Jennifer Bass, MD
Andriana Groisman-Perelstein, MD
Deaprtment of PediatricsJacobi Medical Center
Albert Einstein College of Medicine
PRETEST
Q1. All of the following are typical findings for a child with PWS except:
a. Infantile hypotonia
b. Short stature
c. Developmental delay
d. Hypogonadism
e. Obesity that begins in early infancy
Q2. Which of the following is true regarding the genetic basis of PWS?
a. Chromosome analysis easily can make the diagnosis of PWS
b. PWS is cause by an absence of the maternally derived portion of chromosome 15.
c. Methylation analysis is the most efficient and cost-effective screening test.
d. Individuals with PWS may pass it on to their offspring.
Q3. Which of the following are recommended for management of a school age child with PWS?
a. Use food as a reward or punishment.
b. A diet with more daily calories than other children of similar age.
c. 30 minutes minimum for exercise daily.
d. Ignore bad behavior.
e. Allow a responsible child to control his or her own food intake.
Q4. What medication helps most children with PWS?
a. Growth hormone
b. Respirdol
c. Glucophage
d. Orlistat
e. Ipecac
OBJECTIVES:
At the conclusion of this section, residents will be able to:
1. Identify obesity syndromes associated with short stature
2. Describe the clinical phenotype and typical history of a child with Prader-Willi Syndrome. (PWS)
3. Know the molecular genetic basis for PWS and how to make the diagnosis.
4. Describe the salient maladaptive features.
5. Use a multidisciplinary management approach.
6. Address issues related to weight control specific for children with PWS.
7. Appreciate potential medical issues for children with PWS.
FACILITATOR PREPARATION:
For this section, the facilitator should review Pediatric Nutrition Notes and related topics in the Teacher's Guide including Obesity and Adult onset Diabetes mellitus [hyperlinks]. The PWS Healthcare Guidelines for Individuals with Prader-Willi Syndrome, available at www.pwsausa.org/postion/HCGuide/HCG.htm, provide a comprehensive over view. See also review articles from Couper and Nativio in reference sections. Introduction
Prader-Willi Syndrome is one of the most common genetic etiologies for obesity with short stature. In this case study, the clinical phenotype will be described with the typical clinical course. Diagnosis and treatment will be reviewed as well as common co-morbidities and management considerations.
A Case Study
George K. is a 2 year-old boy that comes to your office for the first time. The family recently moved from another state so his parents bring a copy of his medical record for you to review. George's parent's main complaints are his insatiable appetite and his increased behavior problems.
His family history is unremarkable but George's past medical history is long and full of worrisome findings. In the prenatal period, there were poor fetal movements and during the delivery a cesarean section was required for failure to progress.
He was a small baby who was difficult to feed (not succeeding with breastfeeding or bottle), hypotonic, with poor arousal and week cry. He was admitted at two months of age with diagnosis of Failure to Thrive and tube fed for 4 weeks. At that time all routine labs including a chromosomal analysis and a brain MRI had normal results. With time, his tone improved and he slowly was able to bottle-feed. The parents were very pleased when he began to gain weight around his 9 months of age. By that time he was referred to an Early Intervention program and started with OT/PT regularly.
He sat at 12 months and walked at 26 months. His speech/language was also noted to be delayed so speech therapy was indicated. By 2 years of age, George began to eat excessively and started gaining a lot of weight. At present, his weight is _17___ kg (>95%ile), height of 86 cm___ (50%ile) with a BMI of _23___ (>95th %ile). A diet. history shows that he takes 5 8 oz. bottles or cups of milk, 4 or 5 8 oz bottles or cups of juice, a varied diet containing all food groups as well as cookies and "chips" each day. Both parents are overweight.
Q1. What is your preliminary differential diagnosis for George?
George requires a comprehensive evaluation. While PWS would be on your list because of the early history of hypotonia, developmental delay, and failure to thrive, the history so far would include exogenous obesity associated with a hereditary risk and inappropriate feeding. Endocrine (thyroid and growth hormone deficiencies) and genetic etiologies should be considered.
The Case Study continues
You begin your plan for evaluation, but the family leaves town and does not return for two years. George is now 4 years of age. By now his parents state that food restriction is becoming a challenge and his food seeking behavior is increasingly difficult to manage both at home and at school. George was placed in a special education class because he has learning disabilities, speech delay and behavior problems. However, he still struggles especially with the change in schools.
On first impression, George is a pleasant boy. While you are talking to his parents, he is either looking into his mother's purse or trying to open your desk drawers. He happily engages in playing with the toys you provide, but on and off, he stops to pick at a scab on his right arm.
