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.

Web References

 * www.geneclinics.org