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Increased awareness, earlier detection bring relief to challenges of Prader-Willi syndrome
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Prader-Willi syndrome is a complex disease to manage, and careful consideration of its unique clinical features is essential. Recently, the American Academy of Pediatrics released guidelines on the health supervision of children with Prader- Willi syndrome to help families and health care professionals gain control of the treatment of this disorder.
Current estimates suggest that the syndrome affects one in 10,000 to one in 15,000 live births. It is primarily characterized by insatiable appetite and excessive weight gain, although the condition can have much more serious implications. Premature death from obesity-related comorbidities, including chronic obstructive sleep apnea and cardiac pulmonary problems, is not uncommon, and other aspects of the disease, including hypotonia, hypogonadism, short stature, cognitive impairment and behavioral problems, severely complicate development. Moreover, Prader-Willi syndrome contributes to a whole host of endocrine disorders, such as diabetes and hypothyroidism. Despite these issues, endocrinologists are optimistic.
Jennifer Miller, MD, from the University of Florida, is a leading expert in research and management of Prader-Willi syndrome.
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“Unfortunately, what people read about are the classic textbook cases where every characteristic is portrayed as the most severe possible,” Andrea M. Haqq, MD, MHS, associate professor of pediatrics at the University of Alberta in Canada, told Endocrine Today. “It is important to recognize that there is variability to all these characteristics.”
Improvements in diagnostic tools, life expectancy, treatments and increased awareness of the condition also top physicians’ lists of reasons to remain hopeful.
“The average age of diagnosis has gone down from 8 years in the 1990s to 1.2 months now. Physicians are more aware of Prader-Willi syndrome and are looking for it more. Additionally, because we know the natural history of the disease, we can prevent children with Prader-Willi syndrome from becoming obese, and our new knowledge also allows us to treat patients earlier than before,” Jennifer Miller, MD, assistant professor in the department of pediatric endocrinology at the University of Florida, said in an interview.
To gain insight into the management of Prader-Willi syndrome, Endocrine Today interviewed pediatric endocrinologists about major issues associated with the disease, advances in the field and how best to approach this complicated condition.
Enhanced diagnosis
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According to Shawn E. McCandless, MD, director of the Center for Human Genetics at University Hospitals Case Medical Center in Cleveland, identifying Prader-Willi syndrome as a genetic disorder and discovering the mechanisms through which the disease occurs are particularly significant breakthroughs.
Deletion of genes on the paternal copy of chromosome 15 is the most common cause, McCandless told Endocrine Today, whereas the second most common cause, uniparental disomy, occurs when both of a child’s copies of the chromosome are inherited from the mother. The third and much rarer cause, an imprinting defect, indicates an inability to activate genes on chromosome 15, which earned Prader-Willi syndrome the distinction of being the first disorder associated with imprinting in humans.
Research on the syndrome’s genetic triggers has also honed diagnostic tools. Previously, physicians delayed diagnosis until classic symptoms emerged or they utilized tests that identified only about 70% of children with the syndrome. Now, a simple assay that examines methylation patterns that confirms diagnosis, and DNA tests have the ability to identify 100% of cases at birth. A subsequent test determines the genetic cause.
“The reason to perform the second step is twofold,” McCandless said. “First, children with uniparental disomy may have an increased risk for autism spectrum problems and mental illness. Second, deletion and uniparental disomy are not likely to happen again, but the 2% to 3% that are due to imprinting defects may have as high as a 50% chance of the disease reoccurring in future pregnancies.”
From feeding tubes to food-seeking
Marked by extremes, patients with Prader-Willi syndrome move from one end of the nutritional spectrum to the other in the span of a few years. As newborns, they struggle with weight gain and poor feeding but eventually develop hyperphagia and excessive weight gain in early childhood. This transition, however, is gradual, Miller said.
During the neonatal period, the infant enters phase 1a. He or she displays a decreased interest in food, cannot suck or swallow well and may require assisted feeding via nasogastric intubation or a gastrostomy tube. At about 9 months, phase 1b begins, and growth and appetite normalize. Then, between 18 months and 3 years, children reach phase 2a — a period marked by weight gain without a change in calories.
