SLY SYNDROME
 
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SLY SYNDROME

 

DEFINITION:

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

EPIDEMIOLOGY:

  • incidence: rare (about 20 patients worldwide)
  • age of onset:
    • first years (severe form) -> after 4 years (mild form)
  • risk factors:
    • familial - autosomal recessive
      • chrom. #: 7q21.11-q22.1
      • gene: beta-glucuronidase
    • M = F

PATHOGENESIS:

1. Background

  • beta-glucuronidase is a lysosomal enzyme which catalyzes the breakdown of dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS)
  • disease first described in 1973 by Sly and is now classified as Mucopolysaccharidosis Type VII (MPS-VII)
  • the human beta-glucuronidase gene has been cloned and character-ized and it is a 21kb gene containing 12 exons (Miller et. al., 1990)

2. Genetic Defect

  • genetic defect -> deficiency of beta-glucuronidase activity -> incomplete degradation of DS, HS, and CS -> accumulation of these sulfates in the CNS and peripheral tissues
  • a A619V mutation has been identified in one girl with Sly Syn-drome (Tomatsu et al., 1990)
  • one of the few lysosomal storage diseases to present at birth with hydrops fetalis, dysostosis multiplex, and clinical and pathologic findings of a lysosomal storage disorder
  • Sly patients present with a wide range of clinical severity from the neonatal/early onset variants (severe) to the late onset variant (mild)
  • there are three clinical variants:
  • Type I - Neonatal Form - severe
  • Type II - Early Onset - severe
  • Type III - Late Onset - mild

    • CLINICAL FEATURES:

    1. Central Nervous System Manifestations

    1. Developmental Delay

    • in speech and language

    2. Intelligence

    • moderate mental retardation but not progressive

    2. Musculoskeletal Manifestations

    1. Facial Features

    • moderate/severe involvement
    • coarsened with macrocephaly

    2. Skeletal Features

    • short stature
    • progressive kyphoscoliosis
    • pectus carinatum (pigeon breast)

    3. Other Manifestations

    1. Respiratory

    • repeated episodes of pneumonia

    2. Cardiovascular

    • spared

    3. Gastrointestinal

    • hepatomegaly/hepatosplenomegaly
    • inguinal and umbilical hernias
    • failure to thrive

    4. Ophthalmologic

    • corneal clouding - variable with onset 7 months to 8 years

    INVESTIGATIONS:

    1. Diagnostic

    • deficiency of beta-glucuronidase activity in leukocytes and cultured skin fibroblasts
    • prenatal:
      • deficiency of enzyme activity in cultured choronic villi or amniocytes
      • PCR detection of mutations

    2. Urine

    • 24 hour urine collection: elevated HS, DS, and/or CS
      • variable MPS excretion pattern based on type and age

    3. Imaging Studies

    1. Skeletal X-Rays

    • moderately severe dysostosis multiplex
    • thoracolumbar gibbus deformity

    4. Pathology

    • course metachromatic granulocytic inclusions

    MANAGEMENT:

    1. Supportive

    • no treatment for underlying disease
    • multidisciplinary approach
      • Paediatrics, Neurology, Orthopedics, ENT, Ophthalmology
      • genetic counselling

    2. Experimental

    • gene transfer: correction of murine MPS VII by a human beta-glucuronidase transgene

     

     

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