Handbook of Genetic Counseling/Prader-Willi Syndrome-2
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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
- Recurrence risks (<1% for UPD)
Elicit Interim Medical History
- 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.
- 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
- 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.
- 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
- 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.
- 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
- 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
- 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
- Early adrenarche
- 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
- 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.
- 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
- 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
- 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
- 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
- Thick viscous saliva
- 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.
- 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.
- 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
- Exams to monitor strabismus, myopia and hyperopia
- Emphasis placed on good dental hygiene
- Products that increase saliva flow can be used as necessary
- Scoliosis should be monitored and treated as in the general population
- Calcium and vitamin D levels should be assured
- 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
- 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.
- 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.
The information in this outline was last updated in 2002.