# 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

* 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.