Handbook of Genetic Counseling/Prader-Willi Syndrome - Prenatal

Prader-Willi Syndrome - Prenatal

Introduction

• 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 Information

• 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 History

• 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?

• 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 & Incidence

• 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 History

• 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

Inheritance

• 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%

Diagnosis

• 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 Diagnosis

• 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

Management

• 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

Psychosocial Issues

• 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 Resources

• Prader-Willi Syndrome Association
  • (800) 926-4797
  • www.pwsausa.org
• The Prader-Willi Foundation
  • (800) 253-7993
  • PWSAUSA@aol.com
• March of Dimes information on Spina Bifida, Amniocentesis, Folic Acid, and Maternal blood screening
  • www.modimes.org

1-888-MODIMES

References

• 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.

Notes

The information in this outline was last updated in 2002.