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 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

 * 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-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
 * 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
1-888-MODIMES
 * 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