Handbook of Genetic Counseling/Prader-Willi Syndrome - Prenatal
Prader-Willi Syndrome - Prenatal
Introduction
edit- 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
edit- 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
edit- 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 & Incidence
edit- 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.
- Small deletion in the paternally contributed chromosome 15
- 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
edit- 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
- Language development is delayed
- 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 behavior 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
edit- 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
edit- 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.
- Molecular Genetic Testing
- 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
edit- 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
edit- 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-calorie, 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 characteristics
- 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
- Obesity
- 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
- Obesity
Prenatal Testing
editPsychosocial Issues
edit- 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
edit- 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
Review and summarize major points
editElicit final questions and concerns
editArrange for Follow-up
editReferences
edit- 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
editThe information in this outline was last updated in 2002.