# Handbook of Genetic Counseling/Prader-Willi Syndrome-2

Prader-Willi Syndrome

## Contracting and Introduction

* Establish rapport with small talk and introduce myself
* What concerns do you have that you would like to discuss today?
* Briefly discuss the topics to be covered during the appointment
** Follow up- changes since last visit?
** Prenatal counseling
*** Amnio/CVS
*** Recurrence risks (<1% for UPD)

## Definition

* Prader-Willi syndrome (PWS) is a disorder caused by the inheritance of a paternally derived deletion of the long arm of chromosome 15 and is characterized by abnormalities in physical and mental development.

## Historical significance

* First recognized microdeletion syndrome identified with high-resolution chromosome analysis
* Most common recognized genetic form of obesity
* First recognized human genomic imprinting disorder
* First recognized disorder resulting from uniparental disomy

## Etiology

* Deletion of the long arm of chromosome 15 at q11-q13 (~75% of cases)
** Detectable by high-resolution chromosome analysis or FISH with specific probes
** Paternally derived chromosome has been deleted (maternal genes are inactive due to genomic imprinting)
* Maternal disomy- receiving 2 copies of the maternal 15th chromosome and no paternal copies of the 15th chromosome (~24% of cases)
* Clinical differences exist between deletion patients and those with maternal disomy. Maternal disomy patients are less likely to have typical facial characteristics, slightly higher IQs and milder behavior problems.*
* A defect in the imprinting process occurs due to problems associated with the imprinting center, such as a mutation or deletion resulting in the biparental inheritance and a maternal-only pattern (1% of cases)
* In all cases where there has been a recurrence of Prader-Willi syndrome, there has been an imprinting mutation.

## Molecular Genetics

* The actual genes that cause the phenotypic changes have not been identified.
* Several imprinted and nonimprinted genes have been found to exist in the deletion region (called the PWS/AS critical region).
* A deletion in the nonimprinted P gene, which codes for tyrosinase-positive albinism, is associated with hypopigmentation seen in 33% of patients with PWS.
* The SNRPN is the best described gene likely to cause some of the PWS features
** This ribosome-associated protein functions by controlling gene splicing and may therefore be involved in the control of the synthesis of some proteins
** SNRPN is known to be imprinted in the brain
* SNURF is upstream of SNRPN is a putative imprinting control element for the critical region
* Very small deletions in this gene have been identified in a few cases
* Many other genes have been identified from the critical region, but the function of these genes has yet to be elucidated

## Associated Risks

* Patients with PWS usually have an unremarkable family history
* PWS that is caused by a deletion has a recurrence risk of 1% or less.
* Uniparental disomy is caused by nondisjunction thus the recurrence risk is 1% or less
* When counseling patients with a detected imprinting mutation, a recurrence risk of up to 50% pertains because the mutation is likely dominant and occurred in the paternal grandmother's germ line.

## Incidence

* Approximately 1: 10,000-15,000 live births
* Both sexes and all races are affected
* The majority of affected individuals are the only family member affected

## Diagnostic Criteria

* These criteria were developed before the availability of diagnostic testing and are still valuable in suggesting diagnosis and the need for a diagnostic test.
* Major criteria (1 point each)
** Infantile central hypotonia
** Infantile feeding problems and failure to thrive
** Characteristic facial appearance
** Early-childhood-onset of obesity (2-3 years of age)
** Hypogonadism with genital hypoplasia
** Developmental delay and mild cognitive impairment
** Mild short stature
** Characteristic behavior disorder
* Minor Criteria (1/2 point each)
** Decreased movement and infantile lethargy
** Typical behavior problems
** Sleep apnea
** Short stature
** Hypopigmentation
** Small hands and feet for height and age
** Esotropia, myopia
** Thick, viscous saliva
** Speech articulation defects
** Skin picking
* Supportive criteria (no points)
** High pain threshold
** Decreased vomiting
** Temperature control problems
** Scoliosis
** Early adrenarche
** Osteoporosis
* In children under 3 with 5 points (at least 3 from major criteria) or those above 3 with 8 points (at least 4 from major criteria) a diagnosis should be suspected