On Physical Examinationhis BMI is 26 kg/m2 with a weight of 22 kg_(95%ile) and height of 91.5 cm(3%ile). He has a narrow forehead, is short and centrally obese with small and slender hands and feet. The rest of his physical exam is only relevant for a small penis and undescended testis.
Now, the short stature, however, triggers a concern for concern for an "obesity syndrome."
Weight drives height [hyperlink to obesity]. With exogenous obesity an increase in body fat triggers insulin secretion. Insulin is the body's principle anabolic hormone.. While these insulin levels may not be sufficient to maintain blood sugar levels in the normal range, they do promote linear growth in childhood. Early closure of epiphysis, however, results in relatively shortened stature as adolescents and adults.
Children with "obesity syndromes," however, remain short through early childhood. The primary causes are endocrine and are associated with production or reception deficits. Thyroid and growth hormone function abnormalities are the principal causes.
TEACHING CAPTION: Obesity associated with short stature is a warning of metabolic, genetic or endocrine abnormality
Q2. What clinical findings make you suspect George has Prader-Willi Syndrome?
George has the typical history of infantile hypotonia and feeding difficulty with the associated Failure to Thrive (FTT) followed by hyperphagia by age 2 years. He also has global developmental delays, cognitive impairment, behavior problems, and on physical exam has the characteristic physical finding do Prader Willi Syndrome: central obesity,short stature, narrow forehead, small hand and feet, and hypogonadism.
FIGURE 1: A child with PWS
TEACHING CAPTION: Note the physical features of PWS. These should be in the context of a characteristic history.
Q3. What are the criteria for diagnosis of PWS?
The Table below shows the major and minor criteria for identifying PWS.
TEACHING CAPTION: PWS children are not likely to have all these characteristics.
The criteria are scored as follows:
* Major criteria are one point each.
* Minor criteria are ½ point each.
Children 3 years or younger require 5 points for a diagnosis of PWS, 4 of which should come from the major group.
Older children (over 3 years of age) require a total score of 8 with 5 points from major criteria.
Q4. What genetic testing is indicated in this patient?
DNA methylation analysis is the definitive test for PWS. Fish will allow the identification of microdeletions that are not detectable otherwise.
Q5. What is the incidence and the cause of PWS?
PWS is an uncommon non-inherited genetic disorder of deletion of chromosome 15 affecting all races and both sexes with a prevalence of approximately 1:15,000. Even though is considered a rare disorder, PWS is the most common genetic cause of obesity that has been identified.
The most common cause of PWS is the deletion of the long arm of the paternally contributed chromosome 15 (q11-q13) and the maternal inactivation of the same region of chromosome. (65%-75% of cases) Uniparental disomy occurs when both chromosome15s are maternally derived and inactive, so there is no active genetic material.(20%-25% of cases). The reverse maternal/paternal inactivation of 15q11-13 is associated with the Engelmann Syndrome.
Persons with PWS are sterile so the syndrome cannot be transmitted to offspring. There can be a recurrence risk for other children in the same family if the cause was an imprinting mutation on an intact paternal chromosome or a translocation.
Q6. What has been thought to be the cause of the appetite disorder in patients with PWS?
Hypothalamic dysfunction probably causes the characteristic appetite/satiety disorder in PWS.
Compulsive eating and obsession with food begin usually between ages 2-4, though may start later.
Ghrelin, a hormone secreted by the stomach, is elevated in individuals with PWS. Ghrelin induces adiposity in rodents by increasing food intake and decreasing fat utilization and is a physiologic regulator of appetite in humans. High levels of ghrelin may be responsible for the hyperphagia in PWS. The success of bypass surgery in adults has been associated with a limitation of ghrelin. No studies have been made of children with PWS having bypass surgery. [hyperlink to obesity]
The Case continues
George's family realizes that he is overweight at this point, but they do not understand why. They tell you that he is always looking for food even at odd times and in the most unusual places, and he seems to gain weight rapidly but he doesn't seem to grow at the same pace that his sister. The family wants to know why it is so hard for George to control his weight and what they can do to help.
Q7. What are the major weight management challenges for George and other children with PWS?
In addition to the excessive appetite, patients with PWS, have a decreased calorie utilization (typically 1,000-1200 kcal per day) due to a diminish muscle mass and inactivity. No appetite suppressant has worked consistently for individuals with PWS, although SSRIs have been most effective at times.
Management of PWS is not easy and differs with age and severity of the disease. Behavior management should focus on prevention, planning and anticipation. Weight management should be individualized.
Many parents have to install locks on their cupboards and refrigerator at home. Some children may steal or hoard food, and some may resort to eating nonfood items. It has been said that the hand of a person with PWS is quicker than your eye.
