Ehlers-Danlos syndrome and Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that affects the microfibrils and elastin in connective tissue throughout the body. MFS is associated with disorders of the cardiovascular system (e.g., mitral valve prolapse, aortic aneurysm, and dissection), the musculoskeletal system (e.g., tall stature with disproportionately long extremities, joint hypermobility), and the eyes (e.g., subluxation of the lens of the eye).

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders with variable inheritance (including hypermobility EDS and vascular EDS), characterized by defective collagen synthesis and processing. Symptoms include varying degrees of hyperextensive skin, joint hypermobility, and tissue fragility (including that of vasculature).

The diagnosis of MFS and EDS is based on clinical criteria. Genetic testing can be used additionally to confirm or rule out the diagnosis of certain subtypes. Since there is currently no causal treatment for MFS or EDS, management typically involves an approach focusing on clinical features, including regular monitoring of complications (e.g., imaging of aortic aneurysm) and preventive care (e.g., antihypertensives to prevent aneurysm progression).

Marfan syndrome ^[1][2]

• Mutation of fibrillin-1 gene (FBN1); on chromosome 15 → defective fibrillin (a glycoprotein that forms a supportive sheath around elastin) → defective connective tissue microfibrils → defective elastin
• Several hundred different FBN1 mutations have been described in patients with Marfan syndrome.
• Autosomal dominant; inheritance pattern with variable penetrance

MarFan syndrome is caused by a gene mutation in FBN1 on chromosome 15 (Fifteen), resulting in defective Fibrillin protein.

Ehlers-Danlos syndrome ^[1]

• Mutations in genes (e.g., COL5A1, COL3A1) that control the synthesis and processing of different types of collagen → collagen defects (e.g., a defect in lysine-hydroxylysine cross-linking of tropocollagen leads to unstable collagen fibrils)
• Autosomal dominant or recessive inheritance with varying patterns of inheritance, severity, and type of collagen affected
• Ehlers-Danlos syndrome is subclassified into 13 different types, based on clinical presentation, genetic defect, and type of collagen affected (e.g., hypermobility type, classical type). Only the most common types are discussed here.

Marfan syndrome ^[1][3][4]

Cardiovascular

Cardiac findings in Marfan syndrome include:

• Aortic disease
  • Caused by aortic necrosis (cystic medial degeneration) → weakening of the elastic artery
  • Manifestations include:
    • Aortic aneurysm
      • Thoracic or abdominal aortic aneurysm
      • Aortic root dilation: aneurysm of the proximal thoracic aorta
    • Aortic regurgitation
    • Aortic dissection (typically of the thoracic aorta)
• Mitral valve prolapse
• Berry aneurysms: rupture leads to subarachnoid hemorrhage

Musculoskeletal

• Tall stature and long extremities
• Joint hypermobility
  • Positive thumb sign (Marfan disease): Patients are asked to place their thumbs in the palms of the same hand and then clench to form a fist. A positive sign is present when the thumb protrudes beyond the ulnar border of the hand.
  • Positive wrist sign: Patients are asked to clasp the wrist of the opposite hand. A positive wrist sign is present when the little finger and thumb overlap.
• High-arched palate
• Arachnodactyly; (achromachia): abnormally long, slender fingers and toes
• Pectus deformity
  • Pectus carinatum: a sternal deformity where the middle and lower portion of the sternum protrude forward (also known as sternal kyphosis)
  • Pectus excavatum: a sternal deformity where the middle and lower portion of the sternum protrudes inward
• Pes planus (flat foot) or hindfoot valgus
• Spinal deformities (scoliosis, hyperkyphosis)
• Vertical overdevelopment of the head (dolichocephaly)
• Winged scapula
• Habitual dislocations (particularly the patella and shoulder)
• Acetabular protrusion

Skin

• Hyperextensive skin
• Formation of striae (stretch marks)

Eyes

• Visual impairment: ectopia lentis (lens dislocation) → lens subluxation superiorly and temporally
• Severe myopia
• Retinal detachment
• Glaucoma
• Early cataract formation

Other

• Increased risk of spontaneous pneumothorax
• Lumbosacral dural ectasia

The classic presentation of MFS includes aortic aneurysm or dissection, long extremities, arachnodactyly, joint hypermobility, and subluxation of the lens of the eye.