## Clinical Features

* Hypotonia
** Prenatal in onset and present in nearly 100% of cases
** Causes decreased fetal movement and abnormal fetal position
** The fetus is often breeched in position at the time of delivery, thus delivery is often via a caesarian section.
** The infant usually has a poor suck reflex and fails to awake to feed leading, in many cases, to failure to thrive
** Infantile lethargy and a weak cry are also associated with hypotonia
** Motor milestones are delayed and average age of sitting is ~12 months and walking at 24 months
** Hypotonia results in a decrease in lean body mass leading to a high ratio of fat to lean body mass in children.
** Hypotonia gradually improves, although the adult with PWS remains mildly hypotonic with decreased muscle tone and bulk
** All newborns with persistant hypotonia are suggested to have PWS testing.
* Developmental delay and intelligence
** Motor milestones are delayed in 90-100% of cases (see above)
** Language development is also delayed
*** Verbal skills are a strength in most patients but..
*** Speech is often poorly articulated, nasal and slurred.
** Cognitive abnormalities are present and most patients are mildly mentally retarded with an IQ of 60s-low 70s
** ~40% have borderline MR or low normal intelligence
** ~20% have moderate MR
** Academic performance is poor for cognitive ability
** Strengths are in reading, long-term memory, and visual-spatial skills
** Weaknesses are in math, sequential processing, and short-term memory
** Patients often have an unusual skill with jigsaw puzzles and word-find puzzles.
* Hypogonadism
** Prenatal in onset and persists throughout life
** At birth it is evident by genital hypoplasia
** Cryptorchidism is present in 90-100% of male patients
** Sexual activity is uncommon in both sexes and fertility is rare (one case reported)
* Early-childhood-onset of obesity
** Significant obesity is not found in young infants
** Onset is usually triggered by hyperphagia between 1-6 years of age, but can occur as early as 6 months
** Hyperphagia is due to a hypothalamic abnormality resulting from lack of satiety
** There is a decreased caloric requirement, related to hypotonia and associated decreased activity
** Food-seeking behavior with hoarding and foraging of food is often common in patients with PWS
** Patients often eat unappealing substances such as garbage, frozen food and pet food
** Patients have decreased vomiting activity
** The obesity is central in location
*** Abdomen
*** Buttocks
*** Thighs
** Obesity is the major cause of morbidity and mortality in PWS and longevity can be nearly normal if obesity is avoided.
** Obesity results in complications such as:
*** Cardiopulmonary compromise
*** Diabetes mellitus type II
*** Hypertension
*** Chronic leg edema
*** Sleep apnea
* Characteristic Facial Features that are present at birth or appear over time for MOST patients:
** Narrow bi-frontal diameter
** Almond-shaped palpebral fissures
** Narrow nasal bridge
** Down-turned mouth with a thin upper lip
* Other characteristic physical findings
** Small narrow hands with a straight ulnar border
** Short broad feet, present by age 10 *African Americans are less likely to have small hands and feet*
** Shoulders are usually sloping
** Hypopigmentation manifests as fairer skin, hair, and eye color and occurs in about 1/3 of patients
** Scoliosis and/or kyphosis are common (about 40-80% of cases)
** Short stature is almost always present by the 2nd half of the 2nd decade for 90-95% of patients due to lack of pubertal growth spurt
** Strabismus is found in 60-70% of cases
* Behavior profile is present in 70-90% of cases
** A characteristic profile becomes evident in early childhood, with temper tantrums, stubbornness, controlling and manipulating behavior, OCD, and difficulty with change in routine
** Lying, stealing, and aggressive behavior are also common.
** These behavioral problems interfere with the quality of life for adults
* Others:
** Thick viscous saliva
*** Predispose to dental caries
*** Can result in articulation problems
** High pain threshold
** Skin picking
** Sleep disturbances, especially daytime sleeping
** Osteoporosis, frequent but poorly studied