Table 3. List of "Do's" and "Don't's" in the care of children with PWS.
Teaching Caption: Parental control is essential in the behavioral management of children with PWS.
Q8. What kind of diet would you recommend for George?
Fewer calories are needed to maintain normal growth and activity in children with PWS than normal children. Therefore a balanced, low calorie diet with vitamin and calcium supplementation is recommended. Regular weigh-ins and a periodic diet review are usually needed. The stoplight diet may be a useful modality. Green foods are very low-calorie, have high nutritional value, and may be eaten without restriction. Yellow foods are of average nutritional value and must be limited and closely monitored with appropriate portion sizes. Red foods are high in fat and sugar and must be mostly avoided or consumed infrequently in very limited quantities.
Q9. What is a Prader-Willi Food Pyramid?
The modified Prader-Willi Food Pyramid has been designed by the Children's Institute of Pittsburgh (TRI) and may not be appropriate for young children or those on growth hormone therapy. [Compare with suggestions in Nutrition Notes - hyperlink] Changes to the USDA's Food Guide Pyramid were made in order to reduce the total calorie level to 800 -1200 daily. The baseline has been changed so vegetables are on the lowest level, 6-8 servings, instead of grains. It is important to increase servings of low-calorie vegetables and decrease servings from the grains group (3-5), protein group (1-2), and dairy group (2). Children with PWS have a definite preference for high-carbohydrate foods over obese children without PWS.
Figure 2: The Prader-Willi Food Pyramid
Teaching Caption: Note the similarities of the prader-willi food pyramid [top] and the home plate pyramid [bottom] shown in Pediatric Nutrition Notes and in Appendix
Q10. Describe other behavior management interventions needed to provide an adequate control to George's diet?
The family should provide regularly timed meals and low calorie snacks at specific times so that George's hunger does not get out of control. They should add nonfattening items to his meals to fill up his plate, and they may want to use smaller plates and cups. They should teach George to use utensils at a meal and slow down, and to stay until the meal is finished without additional food. George's parents probably will not be able to reason with him, but they do need to be consistent and set limits.
George's parents will constantly have to monitor and restrict his food. The psychological toll on the family will be enormous, and you may need to refer them to social services or support groups if possible.
Q11. What is the importance of providing intervention strategies to enhance physical activity in patients with PWS?
Energy expenditure plays an important role in the development of obesity and is closely related to fat-free mass. Increasing the activity level improves local body composition, increases physical capacity and improves metabolic conditions.
Regular exercise is essential; George's parents should make sure he has regularly scheduled times when he is involved in physical activity. Other psychomotor activities, like music and dance, are also recommended and may help with social skills and communication.
Q12. What is the importance of Growth Homone therapy for a child with PWS?
Many children have short stature and slow growth. Growth charts specific for PWS should be consulted and testing for growth hormone deficiency may be appropriate. Growth hormone therapy is now approved for PWS. The main goal of GH therapy is improvement in body composition. This may be started as early as 2 years of age. Referral to an endocrinologist is recommended early. [see Carrel]
Q13. What are other major medical issues you need to address as this child's pediatrician?
SUMMARY
Prader-Willi Syndrome is a genetic disorder associated with short stature obesity. Individuals may have hypotonia and failure to thrive during infancy, but develop obesity by the age of 6 years with excessive appetite and compulsive eating. The etiology is usually a deletion on chromosome 15, and there is a hypothalamic dysfunction that causes the impaired appetite and satiety. Individuals also have a decreased energy expenditure and caloric utilization. Diet must be carefully controlled, and exercise is an essential component to the treatment. Growth hormone therapy is now an important adjunct in improving body composition from an early age. There are a variety of medical and psychosocial issues related to PWS, and the management is best accomplished with a multidisciplinary team.
POST-TEST
Q1. All of the following are typical findings for a child with PWS except:
a. Infantile hypotonia
b. Short stature
c. Developmental delay
d. Hypogonadism
e. Obesity that begins in early infancy
answer=b
Q2. Which one of the following support the finding of PWS?
a. Low pain threshold
b. Increased vomiting
c. Sleep disturbances
d. Advanced language skills
answer=c
Q3. Which of the following is true regarding the genetic basis of PWS?
a. Chromosome analysis easily can make the diagnosis of PWS
b. PWS is cause by an absence of the maternally derived portion of chromosome 15.
c. Methylation analysis is the most efficient and cost-effective screening test.
d. Individuals with PWS may pass it on to their offspring.
answer=c
Q4. What may cause the appetite disorder in patients with PWS?
a. Leptin
b. Ghrelin
c. Cortisol
d. Lipase
answer=b
Q5. Which of the following are recommended for management of a school age child with PSW?
a. Use food as a reward or punishment.
