Inherited Connective Tissue Diseases

 

• Marfan's syndrome

  Pathophysiology and epidemiology

  • Defective fibrillin-1, a key component of the extracellular matrix that maintains the structure of connective tissue.
  • Caused by one of many autosomal dominant mutations in FBN1. 25% are de novo.
  • Signs and symptoms may not be apparent until teenage years or even later.
  • Prevalence 1/5000.

  Signs and symptoms

  MSK:

  • Tall stature, with long thin arms and fingers (arachnodactyly) → arm span to height ratio >1.05, thumb sign (thumb protrudes from clenched fist) and wrist sign (thumb overlaps fingers if wrapped around wrist).
  • Hypermobile joints and arthralgia.
  • Other features: high arched palate, scoliosis, spondylolisthesis, pectus carinatum or excavatum, retrognathia, long face, pes planus, hernias.

  Non-MSK:

  • Aortic root aneurysmal dilation → valve regurgitation, aortic dissection/rupture. Mitral valve prolapse and regurgitation is also common.
  • Ocular: upward lens subluxation (ectopia lentis), myopia, retinal detachment, glaucoma.
  • Also: skin striae, pneumothorax, dural ectasia of spinal cord, enophthalmos.

  Diagnosis and investigations

  • Diagnosis is largely clinical, but genetic testing can support the diagnosis and guide treatment. If a mutation is identified (>90% of cases), consider screening 1st degree relatives and prenatal testing.
  • Annual echo to screen for and monitor aortic disease. MRI or CT may provide additional information.
  • Slit-lamp exam.
  • X-rays may demonstrate characteristic skeletal deformities.

  Management

  Preventing death from aortic disease is the focus of treatment:

  • Lifestyle: avoid intense exercise (causing sudden ↑BP) and contact sports.
  • Medical: β-blockers for all those with aortic aneurysm, to slow growth. Adding ARB may help.
  • Surgical: prophylactic aortic root replacement – usually including valve replacement – if diameter >5 cm.

  Other treatments:

  • Bracing or surgery for scoliosis.
  • Ocular disease: vision correction (glasses, laser), lens removal only if cataract or glaucoma develops.

  Prognosis

  Significantly improved with modern treatment, with life expectancy >70 years and approaching normal.

• Ehlers-Danlos syndrome (EDS)

  Pathophysiology and epidemiology

  • Group of inherited conditions characterised by defective collagen synthesis.
  • Usually autosomal dominant (though can be recessive), with 50% de novo.
  • Prevalence 1/5000. Hypermobility EDS is commonest.

  Clinical features and types

  Key features:

  • Hyperextensible skin.
  • Joint hypermobility → dislocation, subluxation, arthralgia.
  • Tissue fragility → mucosal bleeding, vessel/organ rupture.

  Other signs of defective collagen may occur, including pes planus, hernias, uterine or anal prolapse, mitral valve prolapse, aortic root dilation, pneumothorax, pectus excavatum, and high arched palate.

  EDS types

  Classic EDS (types 1 and 2 in old nomenclature):

  • Skin is hyperextensible, smooth, bruises easily, and heals with wide atrophic scars. Subcutaneous nodules may be seen.
  • Joint hypermobility (though absent in 20%).

  Hypermobility EDS (type 3):

  • Joint features predominate. Overlaps with (and may be the same thing as) benign joint hypermobility syndrome.
  • Minimal skin signs except for hyperextensibility.
  • May also feature autonomic dysfunction, IBS, and headaches.

  Vascular EDS (type 4):

  • Rupture of arteries (esp. thoracic and abdominal), bowel, or uterus.
  • Mean age of death 48 years.
  • Skin may be translucent and bruise easily, but with minimal hyperextensibility.

  Other types exist but are rare.

  Diagnosis

  • Largely clinical.
  • Genetic testing useful for classic EDS (COL5A1 and COL5A2) and vascular EDS (COL3A1), but less so for hypermobility EDS (only some have tenascin X mutations).

  Management

  • Supportive: education and counselling, physio/OT, padding to minimize trauma.
  • Careful tissue repair if wounds occur: non-tension sutures, to stay in twice as long as usual.
  • Consider echo to screen for valvular and aortic disease.