercise and contact sports. Isometric exercise risks significant blood pressure elevation and contact sports risk direct trauma, both relevant to aortic and joint-related risk.
• Individualise the advice to the condition and its risk profile.
• Manage vascular Ehlers-Danlos syndrome cautiously, because any invasive procedure carries a substantial risk of spontaneous rupture. Avoid elective surgery and arterial catheterisation wherever possible.
• Pregnancy carries substantial maternal risk and needs careful, individualised management. Highly specialist, experienced multidisciplinary teams with expertise in this rare, high-risk condition should deliver it.
• Hypermobile Ehlers-Danlos syndrome management focuses on symptomatic musculoskeletal care. Structured physiotherapy addresses joint stability and proprioception, because muscular support helps compensate for the underlying ligamentous laxity.
• Manage the frequently significant, chronic pain according to general chronic pain principles. Also manage any associated dysautonomia or functional gastrointestinal symptoms, through a multidisciplinary approach.
• Lifelong, structured cardiovascular surveillance is an essential, non-negotiable component of management for both Marfan syndrome and vascular Ehlers-Danlos syndrome.
• Offer family genetic counselling covering the autosomal dominant inheritance pattern and recurrence risk.
• For women of reproductive age, plan and manage pregnancy carefully. Both conditions carry a substantially elevated risk of aortic dissection during pregnancy, reflecting the combined haemodynamic and hormonal changes.
• Provide psychosocial support for the ongoing burden of chronic pain and activity limitation. For the higher-risk subtypes, significant anxiety about sudden, catastrophic vascular events is common.
• Connect patients with specialist services and patient support organisations as part of compassionate, long-term management.