“Past literature would say that these children have no appetite, and then they develop increased appetite leading to obesity. That’s wrong,” Miller said. “What we have found is that it’s actually weight gain before the appetite increases, so that’s important for parents and endocrinologists to know.”
During phase 2b, which occurs at about age 5 years, interest in food intensifies, yet appetite is not insatiable until children enter phase 3 at approximately 8 to 9 years. Occasionally, in adulthood, some but not all will reach phase 4, at which point the appetite lessens somewhat, according to Miller.
“We don’t exactly know yet [what causes this change in appetite and weight gain]. We think that metabolism probably slows down and changes as children hit that 18-month age point,” Miller said.
Slower gastric motility, changes in the gut’s bacterial overgrowth and neurological changes in the satiety pathways may also be contributors, she said.
Tight metabolic management
Obesity is the most troublesome health issue related to Prader-Willi syndrome, and it often worsens or causes many of the disease’s serious comorbidities, such as hypertension and sleep apnea. Insatiable appetite accounts for a considerable portion of this obesity, but body composition is also a factor.
Children with Prader-Willi syndrome have less muscle mass and more fat mass than their peers, according to McCandless. Consequently, they have lower resting energy expenditure than children of comparable weight.
“These kids have sort of a double whammy,” he said. “They need fewer calories, but they feel hungry all of the time.”
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Prader-Willi syndrome is also associated with a distinctive metabolic profile, according to Haqq. The patients are more insulin-sensitive, have lower fasting insulin and lower measures of insulin resistance, as well as higher amounts of adiponectin. She also said these children, including a subset of infants who have not yet developed hyperphagia or obesity, have higher ghrelin levels, which may be critical for the pathogenesis of weight gain in these children.
Many endocrinologists said the odds are stacked against children with Prader-Willi syndrome in regards to weight management, but fighting hyperphagia and obesity is feasible.
“A mainstay of any sort of treatment definitely needs to include nutrition and exercise, and pediatric endocrinologists can really help to reinforce how important those are as part of their treatment,” Aaron L. Carrel, MD, associate professor of pediatrics at the University of Wisconsin, told Endocrine Today.
Regarding nutrition management, Miller highlighted the importance of meeting with a dietitian to establish a proper plan for both patients and their families. For example, a “traffic-light diet,” which classifies foods as red, yellow or green, depending on what can or cannot be consumed and in what quantities, has been effective for some families, she said.
Moris Angulo, MD, director of medical genetics and associate director of pediatric endocrinology at Winthrop-University Hospital in Mineola, N.Y., said he advocates individualized therapy and generally recommends 8 kcal/cm of height daily for weight loss and 10 kcal/cm of height daily for weight maintenance.
Further, to fight food-seeking behaviors, the American Academy of Pediatrics (AAP) guidelines, which are published in Pediatrics, recommend limiting children’s exposures to food, as well as instilling confidence that they will receive their next meal by strictly maintaining mealtime routines.
Outlining appropriate caloric intake at various stages in the child’s life through parent education is also important, according to the guidelines. Some parents, knowing the natural history of the disease, will make the mistake of restricting calories too early in life.
“We try to balance diet very carefully to make sure these children are getting enough calories so that their development is normal but not so much that they become obese,” Miller said. “It’s like walking a tightrope.”
Progress, problems in GH use
By examining the many aspects of Prader-Willi syndrome related to growth hormone deficiency, including short stature and abnormal body composition, researchers and physicians have been able to find the first FDA-approved treatment for the disease: GH.
Although children with the disease benefit from the significant improvements in lean muscle mass, bone density, final height, strength and agility conferred by GH, uncertainty exists about whether to begin treatment soon after diagnosis or delay until the child displays reduced growth velocity after 2 years of age, as indicated by the FDA.
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Several studies have demonstrated considerable advantages of early initiation of GH treatment. For instance, one study by Carrel and colleagues published in The Journal of Clinical Endocrinology & Metabolism in 2010 associated GH with better motor milestones when initiated during infancy.
“Some people might feel like we should wait until growth itself is a problem, but others might say, ‘If the real goal of therapy is not growth but other parameters, such as body composition, energy expenditures and motor skills, maybe we don’t need to wait that long,’” Carrel said.
