HURLER SYNDROME
 
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HURLER SYNDROME

 

DEFINITION:

A lysosomal storage disorder characterized by the accumulation of acid mucopolysaccharides (heparan and dermatan sulfates) in the central nervous system and peripheral tissues.

EPIDEMIOLOGY:

  • incidence: ?
  • age of onset:
    • 6 to 24 months of age
  • risk factors:
    • familial - autosomal recessive
      • chrom. #: 4p16.3
      • gene: alpha-L-iduronidase
    • M = F

PATHOGENESIS:

1. Background

  • alpha-L-iduronidase is a lysosomal enzyme which catalyzes the breakdown of heparan sulfate (HS) and dermatan sulfate (DS)
  • disease first described in 1919 by Hurler and is now classified as Mucopolysaccharidosis Type IH (MPS-IH)

2. Genetic Defect

  • genetic defect -> deficiency of alpha-L-iduronidase activity -> incomplete degradation of HS and DS -> accumulate in almost every tissue in the body with widespread occurence of vacuolated or "gargoyle" cells containing lysosomes engorged with HS and DS - Hurler (severe) and Scheie (mild) syndromes represent phenotypes at opposite ends of the clinical spectrum of alpha-L-iduronidase deficiency

CLINICAL FEATURES:

1. Central Nervous System Manifestations

1. Progressive Neurologic Disease

  • communicating hydrocephalus with raised intracranial pressure

2. Developmental Delay

  • by 12-24 months of age
  • maximal functional age: 2-4 years
  • limited language skills

3. Intelligence

  • profound mental retardation

2. Musculoskeletal Manifestations

1. Facial Features

  • coarse facies
  • large and long (dolichocephalic) head with frontal bossing
  • prominent sagittal and metopic sutures
  • nose - depressed bridge, broad, flat, and flared
  • eyes - epicanthal folds

2. Skeletal Features

  • carpal tunnel syndrome - peripheral nerve compression
  • joint stiffnes -> deformities -> immobility
  • kyphosis
  • short stature (max. 110 cm)

3. Other Manifestations

1. Respiratory

  • upper respiratory infections
    • copious nasal discharge, recurrent otitis media
  • noisy breathing, COPD

2. Cardiovascular

1. Factors leading to CHF:

  • coronary artery narrowing
  • stiffening of the myocardium
  • thickening of the cardiac valves
  • thickening of the endocardium

3. Gastrointestinal

  • enlargened tongue
  • hepatomegaly/hepatosplenomegaly
  • umbilical and inguinal hernias
  • failure to thrive (fall off the growth curve between 6-18 months)

4. Ophthalmologic

  • clouding of corneas (1st year) -> loss of visual acuity

5. ENT

  • sensorineuronal hearing loss

INVESTIGATIONS:

1. Diagnostic

  • deficiency of alpha-L-iduronidase activity in leukocytes and cultured skin fibroblasts
  • prenatal
    • deficiency of enzyme activity in cultured chorionic villi or amniocytes

2. Urine

  • 24 hour urine collection: elevated HS and DS

3. Imaging Studies

1. Skeletal X-Rays

1. Dystostosis Multiplex

  • large dolichocephalic skull
  • thickened calvarium

2. Skull

  • hyperostosis of cranium
  • sella turcica: boot- or J-shaped

3. Vertebrae

  • gibbus deformity

4. Others

  • thickened medial 1/3 of the clavicle
  • progressive coxa valga deformity of the hips

MANAGEMENT:

1. Supportive

  • no treatment for underlying disease
  • multidisciplinary approach
    • Paediatrics, Neurology, Orthopedics, Cardiology, ENT, Ophthalmology
    • genetic counselling
  • bone marrow transplantation is experimental

2. Prognosis

  • MPS-IH is the most severe of the MPS's
  • life expectancy: 10 years

 

 

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