Prader-Willi Syndrome - PWS

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.

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Clinical Overview

Diagnosis

Indications for Testing

Poor muscle tone, developmental delay, feeding difficulties, and failure to thrive in infant or child
Progression of above symptoms to food cravings, developmental and cognitive delay, behavior problems, especially surrounding food and food cravings, scoliosis, and short stature

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 1 and 6 years, causing central obesity
  - Hyperphagia
  - Characteristic facial features – narrow bifrontal diameter, almond-shaped palpebral fissures, downturned mouth
  - Hypogonadism manifestations
    - Genital hypoplasia
      - Females – small labia minora and clitoris
      - Males – hypoplastic scrotum and cryptorchidism
    - Incomplete and delayed puberty
  - Infertility
  - Developmental delay (mild to moderate), multiple learning disabilities
- Minor criteria
  - Decreased fetal movement and infantile lethargy that improve 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 years (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
- Major criteria are weighted at 1 point each, and minor criteria are weighted at 1/2 point each; supportive findings increase 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, and 5 or more points should come from major criteria

Laboratory Testing

Absolute diagnosis depends on genetic testing
Initial diagnostic testing – methylation polymerase chain reaction (PCR)
- Confirms Prader-Willi syndrome (PWS) in 99% of individuals with symptoms meeting consensus criteria
Determination of molecular mechanism for PWS
- Methylation-sensitive PCR detects 99% of affected individuals but will not specify molecular mechanism of PWS; however, current standard of care for patients with PWS does not differ based on identified molecular mechanism
- Cytogenetic testing (fluorescence in situ hybridization [FISH] metaphase) detects a deletion in the Prader-Willi-Angelman critical region (PWACR) on chromosome 15 (15q11-q13) in 70% of affected individuals
- Uniparental disomy testing detects 20-25% of cases
- Chromosome analysis detects balanced chromosome rearrangements that interrupt the PWACR in <1% of affected individuals
Prenatal diagnosis – rarely made, but theoretically, amniocentesis or chorionic villus sampling samples could be used

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 and Albright hereditary osteodystrophy

Background

Epidemiology

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

Recurrence Risk

Recurrence risk for parents
- Dependent on specific genetic mechanism causing PWS in prior affected child
- Previous affected child has an imprinting center mutation – up to 50%
- Previous affected child has PWS due to any mechanism other than an imprinting center mutation – <1%

Pathophysiology

15q11-q13 region harbors several genes regulated by genomic imprinting
- Genes are expressed from 1 parental allele – gene is functionally haploid
3 disorders occur from deletion/duplications at this locus – PWS, Angelman syndrome (AS), dup 15q syndrome
- 70% have a deletion on 1 chromosome 15 involving bands 15q11-q13, known as the Prader-Willi-Angelman critical region (PWACR)
- 25% have maternal uniparental disomy of chromosome 15
- <5% have an imprinting center defect

Clinical Presentation

Severe hypotonia and feeding difficulties in infancy
Delayed motor and language milestones (developmental delay)
Behavioral problems
- Temper tantrums, stubbornness, obsessive-compulsive traits
- Autism reported in patients with maternal uniparental disomy
Hypogonadism, cryptorchidism
Short stature, small hands and feet
Facial features – narrow bifrontal diameter, downturned mouth, almond-shaped palpebral fissures
Hyperphagia and morbid obesity (begins between 1 and 6 years)
Complications of obesity are main cause of morbidity and mortality
- Diabetes mellitus
- Obstructive sleep apnea
- Cardiorespiratory insufficiency

ARUP Lab Tests

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.

Angelman Syndrome and Prader-Willi Syndrome by Methylation-Sensitive PCR 2005077
Method: Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring

Recommended Use

Preferred initial diagnostic test for Angelman syndrome (AS) or Prader-Willi syndrome (PWS)

Clinical sensitivity – 78% (Lossie, 2001)

Limitations

Specific molecular mechanism responsible for abnormal methylation results cannot be determined

AS resulting from molecular mechanisms that do not affect methylation patterns will not be identified

Diagnostic errors can occur due to rare sequence variations

Chromosome FISH, Metaphase 2002299
Method: Fluorescence in situ Hybridization

Recommended Use

Fluorescence in situ hybridization (FISH) probes for specific microdeletion/microduplication syndromes must be specified

If no specific syndrome is in question, genomic microarray should be ordered instead of screening multiple loci by FISH

Follow-up for abnormal methylation test for AS

ARUP Constitutional FISH Probes menu

Medical Experts

Lamb, Allen N., PhD, FACMG, Laboratory Section Chief, Cytogenetics and Genomic Microarray, ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Lyon, Elaine, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, Medical Director, Pharmacogenomics at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

References

General References

Buiting K. Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C Semin Med Genet. 2010; 154C(3): 365-76. PubMed

Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012; 14(1): 10-26. PubMed

Chen C, Visootsak J, Dills S, Graham JM. Prader-Willi syndrome: an update and review for the primary pediatrician. Clin Pediatr (Phila). 2007; 46(7): 580-91. PubMed

Driscoll D, Miller J, Schwartz S, Cassidy S. Prader-Willi Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated: Feb 2016; Accessed: Sep 2017]

Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M, speakers contributors at the Second Expert Meeting of the Comprehensive Care of Patients with PWS. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008; 93(11): 4183-97. PubMed

Kalsner L, Chamberlain SJ. Prader-Willi, Angelman, and 15q11-q13 duplication syndromes. Pediatr Clin North Am. 2015; 62(3): 587-606. PubMed

Wattendorf DJ, Muenke M. Prader-Willi syndrome. Am Fam Physician. 2005; 72(5): 827-30. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Procter M, Chou L, Tang W, Jama M, Mao R. Molecular diagnosis of Prader-Willi and Angelman syndromes by methylation-specific melting analysis and methylation-specific multiplex ligation-dependent probe amplification. Clin Chem. 2006; 52(7): 1276-83. PubMed

Testing Algorithms

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Read more about Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Last Update: March 2018

Prader-Willi Syndrome - PWS

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Recurrence Risk

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Prader-Willi Syndrome - PWS. ARUP Consult^©. Retrieved April 17, 2019, from: https://arupconsult.com/content/prader-willi-syndrome

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Prader-Willi Syndrome - PWS

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Recurrence Risk

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

ARUP Websites

ARUP Consult