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Genetic counseling: Prader-Willi Syndrome - Prenatal

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Prader-Willi Syndrome - Prenatal


  • Discuss the reason for referral.
  • Elicit prior knowledge about Prader-Willi syndrome.
  • Elicit prior knowledge about prenatal diagnosis.
  • Assess concerns and set goals for the session.
  • Provide overview of topics for counseling session.

Client & Partner InformationEdit

  • Discuss why it's important to get pregnancy, personal, and family history.
    • Explain that it is a way to identify other potential risk factors
    • Use examples: seizure medication, diabetes, etc.
  • Go over pregnancy history:
    • How has the pregnancy been going?
    • G1P1? Any stillbirths? Spontaneous or elective abortions?
    • Was the pregnancy planned? If so, how long did it take to become pregnant?
    • LMP? EDC?
    • Any bleeding?
    • Any illnesses during the pregnancy?
      • Infection, cold, rash, fever?
    • Any chronic illnesses?
    • Any exposures during the pregnancy?
      • X-rays, smoking, alcohol, recreational drugs?
    • Medications:
      • Currently?
      • Earlier in the pregnancy?
  • Personal background:
    • Occupation?
    • Do you have a religious preference?
    • Psychosocial assessment
      • Financial, insurance concerns?
      • Support system?
    • Information about the father:
      • Name, age, occupation?
      • Any exposures?
      • Any chronic illnesses?

Elicit HistoryEdit

  • Construct pedigree:
    • Abnormal # miscarriages, stillbirths, infant deaths?
    • Previous children with chromosome abnormality, Down syndrome, birth defects, mental retardation?
    • Consanguinity? Ethnicity? Other concerns/risk factors?

What is Prader-Willi Syndrome?Edit

  • A complex, multi-system mental retardation disorder
  • The first recognized microdeletion syndrome identified when high-resolution chromosome analysis was introduced
  • Now known to be one of the most common microdeletion syndromes
  • Also one of the most common recognized genetic forms of obesity
  • Caused by several different genetic alterations of proximal chromosome 15q

Etiology & IncidenceEdit

  • History
    • Prader-Willi syndrome was first described in 1956.
  • The basis of Prader-Willi syndrome
    • Caused by the lack of expression of normally active paternally inherited genes at chromosome 15q11-q13
    • The maternally inherited genes are normally inactive due to genetic imprinting
      • Imprinting is a phenomenon by which some genes are modified in different ways depending on the genederof the parent from whom they were inherited
    • There are 3 ways in which P-W syndrome can be caused.
      • Small deletion in the paternally contributed chromosome 15
        • This is seen in 75% of patients
        • Usually the deletion is 4-Mb or smaller
      • Uniparental disomy 15 (UPD)
        • Inheritance of 2 maternal chromomes 15 but no paternal chromosome 15
      • Defect in the imprinting process
        • Seen in approximately 1% of patients
        • Very small deletion or other abnormality in the imprinting center
        • All studied families in which there has been a recurrence of P-W have had an imprinting mutation.
    • The actual genes whose deficiency that cause the phenotype have not yet been identified
    • One-third of patients with P-W exhibit hypopigmentation due to deletion of a gene associated with tyrosinase-positive albinism
  • Incidence
    • 1 in 10,000 - 15,000
    • Occurs in both sexes and all races
    • Diagnosis is often delayed or missed in many cases

