Prader-Willi Syndrome - PWS

Diagnosis

Indications for Testing

• Suspicion based on physical findings

Criteria for Diagnosis

• Consensus criteria for testing
  • Major criteria
    • Neonatal and infantile central hypotonia with poor suck; improvement with age
    • Feeding problems and/or failure to thrive in infancy, with need for gavage feeding or other special feeding techniques
    • Onset of rapid weight gain between ages 12 months and six years, causing central obesity
    • Hyperphagia
    • Characteristic facial features – narrow bifrontal diameter, almond-shaped palpebral fissures, down-turned mouth
    • Hypogonadism manifestations
      • Genital hypoplasia – small labia minora and clitoris in females; hypoplastic scrotum and cryptorchidism in males
      • Incomplete and delayed puberty
    • Infertility
    • Developmental delay (mild to moderate), multiple learning disabilities
  • Minor criteria
    • Decreased fetal movement and infantile lethargy, improving with age
    • Behavior problems, including temper tantrums, obsessive-compulsive behavior, stubbornness, rigidity, stealing, and lying
    • Sleep disturbance or sleep apnea
    • Short stature by age 15 (based on the individual family)
    • Hypopigmentation
    • Hands and feet small for height age
    • Narrow hands with straight ulnar border
    • Esotropia, myopia
    • Thick, viscous saliva
    • Speech articulation defects
    • Skin picking
  • To score, major criteria are weighted at 1 point each, and minor criteria are weighted at 1/2 point each; supportive findings increase the certainty of diagnosis but are not scored
    • For children ≤3 years, 5 points are required, 4 of which should come from major criteria
    • For children >3 years and for adults, 8 points are required with 5 or more points coming from major criteria

Laboratory Testing

• Absolute diagnosis depends on genetic testing
• Diagnostic confirmation
  • Methylation testing confirms PWS in 99% of individuals with symptoms meeting consensus criteria
  • PWS patients possess a maternal-only imprint
• Determination of molecular mechanism
  • Cytogenetic testing (FISH metaphase) detects a deletion in the Prader-Willi Critical Region (PWCR) in 70% of affected individuals
  • Uniparental disomy testing detects 20-25% of cases
  • Methylation-sensitive PCR detects 99% of affected individuals but will not specify molecular mechanism of PWS; however, current standard of care for PWS patients does not differ based on identified molecular mechanism
  • Chromosome analysis detects balanced chromosome rearrangements that interrupt the PWCR in <1% of affected individuals
• Prenatal diagnosis – rarely made but theoretically could use amniocentesis or chorionic villus sampling samples

Differential Diagnosis

• Craniopharyngioma
• Growth hormone deficiency
• Hypotonia in infancy
  • Congenital myotonic dystrophy
  • Spinal muscular atrophy
• Bardet-Biedl syndrome
• Developmental delay in childhood
  • Fragile X syndrome
  • Rett syndrome
  • Other rare developmental delay disorders including Cohen syndrome, Albright hereditary osteodystrophy

Clinical Background

Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder characterized by severe hypotonia and feeding difficulties in infancy with gradual development of hyperphagia and morbid obesity in early childhood, as well as development of short stature, scoliosis, and maladaptive and compulsive behaviors.

Epidemiology

• Incidence – 1/10,000-1/25,000
• Sex – M:F, equal

Inheritance

• 70% have a microdeletion of the PWS/AS (Angelman syndrome) critical region
• 25% have maternal uniparental disomy of chromosome 15
• <5% have an imprinting center defect  

Recurrence Risk

• To determine the recurrence risk for parents, the specific genetic mechanism causing PWS in the prior affected child must be determined
  • Recurrence risk for parents whose previous child has an imprinting center mutation – up to 50%
  • Recurrence risk for parents whose affected child has PWS due to any mechanism besides an imprinting center mutation – <1%

Pathophysiology

• Spectrum of neuroendocrine disturbances suggests developmental abnormalities of the hypothalamus

Clinical Presentation

• Severe hypotonia and feeding difficulties in infancy
• Delayed motor and language milestones (developmental delay)
• Behavioral problems – temper tantrums, stubbornness, obsessive-compulsive traits
• Hypogonadism, cryptorchidism
• Short stature
• Facial features – narrow bifrontal diameter, down-turned mouth, almond-shaped palpebral fissures
• Hyperphagia and morbid obesity (begins between ages 1-6 years)
• Complications of obesity are the main cause of morbidity and mortality
  • Diabetes mellitus
  • Obstructive sleep apnea
  • Cardiorespiratory insufficiency

Treatment

• Multidisciplinary approach – physical, speech, occupational and behavioral therapies
• Consider growth hormone treatment
• Orthopedic treatment for scoliosis
• Screen for causes of possible morbidity including central adrenal insufficiency due to stressful conditions and obstructive/central sleep apnea
• Weight management programs
• Consider sex steroid replacement based on individual assessment and bone mineral density
• Discourage pregnancy in females because of cognitive dysfunction and the risk of Angelman syndrome in offspring of mothers with 15q11-q13 deletion
• Alert medical team performing surgical procedures to potential increased risk of complications from anesthesia

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Angelman Syndrome (UBE3A) Sequencing 2005564 Method: Polymerase Chain Reaction/Sequencing	Confirm diagnosis of Angelman syndrome in individuals with normal DNA methylation test

Diagnostic Algorithm

  Developmental Delay (DD) Testing Algorithm