Last modified on 5 May 2009, at 02:11

Handbook of Genetic Counseling/Prader-Willi Syndrome-2

Prader-Willi Syndrome

Contracting and IntroductionEdit

  • 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)

Elicit Interim Medical HistoryEdit

DefinitionEdit

  • 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 significanceEdit

  • 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

EtiologyEdit

  • 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 GeneticsEdit

  • 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 RisksEdit

  • 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.

IncidenceEdit

  • 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 CriteriaEdit

  • 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 FeaturesEdit

  • 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 TestingEdit

  • 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 OptionsEdit

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 IssuesEdit

  • 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.

ReferencesEdit

  • 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 ReferencesEdit

  • www.geneclinics.org

NotesEdit

The information in this outline was last updated in 2002.