Clinical Features & Natural HistoryEdit

  • Neonatal hypotonia and failure to thrive
    • Hypotonia is prenatal in onset and nearly uniformly present
    • Causes decreased fetal movement, frequent abnormal fetal position, and difficulty at time of delivery
    • State of hypoarousal are associated with poor suck and lack of awakening to feed
    • Hypotonia gradually improves
    • Motor milestones are delayed
      • Average age of sitting is 12 months
      • Average age of walking is 24 months
    • It is recommended that all newborns with persistent hypotonia be tested for P-W
  • Developmental delay and mild cognitive impairment
    • Language development is delayed
      • Speech is often poorly articulated, having a nasal and/or slurred character
    • Most patients are mildly retarded
      • Mean IQ 60s to low 70s
    • Approximately 40% have borderline retardation or low normal intelligence
    • 20% have moderate retardation
  • Characteristic facial appearance
    • Narrow bifrontal diameter
    • Almond-shaped palpebral fissures
    • Narrow nasal bridge
    • Downturned mouth with a thin upper lip
  • Early-childhood-onset obesity
    • Hyperphagia begins generally between ages 2 and 4 leading to significant obesity
    • Hypothalamic abnormality results in lack of satiety
    • There is a decreased caloric requirement likely related to hypotonia and decreased activity
    • Food seeking behaior with hoarding or faraging for food and stealing food or money to buy food are common
    • High threshold for vomiting may complicate binging on spoiled food
    • The obesity is central in distribution, with relative sparing of the distal extremities
    • Obesity is the major cause of morbidity and mortality in P-W syndrome
  • Hypogonadism with genital hypoplasia
    • Hypogonadism is prenatal in onset and persists throughout life
    • Genital hypoplasia is evident at birth
    • Pubertal development is abnormal
    • In both males and females, sexual activity is uncommon and fertility is rare
  • Mild short stature
    • If not apparent in childhood, it is almost always present by the second half of the second decade
    • Average height is 155cm for males and 148cm for females
    • African-Americans tend to be taller
  • Characteristic behavior profile
    • Becomes evident in early childhood
    • Tempor tantrums, stubbornness, controlling and manipulative behavior
    • Obsessive-compulsive characteristics
    • Difficulty with change in routing
    • Lying, stealing, and aggressive behavior
    • True psychosis is evident in young adulthood in approximately 5-10%
  • Sleep disturbances
    • Excessive daytime sleepiness and oxygen desaturation in REM sleep
    • These are common even in the absence of obesity


  • P-W is caused by a lack of expression of the paternally derived PWS/AS region of chromosome 15q11-q13 by one of several genetic mechanisms
  • Deletion of PWS/AS region
    • 70% of patients have P-W syndrome by this genetic mechanism
    • <1% risk to siblings of an affected proband
    • Most of these cases are de novo deletions
    • A small number of cases are due to translocation with a concomitant deltion
    • If a parent has a balanced chromosomal translocation the recurrence risk could be as high as 25%
  • Uniparental disomy
    • 25% of patients have P-W syndrome by this genetic mechanism
    • <1% risk to siblings of an affected proband
  • Imprinting defect
    • <5% of patients have P-W syndrome by this genetic mechanism
    • The risk to siblings of an affected proband is up to 50%
    • A healthy parent can carry this imprinting defect
    • But recurrence risk may be lower because imprinting defects can be de novo mutations
  • Balanced chromosome translocation within 15q11-q13 or abnormality
    • <1% of patients have P-W syndrome by this genetic mechanism
    • All of these cases have been de novo
    • Risk to siblings of an affected proband is <1%
    • If a familial case is detected, the theoretical risk of inheritance of the balanced translocation could be as high as 25%


  • Genetic testing
    • Molecular Genetic Testing
      • Testing for the parent-specific methylation imprint detects over 99% of cases and is highly specific
      • Methylation-specific testing is important to confirm the diagnosis in all children
      • The methylation abnormality can be determined by southern blot hybridization using a methylation-sensitive probe (SNRPN or PW71B) or with parent-specific PCR primers
      • If the methylation pattern is characteristic of maternal inheritance only, then the diagnosis is confirmed
      • DNA methylation testing detects all cases caused by deletions, UPD, and imprinting defects
      • Once the diagnosis is established, further tests are done to classify the mutation
        • Deletions can be detected using FISH analysis
        • UPD can be detected with informative microsatellite markers
        • An imprinting defect is presumed to be present in patients with an abnormality in the parent-specific methylation imprint without evidence of a deletion or UPD
    • Cytogenetic Analysis
      • 1% of patients have a detected chromosomal rearrangement resulting in a deletion of bands 15q11-q13
      • Deletion can be detected using high resolution chromosome studies at the 650 band level and FISH.
  • Clinical diagnosis
    • Consensus diagnostic criteria were developed in 1993
    • Major Criteria
      • Neonatal and infantile hypotonia with poor suck
      • Feeding problems and/or FTT in infancy
      • Onset of rapid weight gain between 1-6 years of age causing central obesity
      • Hyperphagia
      • Characteristic facial features
      • Hypogonadism
        • Genital hypoplasia
        • Incomplete and delayed puberty
        • Infertility
      • Developmental delay or mild to moderate MR or multiple learning disabilities
    • Minor Criteria
      • Decreased fetal movement and infantile lethargy
      • Typical behavior problems
      • Sleep disturbance/sleep apnea
      • Short stature for the family by 15 years of age
      • Hypopigmentation
      • Small hands and feed for height age
      • Narrow hands with straight ulnar border
      • Esotropia, myopia
      • Thick, viscous saliva
      • Speech articulation defects
      • Skin picking
    • Supportive Findings
      • High pain threshold
      • Decreased vomiting
      • Scoliosis and/or kyphosis
      • Early adrenarche
      • Osteoporosis
      • Unusual skill with jigsaw puzzles
      • Normal neuromuscular studies such as muscle biopsy

