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Prader-Willi Syndrome - Initial Diagnosis

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Overview

Individuals with Prader-Willi syndrome (PWS) may be first diagnosed as a newborn, infant, toddler, young child, adolescent or even as an adult. The diagnosis is usually suspected because of clinical findings and is confirmed through genetic testing. The timing of the diagnosis may depend on the severity of the symptoms or access to health care professionals familiar with the diagnosis and it will have an impact on clinical management.

Presentations

The diagnosis or suspected diagnosis is based on clinical findings and confirmed by genetic testing. Clinical findings will vary with age as the course of PWS can be divided into two clinical stages. The first stage presents with profound hypotonia, feeding difficulties and poor weight gain, and developmental delays. The second stage, which begins sometime between 2 and 4, is characterized by the onset of hyperphagia leading to obesity and continued developmental delays.

Diagnostic Criteria

A consensus diagnostic criteria for PWS was developed in 1993 by Holm et al. [Holm: 1993] Revised diagnostic criteria were developed in 2001 by Gynay-Aygun et al. [Gunay-Aygun: 2001] The new criteria are based on the individual's age and clinical presentation:
  • Birth to 2 years:
    • Recognizable facial features, hypotonia with related feeding difficulties and failure to thrive, hypogonadism.
  • 2 to 6 years:
    • Recognizable facial features, hypotonia with gross motor delays, development of hyperphagia and weight gain, typically shorter stature and smaller OFC.
  • 6 to 12 years:
    • Development of unusual behaviors, learning disabilities, and cognitive impairments.
    • Physical features may be more difficult to recognize, hands and feet may become relatively smaller in these years.
    • Excessive eating with central obesity if uncontrolled.
  • 13 years to adulthood:
    • Cognitive impairment, usually mild mental retardation;
    • Excessive eating with central obesity if uncontrolled; and
    • Hypothalamic hypogonadism and or typical behavior problems.

Genetic testing confirms the clinical findings (see Genetic Testing below).

Practice Guidelines

Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M.
Recommendations for the diagnosis and management of Prader-Willi syndrome.
J Clin Endocrinol Metab. 2008;93(11):4183-97. PubMed abstract

Differential Diagnosis

The differential diagnosis of PWS varies depending on the age of the patient. During infancy and the failure to thrive stage, the differential diagnosis includes:
  • neonatal sepsis;
  • central nervous system anomalies;
  • inborn errors of metabolism;
  • microdeletion syndromes such as 22q11.2 and 1p36.3;
  • infantile botulism;
  • congenital myotonic dystrophy; and
  • spinal muscular atrophy.
During childhood and the hyperphagic obesity stage of PWS, the differential diagnosis includes:
  • familial obesity;
  • fragile X syndrome;
  • inborn errors of metabolism;
  • leptin deficiency (very rare);
  • SIM 1 gene mutations;
  • Albright hereditary osteodystrophy;
  • Bardet-Biedl, Alstrom, and Cohen syndromes; and
  • chromosomal abnormalities including 1p36 deletion, 3p25 duplication, and uniparental disomy 14.
See Online Mendelian Inheritance in Man (OMIM) for more information on specific syndromes.

History And Examination

Family History

Not likely to be helpful because the vast majority of cases are sporadic.

Pregnancy/Perinatal History

Ask about fetal movement, which is often limited and of low velocity, consistent with hypotonia. Depressed Apgar scores at birth may occur due to hypotonia. Infants with PWS are typically born at or near term, and often have a slightly low, but not usually abnormal birth weight. Ask about perinatal problems, particularly a history of poor feeding and low tone.

Medical History

Ask about hyperphagia and rumination. Ask about episodes of gastric distention. Does the child exhibit skin picking or other obsessive behaviors? Ask about chronic respiratory infections, reactive airway disease, and sleep problems such as snoring, frequent awakenings from sleep and excessive daytime sleepiness. Individuals may have sleep apnea, obstructive, central, or mxed, and hypoventilation with hypoxia.

Developmental and Educational History

Ask about achievement of developmental milestones and behavior issues. Ask about learning problems and symptoms of hyperactivity. Ask about speech articulation problems.

Physical Exam

General

Look for the characteristic appearance including dolicocephaly, narrow bifrontal diameter, distinctive (almond-shaped) eyes, small up-turned nose, and down-turned corners of the mouth. [Holm: 1993], [Hawkey: 1976], [Loos: 2003]

Growth Parameters

Weight, height, and BMI. Short stature and small hands and feet are present in the majority of individuals with PWS.

HEENT

Screen for strabismus or myopia, sticky saliva, and dental enamel defects.

Musculoskeletal

Check spine for scoliosis and kyphosis.

Neurologic Exam

Look for hypotonia in infants and toddlers.

Testing

Imaging and EEG

Spinal Xrays may pick up scoliosis and kyphosis not obvious on clinical exam.

Genetic Testing

Genetic testing is complex and recommended approaches to genetic testing for children suspected of having PWS vary among specialists - consulting pediatric genetics in your area is advised. If the diagnosis is confirmed, identification of the genetic subtype is important to guide clinical management and to advise regarding recurrence risks.