Ehlers-Danlos syndrome ^[5]

The clinical features discussed here are seen in all types of EDS, but their severity may vary and certain symptoms predominate depending on the specific type.

Cardiovascular

Cardiac findings in Ehlers-Danlos syndrome include:

• Heart valve defects (e.g., mitral valve prolapse)
• Cystic medial degeneration: can lead to aortic dilation, aneurysms, or dissection
• Aneurysms/dissections of the iliac, splenic, or renal arteries
• Berry aneurysms: rupture leads to subarachnoid hemorrhage

Musculoskeletal

• Joint hypermobility with a tendency towards dislocation
• Skeletal abnormalities (e.g., scoliosis, pectus deformity)

Skin

• Tendency to bruise easily
• Skin hyperextensibility
• Frequent skin lacerations (e.g., with minor scratches)
• Poor skin healing (e.g., following surgery )
• Atrophic scars

Eyes

• Myopia
• Retinal detachment and tears

Other

• Hernias
• Organ rupture (e.g., gravid uterus) causing pain and (potentially life-threatening) internal bleeding, especially seen with vascular EDS
• Cervical insufficiency, uterine prolapse
• Dental abnormalities: hypodontia, delayed eruption, molluscoid pseudotumors

The classic presentation of EDS involves hyperextensible skin, joint hypermobility, and a tendency to bleed easily.

• MFS and EDS are typically clinical diagnoses.
• MFS and certain types of EDS can be confirmed or ruled out with genetic testing.
• Tests to identify specific manifestations:
  • Echocardiography (cardiovascular manifestations)
  • Slit-lamp examination (to rule out lens abnormalities)
  • Imaging: skeletal x-rays and MRI (dural ectasia in Marfan syndrome) ^[6][7]

• Cystic medial degeneration: a degeneration (necrosis) of large blood vessels such as the aorta. ^[8]
  • Seen in disorders that cause increased arterial wall stress (e.g., hypertension, coarctation of the aorta) as well as connective tissue disorders (especially MFS and EDS)
  • Can lead to aortic aneurysm and aortic dissection
  • Histopathology
    • Loss, thinning, disorganization, and fragmentation of elastic tissue in the media
    • Accumulation of mucoid extracellular matrix
    • Loss of smooth muscle nuclei

Marfan syndrome classically manifests with a superior and temporal displacement of the lens (upward and outward). Homocystinuria also results in a Marfanoid habitus, but manifests with inferior and medial displacement of the lens (downward and inward).

The differential diagnoses listed here are not exhaustive.

Applicable to MFS and EDS

• No causal treatment
• Interdisciplinary treatment of specific symptoms and manifestations, including:
  • Aortic dilatation: beta blockers and, if necessary, aortic root replacement surgery
  • Scoliosis: bracing and, if necessary, surgery
  • Physical therapy
  • Pain: analgesia
• Regular orthopedic, ophthalmological, and cardiological check-ups

Specific treatment ^[12]

• Marfan syndrome
  • Angiotensin receptor blockers (ARBs) can be used in combination with beta blockers to lower blood pressure.
  • The efficacy of ARBs (e.g., losartan) in preventing aortic root dilation is subject to current research.
• Ehlers-Danlos syndrome: High-contact sports should be avoided and surgical procedures should be performed with caution in order to avoid excessive bruising and internal bleeding.

Marfan syndrome ^[1][13]

• Normal life expectancy: if diagnosed early and complications are managed appropriately
• Cardiovascular complications: Disease progression should be carefully monitored and managed accordingly to prevent cardiovascular complications (e.g., aortic dissection).
• Aortic root disease (e.g., aneurysm, dissection) is the most common cause of death.

Ehlers-Danlos syndrome ^[7][14][15]

• Normal life expectancy in all types of EDS except vascular type
• Life expectancy in vascular type: approx. 50 years