Differential DiagnosisEdit

  • Hypotonia in infancy
    • Neonatal sepsis
    • CNS depression
    • Congenital myotonic dystrophy
    • Several myopathies and neuropathies
  • Developmental delay/mental retardation, obesity, and hypogonadism
    • Albright hereditary osteodystrophy
    • Bardet-Biedl syndrome
    • Cohen syndrome
    • Borjeson-Forssman-Lehmann syndrome
    • Some patients with Fragile X syndrome
    • Possible 6q or 1p deletions


  • Infancy
    • Special feeding techniques, including special nipples or gavage feeding to assure adequate nutrition
    • Physical therapy may improve muscle strength and encourage achievement of milestones
    • Screening for strabismus should start in infancy
  • Childhood
    • Obesity
      • Monitoring of weight and nutritional counseling are critical
      • Low-calrie, well-balanced diet with regular exercise and close supervision to minimize food stealing should be instituted before the onset of excessive weight gain
      • Energy requirement should rarely exceed 1000 to 1200 Kcal/day
    • Learning disabilities should be evaluated, and educational planning instigated
    • Speech therapy is often needed
    • Growth hormone replacement
      • Normalizes height and increases lean body mass
      • Growth hormone evaluation is recommended if growth rate is reduced or height is less than the 3rd percentile
    • Behavioral disturbances
      • Often follow excessive weight gain
      • Firm limit-setting should be instituted
      • Serotonin re-uptake inhibitors have helped many patients with managing behavior
    • Sex hormone replacement is controversial
      • Produces adequate secondary sexual characteristis
      • Testosterone replacement may play a role in male behavior problems
      • Estrogen replacement may increase risk of stroke and osteoporosis in females
    • Scoliosis screening should be routine
  • Adulthood
    • Obesity
      • The major cause of morbidity and mortality in adults
      • Can cause medical complications
        • Cardiopulmonary compromise
        • Type II diabetes mellitus
        • Thrombophlebitis
        • Chronic edema
      • If obesity is avoided, longevity may be nearly normal
    • Psychiatric and behavioral disturbances may require hospitalization and medication
      • Psychosis
      • Manic-depressive illness
      • Obsessive-compulsive disorder
    • Group homes specifically designated for patients with P-W have been successful

Prenatal TestingEdit

Psychosocial IssuesEdit

  • Uncertainty because symptoms and severity vary widely
    • Uncertainly may make goal-setting and future planning problematic
  • Feelings of isolation, loneliness, and despair.
  • Frustration due to ignorance about the disease.
  • Coping with chronic pain and fatigue
  • Burden of dealing with a chronic, rare, progressive disease
  • Body image and self-esteem issues due to spleen or liver enlargement or growth retardation
  • Guilt about passing on the gene to one's children.
  • Family dynamic changes
    • Stress in the marriage
    • Sibling relationships
    • Family members may feel guilty or resentful
  • Depression and frustration about the requirement for lifelong management.
  • Shock, fear, and denial over the diagnosis.

Offer ResourcesEdit

  • Prader-Willi Syndrome Association
    • (800) 926-4797
  • The Prader-Willi Foundation
    • (800) 253-7993
  • March of Dimes information on Spina Bifida, Amniocentesis, Folic Acid, and Maternal blood screening


Review and summarize major pointsEdit

Elicit final questions and concernsEdit

Arrange for Follow-upEdit


  • National Organization for Rare Disorders
  • Online Mendelian Inheritance in Man
  • Geneclinics GeneReviews
  • Living with Gaucher Disease: A guide for patients, parents, relatives, and friends
    • Brochure copyright 1991, Genzyme Corporation
  • Charrow, J. et al. "Gaucher Disease: Recommendations on Diagnosis, Evaluation, and Monitoring." Archives of Internal Medicine; vol 158, p 1754, September 14, 1998.


The information in this outline was last updated in 2002.

This material has been imported fom the wikibook "Genetic counseling"[] under the GNU Free Documentation License.

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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