The AAP guidelines acknowledge these benefits and said clinical experience suggests that treatment can begin as early as 2 to 3 months of age. However, the guidelines also include recommendations for parents to discuss the decision thoroughly with their pediatric endocrinologists and initiate treatment after they feel comfortable.
Some physicians are also cautious about GH use in general due to data linking the treatment to elevated risks for scoliosis and respiratory problems. However, Angulo said prevalence and progression of scoliosis remain the same among treated and untreated children, adding that respiratory issues, such as sleep apnea, are also already common in these children.
Further, because the AAP recommends regular screening for scoliosis and routine sleep studies, physicians are constantly monitoring the potential for adverse events and would discontinue treatment if problems arise, Angulo said.
Before the FDA approved GH for use in children with Prader-Willi syndrome in 2000, aggressive weight management strategies were all that physicians had at their disposal. To date, it remains the only approved treatment for the disease. Researchers are currently investigating neuroactive drugs’ potential for curbing appetite, but these studies are still in their infancies, according to Miller.
The hurdle of hypogonadism
Many elements of Prader-Willi syndrome complicate growth and development, but hypogonadism may hit patients hardest, especially during adolescence.
Present at birth, girls often have genital hypoplasia and boys have cryptorchidism. Boys typically undergo surgery to treat undescended testes, but before the procedure, the guidelines recommend treatment with human chorionic gonadotropin (hCG). McCandless, co-author of the AAP’s recommendations, said use of hCG increases the orchidopexy’s chance of success.
“Because the scrotal sac is so hypoplastic, when boys used to get an orchidopexy to bring down their testes, there just wasn’t enough room in the scrotal sac for the testes,” Miller said. “With hCG, the scrotal sac size increases and is able to hold the testes so they stay down better after the procedure.”
Premature adrenarche is common with the condition, yet breast and testicular development generally halt at Tanner stage 3. Regular menstrual periods are rare in girls, and boys usually have testosterone insufficiency.
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As treatment, physicians prescribe hormone supplementation. Testosterone use in boys, however, is somewhat complex. Having had little exposure to androgens, introducing too much of the hormone too quickly may lead to aggressive behavior. Therefore, beginning with lower doses is key, Angulo said.
In girls with Prader-Willi syndrome, hormone therapy may have multiple benefits because estrogen can protect bone density, as well as act as contraception. However, only a few cases of reproduction in women with the disease and no cases of reproduction in men with the disease have been documented, according to Miller.
Behavioral, cognitive dilemmas
Obesity and its subsequent complications often eclipse the severity of other symptoms in Prader-Willi syndrome, but behavioral problems and cognitive impairment challenge parents and physicians on a daily basis.
“Patients with Prader-Willi syndrome have a tendency toward obsessive compulsive characteristics, and there’s actually an increased incidence of frank obsessive compulsive disorder later in life,” McCandless said. “They also have difficulty transitioning from one activity to another, and they have rapid escalation of temper tantrums.”
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Photo courtesy of: Moris Angulo,
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As appetite increases, children with the disease occasionally exhibit more emotional lability and develop intense food-seeking behaviors as well. Nevertheless, visiting a behavioral psychologist at a young age can combat these problems as they arise, McCandless said. The guidelines highlight reward systems as especially effective tools for behavior modification, but said food should never be included as an incentive or punishment.
Children with Prader-Willi syndrome also have a higher pain tolerance, leading them to explore their unique compulsion of skin picking, despite open sores and skin infections. The higher pain threshold, however, also has more serious implications.
“It’s difficult [to diagnose other health problems in children with Prader-Willi syndrome] because most of us as doctors expect to see all the signs of someone complaining about their illness,” Angulo said, noting that it is important to seek immediate medical attention at any sign of discomfort. In some cases, children with the disease can sustain severe injuries, such as broken bones or ruptured organs, while giving little indication that they are hurt.
Cognitive disabilities hinder children with the disease from understanding and predicting the consequences of their actions, but, unlike in the past, many are also high functioning and now participate in regular classrooms.