b. A diet with more daily calories than other children of similar age
c. 30 minutes minimum for exercise daily
d. Ignore bad behavior.
e. Allow a responsible child to control his or her own food intake.
answer=c
Q6. Which of these strategies is recommended for dealing with a child with PWS?
a. Try to keep meal timing unpredictable
b. Use large plates and cups.
c. Allow the child to eventually control his own food intake.
d. Keep food locked up and out of sight
answer=d
Q7. What medication helps most children with PWS?
a. Growth hormone
b. Respirdol
c. Glucophage
d. Orlistat
e. Ipecac
answer=a
Q8. What is the main goal of growth hormone therapy?
a. Improvement of obsessive compulsive behavior
b. Improvement in body composition
c. Decreasing hunger
answer=b
REFERENCES
Bekx MT, Carrel AL, Shriver TC, Li Z, Allen DB. Decreased energy expenditure is caused by abnormal body composition in infants with Prader-Willi Syndrome. Journal of Pediatrics 2003; 143 (3): 372-376.
Carrel AL, Myers SE, Whitman BY, and Allen DB. Benefits of Long-Term GH Therapy in Prader -Willi Syndrome: A 4-Year study. Journal of Clinical Endocrinology and Metabolism 2002; 87(4): 1581-1585.
Couper RTL. Review Article: Prader-Willi syndrome. Journal of Paediatric Child Health 1999; 35: 331-334.
Delparigi A, Tschop M, Heiman ML, Salbe AD, Vozarova B, Sell SM, Bunt JC, and Tantanni PA. High Circulating Ghrelin: A Potential Cause for Hyperphagia and Obesity in Prader-Willi Syndrome. Journal of Clinical Endocrinology and Metabolism 2002; 87(12): 5461-5464.
Eiholzer U, Nordmann Y, L'allemand D, Schlumpf M, Schmid S, Kromeyer-Hauschild K. Improving body composition and physical activity in Prader-Willi Syndrome. Journal of Pediatrics 2003; 142(1): 73-78.
Fieldstone A, Zipf WB, Schwartz HC, and Berntson GG. Food preferences in Prader-Willi syndrome, normal weight and obese controls. International Journal of Obesity 1997; 21: 1046-1052.
Goldberg DL, Garrett CL, Van Riper Cm Warzak WJ. Coping with Prader-Willi syndrome. Journal of the American Dietetic Association 2002; 102(4): 537-542.
Goldsone AP, Thomas EL, Brynes AE, Bell JD, Frost G, Saeed N, Hajnal JV, Howard JK, Holland A, Bloom SR. Visceral Adipose Tissue and Metabolic Complications of Obesity are Reduced in Prader-Willi Syndrome in Female Adults: Evidence for Novel Influences on Body Fat Distribution. Journal of Clinical Endocrinology and Metabolism 2001; 86(9): pages 4330-4338.
Hassink, S. Problems in childhood obesity. Primary Care; Clinics in Office Practice 2003; 30(2): 357-374.
Levine MD, Carey WB, Cracker AC. Developmental - Behavior Pediatrics. WB Saunders Company, Philadelphia, PA. 3rd Edition. 1999
Nativio DM. The Genetics, Diagnosis, and Management of Prader-Willi Syndrome. Journal of Pediatric Health Care 2002; 16 (6): 298-303.
www.pwsausa.org
ANNOTATED PRETEST ANSWERS
A1. E; While morbid obesity is the most obvious and most life threatening characteristic of PWS, in fact, it may not begin until late infancy or even in early childhood. The hypotonicity and failure to thrive found in these children cause parents to worry that they will not get enough food. They are characteristically developmentally delayed and may have hypogonadism and delayed sexual development.
A2. C; Currently, methylation analysis is the most efficient and cost-effective screening test. The actual appearance of the chromosome may not be aberrant. Angelman's "Happy puppet" syndrome is seen with maternal transmission of the syndrome. Adults with PWS are sexually undeveloped and unlikely if not actually unable to reproduce.
A3. C; Accuracies is essential. The first law of thermodynamics [the conservation of energy] applies to all of us whatever the genetic or hormonal impetus for weight gain. Moreover, children and adults with PDS need limit setting with respect to caloric intake and behavior.
A4. A; Children with PDS seem to benefit from use of growth hormone as the disorder affects pitutitary hypothalamic axis function and disrupts growth. Achieving a more normal stature, with control of the weight gain, decreases the BMI. While there are severe emotional difficulties found in these children, the primary care does not require agents affecting emotional state, nor are the medications used in treating diabetes mellitus appropriate a primary treatment for children with PWS. One does not treat obesity with agents associated with eating disorders such as ipecac.
