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.