“[The cognitive disabilities] used to be moderate to severe,” Miller said. “The average IQ was 63, so it did interfere with learning and school programs, but now, with earlier diagnosis, earlier therapies and early intervention, the IQ in these children is much better than it was 10 years ago.”
Other considerations
Outcomes for children with Prader-Willi syndrome are improving, but physicians must still bear certain issues in mind.
In 2008, a study published in The Journal of Clinical Endocrinology & Metabolism reported a 60% prevalence of central adrenal insufficiency in children with the disorder. Since then, several studies from 2010 published in the same journal contradict these findings. Nevertheless, the guidelines remind endocrinologists to be aware of this potential issue.
Additionally, parents and physicians should become familiar with some of the lesser-known characteristics accompanying the condition. For example, Angulo said the children are prone to frequent cavities because their tooth enamel is very thin, and some may have very fair skin and increased sensitivity to sun exposure because the association with chromosome 15 genetically links the disease to albinism.
Finally, standard care, including vaccinations and well visits, from a general pediatrician who is aware of the condition is needed.
“It’s a team effort,” Angulo said. “You need pediatricians, psychologists, dentists, surgeons, dietitians and endocrinologists to address everything that goes on with Prader-Willi syndrome.”
As patients with the syndrome begin to survive into their 50s and 60s, the issue of passing from pediatric to adult care or group homes demands attention. Although encouraging, some endocrinologists also find the transition difficult because not all physicians have an interest in the disease. The guidelines recommend identifying health care providers willing to learn about Prader-Willi syndrome or those who already have special experience with the disease. Clear communication is also essential, Haqq said.
Although GH is the only FDA-approved treatment for the syndrome, the disease’s improving outcomes convince McCandless that the outlook is promising.
“I just can never say enough that Prader-Willi syndrome is a beautiful example of how, with thoughtful and careful management of the clinical problems, you can successfully treat a genetic disorder,” he said. “We can’t cure it, but we can make life a whole lot better for people with Prader-Willi syndrome by being attentive to their clinical needs and developing treatments to specifically manage each of the complications. It makes me hopeful for a variety of other genetic disorders.” – by Melissa Foster
For more information:
- Carrel AL. J Clin Endocrinol Metab. 2010;95:1131-1136.
- De Lind van Wijngaarden RF. J Clin Endocrinol Metab. 2008;93:1649-1654.
- McCandless. Pediatrics. 2011;127:195-204.
- Nyunt O. J Clin Endocrinol Metab. 2010;95:E464-E467.
Disclosures: Drs. Angulo, Carrel, Haqq, McCandless and Miller report no relevant financial disclosures.
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When should growth hormone
therapy be initiated in children with Prader-Willi syndrome?
Early treatment has earlier benefits but remains a difficult decision
Initiating growth hormone therapy early in children with Prader-Willi syndrome has significant developmental benefits. The treatment assists babies with the syndrome in gaining muscle tone and achieving certain gross motor skills. For example, GH can improve babies’ truncal strength, thereby allowing them to sit independently. In addition, early influences of excess weight may have an impact later in life in these children. Therefore, the fact that the treatment simultaneously improves growth, body composition and developmental progress early in life compels me to treat within the first year of diagnosis — typically around 6 months of age.
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Despite these benefits, many physicians may still be hesitant to treat before 2 years of age, as indicated by the FDA. Yet, it’s important to understand the difference between FDA indication and clinical practice. The FDA’s decisions are based on studies conducted in children aged older than 2 years because many researchers may be reluctant to pursue clinical trials in infants. Hence, information on the use of GH in this population may not be available to the FDA, although several studies show the advantages of starting treatment in infancy.
Precedents for off-label use, such as with Turner’s syndrome, do exist, however, and clinical experience may be a significant factor. For instance, if a physician has been successful with off-label use in the past, he or she may be more comfortable with starting treatment earlier. Nevertheless, the decision to treat is complicated. Even robust studies do not always offer clear-cut evidence for use, so much of what is done is based on clinical judgment and clinical experience. What we need are more studies, as well as larger studies, to answer the question of what is the absolute best treatment course to pursue for patients with Prader-Willi syndrome.
Henry Anhalt, DO, is a pediatric endocrinologist in private practice. He is also a member of the Advocacy and Public Outreach Core Committee of The Endocrine Society.
