PRADER-WILLI SYNDROME
 
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PRADER-WILLI SYNDROME

 

DEFINITION:

A chromosomal disorder resulting in a syndrome characterized by infantile hypotonia, hypogonadism, and obesity.

EPIDEMIOLOGY:

  • incidence: 1/10,000 - 1/25,000 live births
  • age of onset:
    • newborn (hypotonia, hypogonadism)
  • risk factors:
    • paternal chromosomal damage - chromosome 15qll-13
    • M = F
    • occurs in all races

PATHOGENESIS:

1. Historical Background

1. 17th Century

  • Eugenia Martinez Vallejo ("La Monstrua) was the subject of a painting by Juan Carreno de Miranda, a painter to the Spanish Court at the order of King Charles II in 1680 - she was a 6 year old weighing 120 lbs with excessive central obesity, a small triangular mouth, and small hands and feet

2. 19th Century

1. J.L.H Down (1887)

  • described a case of "polysarcia"
  • patient was 4'4", 210 lbs., with small hands and feet, little body hair, mentally retarded, and not menstruating
  • she had been thin and delicate up to the age of 7 but then had become hyperphagic

3. 20th Century

1. Prader, Labhart, and Willi (1956)

  • published a brief article describing a new syndrome characterized by:
    • obesity
    • short stature
    • lack of muscle tone in infancy
    • cryptorchism
    • mental retardation
  • presented at the 8th International Paediatric Congress in Copenhagen emphasizing the most distinctive feature to be hyperphagia leading to excessive obesity

2. Prader and Willi (1963)

  • analyzed 14 cases and in addition to the original characteristics described:
    • paucity of fetal movements
    • IQ of 40-50
    • tendency towards diabetes mellitus

3. Gablian and Royer (1968)

  • analyzed 11 cases and first to describe:
    • strabismus
    • orthopedic problems (scoliosis, lordosis, coxa valga, hip dislocation, epiphysiolysis)

4. Zellweger and Schneider (1968)

  • analyzed 14 cases and identified two stages:
  • 1st - infantile hypotonia
  • 2nd - obesity
  • speculated a hypothalamic disorder as a cause

5. Hall and Smith (1972)

  • analyzed 32 cases and found that 100% of cases were characterized by:
    • hypotonia
    • gross motor developmental delay
    • feeding problems
    • male hypogenitalism
    • obesity
  • also identified severe personality problems

2. Genetic Defect

  • environmental trigger -> paternal chromosomal damage -> Prader-Willi Syndrome (PWS) phenotypes

1. Environmental Trigger

  • may be an association of PWS with fathers employed in hydrocarbon-related occupations at the time of conception (factory workers, lumbermen, machinists, chemists, heavy machine operators, mechanics)

2. Cytogenetic Findings

1. Chromosomal 15 Analysis

  • interstitial deletions (69%)
  • unbalanced reciprocal translocations (13%)
  • small additional chromosomes (7%)
  • Robertsonian translocations (6%)
  • balanced reciprocal translocations (2%)
  • percentric inversions (1%)

2. Interstitial Deletion of Chromosome 15q11-13

  • first reported by Ledbetter et al., (1980)
  • involves proximal region of the long arm of chrom. 15
  • represents a sporadic occurrence
  • cytochemical properties of this region of chrom. 15
    • large amounts of 5-methylcytosine-rich DNA
    • high number of inverted DNA sequences
  • instability or fragility of chrom. 15 may be due to:
    • large number of sister chromatid exchanges
    • large number of chromosomal breakages

3. Endocrine-Related Features

  • disruption of chromosome 15q11-13 may lead to a developmental defect of the hypothalamus (involving disordered control of GnRH synthesis and/or release) leading to a hypogonadotropic hypogonadism
  • may represent an isolated gonadotrophin deficiency as other Hypothalamic-Pituitary Axes tend to be normal

CLINICAL FEATURES:

1. Gestational

  • reduced fetal activity (76%)
  • nonterm delivery (41%)
  • breech presentation (26%)

2. Neonatal/Infancy

  • gross motor developmental delay (98%)
  • infantile hypotonia* (94%)
  • feeding problems* +/- failure to thrive (93%)
  • low birth weight (<2.27 kg) - 30%

3. Neurological Manifestations

  • mental retardation* (97%)
  • skin picking (79%)
  • personality problems (41%)
  • seizures (20%)

4. Endocrine Manifestations

  • hypogenitalism/hypogonadism* (95%)
  • obesity (94%)
  • cryptorchidism (88%)
  • short stature (76%)
  • delayed bone age (50%)
  • menstrual problems (39%)

5. Craniofacial Manifestations*

  • almond-shaped eyes (75%)
  • narrow-bifrontal diameter (75%)
  • strabismus (52%)
  • early dental caries/enamel hypoplasia (40%)

6. Musculoskeletal Manifestations

  • small hands and feet (83%)
  • scoliosis (44%)

 

*Features considered essential for the diagnosis of PWS.

7. Specific Features

1. Infantile Hypotonia

  • presents in the first several months of life
  • non-progressive and spontaneously resolves between 8-11 months of life
  • generalized and severe in a majority of cases

1. Symptoms

  • decreased fetal activity
  • breech presentation
  • prolonged initial hospital stay due to weak suck with feeding problems
  • failure to thrive noted after 3 months of age
  • delayed motor milestones:
    • 12-13 months - independent sitting
    • 24-30 months - independent walking
    • 4.2 years - tricycle riding

2. Signs

  • absent or decreased suck
  • decreased spontaneous movements
  • expressionless face
  • flaccid muscles
  • generalized severe hypotonia
  • joint contractures
  • plagiocephaly
  • thin habitus
  • unresponsive
  • weak cry

2. Endocrine-Related Features

1. Infancy (1st Stage)

  • hypogonadism with genital hypoplasia
    • females - small labia majora, absent minora
    • males - micropenis, scrotal hypoplasia, cryptorchidism

2. Childhood/Adolescence (2nd Stage)

  • hypogonadism
  • incomplete or late sexual development
  • obesity with pseudogynecomastia
  • short stature

INVESTIGATIONS:

1. Neurologic

  • for investigation of infantile hypotonia
    • normal motor nerve conduction velocity, EMG, serum CPK
    • muscle biopsy
      • LM - normal or type II fibre atrophy (disuse atrophy)
      • EM - non-specific findings

2. Endocrine

  • for investigation of hypogonadotropic hypogonadism
    • low basal levels of FSH and LH
    • blunted response of LH and FSH to GnRH
    • augmented response of LH and FSH to GnRH after clomiphene therapy or repeated GnRH therapy
    • these results indicate a potential for hypothalamic maturation and sustained gonadotrophin release
  • absence of any lesions in the hypothalamus at autopsy
  • testicular biopsy
    • immature tubules and arrested tubular development

MANAGEMENT:

1. Supportive

  • multidisciplinary approach
    • Paediatrics, Neurology, Endocrinology, Ophthalmology,
    • Orthopedics, PT
    • Genetic Counselling - to discuss recurrence risk

2. Neurological Manifestations

1. Hypotonia

  • supplemental feeds
    • prolonged NG feeding
  • physiotherapy
    • passive exercises and frequent change in position to prevent disuse atrophy and joint contractures

3. Endocrine Manifestations

1. Obesity

  • diets, behavioural modification, limit access to food, increase activity level

2. Hypogonadotropic Hypogonadism

  • low dose androgen (may aggavate obesity)

 

INTERNET LINKS:

Prader-Willi Syndrome Association (USA)

 

 

Pediatric Database - PRADER-WILLI SYNDROME

 

Pediatric Organization - Pedbase [at] Gmail.com

 
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