To confirm clinical findings of PWS, some clinicians begin with methylation analysis of the PWS critical region on CH 15q11 (99% sensitive).
  • If this test is positive, cytogenetic analysis with FISH (fluorescent in situ hybridization, see Explanation of FISH (genome.gov)) using the SNRPN probes will identify the 15q11-q13 deletion seen in the majority of subjects (70-75%);
  • If the methylation test is negative, PWS is unlikely to be the diagnosis and other diagnoses should be considered. If PWS is still strongly suspected, targeted sequence analysis may be available at a small number of reference labs (see PWS genetic testing (GeneTests)).

DNA methylation is 99% accurate but will not pick up small deletions, maternal disomy 15, or an imprinting defect.
Some clinicians prefer to start with a cytogenetic analysis with FISH using the SNRPN probes to identify the typical 15q11-q13 deletion. If neither a deletion of chromosome 15 or any other cytogenetic abnormality is identified, DNA methylation testing is then performed. If the methylation study is positive for PWS, then testing for other subtypes (maternal disomy or imprinting defect) should be pursued.

See Prader-Willi syndrome genetics for more information, PWS genetic testing (GeneTests) for laboratories that offer testing for PWS, and Subspecialist Evaluations below for consultation resources.

Subspecialist Evaluations

It is critical that the diagnosis be made as early as possible, since early management of their special needs can improve outcomes for individuals with PWS.

Pediatric Medical Genetics (see Services below for relevant providers)

To perform or guide the genetic evaluation and diagnosis of children suspected of having PWS and consideration of other conditions if the diagnosis is not confirmed; provide genetic counseling for families.

Resources

Information & Support

For Professionals

Prader-Willi Syndrome Review (GeneReviews)
Detailed overview of Prader-Willi syndrome, testing, genetics, resources, reviews, and research; hosted by NCBI (National Center for Biotechnology Information).

Prader-Willi syndrome (OMIM)
Extensive review of the literature, including clinical features and gene therapy; from the Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

For Parents and Patients

Support

Prader-Willi Syndrome Association (USA)
A strong national organization of families and professionals, PSWA (USA) offers a toll-free helpline, a bimonthly newsletter and numerous publications about PWS, a World-Wide-Web page, and annual family conference and scientific meeting, and chapters throughout the country to provide local family support and advocacy.

General

Prader-Willi Syndrome Association (USA)
A strong national organization of families and professionals, PSWA (USA) offers a toll-free helpline, a bimonthly newsletter and numerous publications about PWS, a World-Wide-Web page, and annual family conference and scientific meeting, and chapters throughout the country to provide local family support and advocacy.

Prader-Willi syndrome (Genetics Home Reference)
Information about PWS from the National Library of Medicine's Genetics Home Reference site.

Practice Guidelines

Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M.
Recommendations for the diagnosis and management of Prader-Willi syndrome.
J Clin Endocrinol Metab. 2008;93(11):4183-97. PubMed abstract
Written by an open international multidisciplinary expert group that met in October 2006 in France with 37 invited speakers/session chairs and 85 additional participants. The guidelines were developed from published evidence-based data, unpublished data from personal experience, previous National and International PWS Conferences and Prader-Willi Syndrome Association (USA) Clinical Advisory Groups.

Services

Pediatric Medical Genetics

Medical Genetics, more info...
100 North Mario Capecchi Dr
Salt Lake City, UT 84132
Phone: 801-581-8943
Fax: 801-585-7252
http://www.ped.med.utah.edu/divisions/genetics.cfm

See all Pediatric Medical Genetics services providers (3) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors

Author: Judy L. Welch RN, BSN, 8/2008
Contributing Author: Merlin G. Butler MD, PHD, 8/2008
Reviewing Authors: Alan Rope MD, 11/2008
Kyna Byerly MS, CGC, 8/2008
Content Last Updated: 12/2008

Funding/Support

This module was developed in partnership with the Heartland Regional Genetics and Newborn Screening Collaborative Heartland Regional Genetics and Newborn Screening Collaborative and was funded in part by a Health Resources Services Administration (HRSA) cooperative agreement (U22MC03962).

We appreciate the Prader-Willi Syndrome Association (USA) for their outstanding support of individuals with PWS and their families and for the information they provide on their website – www.pwsausa.org – to which we have provided several links within the Diagnosis Module.

Page Bibliography

Gunay-Aygun M, Schwartz S, Heeger S, O'Riordan MA, Cassidy SB.
The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria.
Pediatrics. 2001;108(5):E92. PubMed abstract / Full Text

Hawkey CJ, Smithies A.
The Prader-Willi syndrome with a 15/15 translocation. Case report and review of the literature.
J Med Genet. 1976;13(2):152-7. PubMed abstract / Full Text
Includes images of facial and genital characteristics.

Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F.
Prader-Willi syndrome: consensus diagnostic criteria.
Pediatrics. 1993;91(2):398-402. PubMed abstract / Full Text

Loos HS, Wieczorek D, Würtz RP, von der Malsburg C, Horsthemke B.
Computer-based recognition of dysmorphic faces.
Eur J Hum Genet. 2003;11(8):555-60. PubMed abstract / Full Text
Includes images of facial characteristics.