• Clinical science

Ehlers-Danlos syndrome and Marfan syndrome

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder affecting the microfibrils and elastin in connective tissue throughout the body. MFS is associated with pathological manifestations in 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 six connective tissue disorders with variable inheritance in which the synthesis and processing of collagen are defective. Patients present with varying degrees of hyperelastic skin, joint hypermobility, and tissue fragility (including that of vasculature).

The diagnosis of MFS and EDS is based on clinical criteria, and genetic testing can be used additionally under certain circumstances. There is currently no causal treatment for MFS or EDS; a symptom-based approach is generally necessary. Primary prevention includes genetic counseling, while tertiary prevention involves regular monitoring for complications.

Etiology

Marfan syndrome

Ehlers-Danlos syndrome

  • Various mutations in genes that control the synthesis and processing of collagen (e.g., defect in lysine-hydroxylysine cross-linking of tropocollagen → unstable collagen fibrils)
  • EDS type (Villefranche classification): Inheritance patterns and type of collagen affected vary (can be autosomal dominant or recessive)
    • Mutation of type V collagenClassic EDS (types I and II) in which joint and skin manifestations predominate
    • Hypermobility EDS (type III) in which joint manifestations predominate
    • Mutation of type III collagenVascular EDS (type IV) in which cardiovascular manifestations predominate
    • Other types: kyphoscoliosis, arthrochalasia, dermatosparaxis

References:[1][2][3]

Clinical features

Marfan syndrome

Cardiovascular
Musculoskeletal
  • Tall stature with rapid linear growth and long extremities
  • Joint hypermobility
    • Thumb sign: Patients are asked to place their thumbs in the palms of the same hand and then clench to form a fist. A positive thumb sign is present when the thumb protrudes beyond the ulnar border of the hand.
    • 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)
  • Pectus deformity (pectus carinatum or pectus excavatum)
  • Pes planus (flat foot) or hindfoot valgus
  • Spinal deformities (scoliosis, hyperkyphosis)
  • Vertical overdevelopment of the head (dolichocephaly = elongated head)
  • Winged scapula
  • Habitual dislocations (particularly the patella and shoulder)
  • Acetabular protrusion //
Skin
  • Loss of skin elasticity/striae (stretch marks)
Eyes
Other

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

Cardiovascular
Musculoskeletal
  • Joint hypermobility with tendency to dislocate
  • Skeletal abnormalitis (e.g., scoliosis)
Skin
  • Tendency to bruise easily
  • Skin hyperextensibility
  • Frequent skin lacerations and poor skin healing (e.g., following surgery)
Other

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

References:[4][1][1][1][1][1][5][3][6][7][8]

Diagnostics

  • Both are typically clinical diagnoses; can be confirmed with genetic testing
  • Tests to identify specific manifestations

References:[5][9][10]

Differential diagnoses

Differential diagnosis of a marfanoid body habitus
Marfan syndrome Homocystinuria Multiple endocrine neoplasia 2B (MEN 2B)
Shared features
  • Joint hypermobility
  • Skin hyperextensibility
  • Scoliosis
  • Pectus deformity
  • Arachnodactyly
  • Tall stature (increased arm to height ratio)
Characteristic features

References:[1][1]

The differential diagnoses listed here are not exhaustive.

Treatment

  • No causal treatment
  • Interdisciplinary treatment of specific symptoms and manifestations (e.g., aortic dilatation treated with beta-blockers and, if the necessity arises, surgery; scoliosis treated with bracing and, if the necessity arises, surgery; physical therapy, analgesia for pain)
  • Regular orthopedic, ophthalmological, and cardiological check-ups
  • Specific therapy
    • Marfan syndrome: Preliminary data suggest that ARBs (e.g., losartan) may have a protective or even reversing effect in some of the clinical manifestations of MFS.
    • Ehlers-Danlos syndrome: High-contact sports should be avoided and surgical procedures should be performed with caution.

References:[5][11][12]

Prognosis

  • Marfan syndrome: patients can expect a normal lifespan, if the disorder is diagnosed early and complications are managed appropriately
  • Ehlers-Danlos syndrome: Life expectancy is typically normal with the exception of vascular EDS, which has a reduced life expectancy of ∼ 50 years.

References:[10][13][14][15][#8376}