Disclosure: Dr. Anhalt reports no relevant financial disclosures.
GH treatment may not be necessary for all patients
In my opinion, growth hormone treatment is not standard of care. Although FDA approval is based on 1-year studies demonstrating increased height velocity, most practitioners use GH in toddlers and infants because some parents are extremely vocal about starting treatment as early as possible. Some believe that early treatment may mitigate symptoms upon which GH has no impact, such as cognitive ability. That is a total misconception. These assumptions are based on studies showing children achieving gross motor milestones sooner than untreated children, but motor developmental outcomes in a 2-year-old are not indicators of intelligence.
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Other advocates for GH treatment note that GH deficiency is common among children with the condition. However, the obesity experienced by some of these children can decrease GH response to stimuli. This presents a chicken-and-egg question: Do all children with Prader-Willi syndrome have true GH deficiency or is it secondary to obesity in some children? Further, although GH definitely improves their unusual body composition, the treatment does not normalize it, and research indicates that its efficacy wanes after the first year.
By using GH to improve outcomes other than height velocity and by treating children in infancy, we are trying to move the goal posts. To accomplish this, we require data from long-term, double blind, randomized, controlled studies in this young population with those outcomes. A few studies suggest the benefits of treating younger children, but the cohorts may not necessarily be comparable or contemporary, as the researchers did not examine potential confounders, such as the parents’ social and educational levels.
In Canada, where I practice, the Canadian equivalent to the FDA — the Health Protection Branch of Health Canada — has not yet approved GH for treatment of Prader-Willi syndrome without evidence of short stature. I encourage my colleagues to conduct these studies so that we can determine whether GH has significant benefits for children with the disease.
Guy Van Vliet, MD, is professor of pediatrics at the University of Montreal and chief of endocrinology service at Sainte-Justine Hospital in Montreal, Canada.
Disclosure: Dr. Van Vliet reports no relevant financial disclosures.
Treat children with Prader-Willi syndrome cautiously, but fairly
I am generally restrictive in my use of growth hormone therapy, particularly with regard to height manipulation. However, in children with Prader-Willi syndrome, the benefits are more global than achieving a few more inches of height. Treatment often translates to improved body composition with demonstrable changes in motor skills and physical function. Furthermore, studies at the University of Wisconsin suggest that early initiation of therapy is advantageous. Children who began treatment between ages 6 and 18 months demonstrated more effect of GH on acquisition of better motor development skills than those who began treatment after 18 months. In addition, children with Prader-Willi syndrome who began treatment in the first 2 years of life showed significant improvements in strength, agility and lipid profiles, as well as height, compared with untreated children of comparable ages.
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Although I am encouraged by our findings, I will feel more confident when additional controlled studies from around the world confirm our findings of improved early life motor development and subsequent beneficial long-term physical function and metabolic effects. Unfortunately, controlled research trials on GH’s use in younger children with Prader-Willi syndrome seems to have slowed because, in part, many parents will not consent to foregoing or delaying therapy to participate in randomized, placebo-controlled clinical trials now that GH is FDA-approved for treatment of Prader-Willi syndrome. Consequently, we are dependent on historical controls.
Regarding very early institution of GH, as early as age 2 to 3 months, for example, ethically, we should treat children with Prader-Willi syndrome as we would any child. A very young infant with Prader-Willi syndrome who is clearly suffering from GH deficiency deserves treatment like any other infant struggling with GH deficiency. Treatment should be individualized, but clearly the family should be aware of the lack of published information on the benefits and side effects. Still, I would not deprive a child with Prader-Willi syndrome of GH treatment that I feel would truly help them.
In addition to more knowledge about safety and efficacy of GH use in very young children with Prader-Willi syndrome, we also need more information about the relative importance of continued GH therapy after puberty onset or initiation during adulthood.
David B. Allen, MD, is professor of pediatrics at the University of Wisconsin School of Medicine and Public Health and head of endocrinology at the UW American Family Children’s Hospital in Madison, Wis. He is also president of the Pediatric Endocrine Society.
Disclosure: Dr. Allen reports no relevant financial disclosures.