## Diagnostic Testing

* Methylation analysis
** PCR test that can detect all three causes of PWS
** All three causes result in the genes for PWS being methylated
** Methylated DNA is cut differently by restriction enzymes than unmethylated DNA
** The differences in the sizes of DNA can be detected
** This test can be used for both prenatal and postnatal testing
* Chromosome analysis using the FISH probe for SNRPN
* High resolution chromosome analysis alone is insufficient due to false positives and false negatives
* Uniparental disomy can be identified using microsatellite repeat sequences from chromosome 15 in the patients and the parents; if none of the variants of these repeats that are present in the father are seen in the child, then all the genetic information from chromosome 15 has been maternally derived.
* The presence of a normal FISH test plus abnormal methylation analysis indicates a probable imprinting center error

## Management and Treatment Options

Intervention and management of PWS can significantly impact the health, functional abilities, and life of patients.
* Infantile FTT-
** Special feeding techniques are required because breast feeding is usually inhibited by the hypotonia
* Short Stature-
** Growth hormone has been shown to increase height and muscle tone
** Good results have been shown for adolescents.
* Development and behavior-
** Closely monitor development and behavior in infancy and toddler-hood.
** Developmental assessments should be conducted on patients and they should have early intervention services as soon as possible.
** Educational intervention should occur throughout school years. Most children require special education classes, speech therapy, and physical/occupational therapies.
** It is important to apply specific and consistent limits at home and school. Most individuals require consistency in daily routines and should be prepared in advance for changes in routine or activities.
** Those with severe behavioral problems may respond to psychotherapy. Medication for treatment of psychiatric problems is often needed.
* Obesity-
** Avoidance of obesity is extremely important, yet very difficult to achieve.
** Close monitoring of weight percentiles and height to weight ratio is critical throughout life
** Those who are extremely obese should have an assessment of glycosylated hemoglobin levels
** Decrease caloric intake, to1000-1200 Kcal/day or less.
** Vitamins and calcium should be taken everyday (100% of daily recommended)
** Keeping food under lock and only keeping healthy low calorie food in the house is critical
** Involve teachers and employers of individuals with PWS in food monitoring
** Regular exercise is extremely important; a program should be initiated as early as possible.
* Hypotonia-
** Physical therapy is appropriate
** Evaluation of hypothyroidism if hypotonia is persistant
* Hypogonadism (endocrine)-
** Administration of hCG may stimulate testicular descent
** Administration of testosterone in males or estrogen in females to improve secondary sex characteristics
* Ophthalmologic-
** Exams to monitor strabismus, myopia and hyperopia
* Dental-
** Emphasis placed on good dental hygiene
** Products that increase saliva flow can be used as necessary
* Musculoskeletal-
** Scoliosis should be monitored and treated as in the general population
** Calcium and vitamin D levels should be assured
* Dermatologic-
** Examination of the skin should occur to monitor the presence of sores from skin picking
** Keep lesions moist and covered
** Behavior modification techniques may be necessary

## Psychosocial Issues

* Parents often must monitor children with PWS 24 hours a day to control symptoms such as obesity; this is draining for the parents.
* Fathers often struggle with guilt, blaming themselves for the occurrence of the syndrome.
* Important for counselors to ask how the parents are coping and how they are handling the situation.

## References

* Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company.
* Allanson JE, Cassidy SB (2001). Management of Genetic Syndromes. New York: Wiley-Liss, Inc.
* Jorde LB, Carey JC, Bamshad MJ, White RL (1999). Medical Genetics. 2nd ed. Philadelphia: Mosby.
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## Web References

* www.geneclinics.org

## Notes

The information in this outline was last updated in 2002.