By Gary Wolfe

Imagine experiencing a chronic hunger so intense and so pervasive that you are driven unrelentingly to seek and eat food without knowing the feeling of satiation ever.

magine an unabated hunger that may, inevitably, lead to morbid obesity and, likely, an early death unless you are closely monitored virtually all of the time by your family, friends, neighbors, teachers, and caregivers to ensure you receive only the nourishment that your body actually requires.

Now imagine that this same disease will also cause you to experience growth abnormalities, probable infertility, respiratory problems, learning disabilities, behavioral problems, possible mental retardation, and more.

For those who suffer from Prader-Willi syndrome (PWS), these scenarios are all too real, and they tell only a small part of the story. To learn more, we interviewed Janalee Heinemann, MSW, the executive director of the Prader-Willi Syndrome Association (USA). Heinemann has both a longstanding (22 years) professional interest in PWS and a personal interest: She has an adult son with the syndrome.

This conceptual image differentiates normal chromosome 15s from Prader-Willi Syndrome and from Angelman Syndrome.

What Is Prader-Willi Syndrome?
First described to the medical community in 1956 at the Univerity of Zurich by Doctors Prader, Labhart, and Willi, PWS is a predominantly nonhereditary, two-stage (or multistage) genetic disease that afflicts both males and females. There is no cure. The incidence rate is variously cited as 1 in 12,000 to 1 in 15,000 births. The disease typically originates from a spontaneous genetic defect involving 5 to 10 genes on either the patient’s maternal or paternal chromosome 15.

“The most common cause, representing about 70% of cases, is a deletion of genetic material from the paternal chromosome 15. This is the ‘classic’ case,” says Heinemann. “Less frequently—in about 25% of cases—the cause is uniparental disomy in which two maternal (and no paternal) chromosome 15s are present. The third and rarest cause is attributable to imprinting genetic mutations, translocations, or inversions. Research has shown that the missing genes are essential to the proper functioning of the hypothalamus with regard to appetite control and of the pituitary with regard to growth and sexual development.”

Heinemann adds that in some instances where the hypothalamus has been subjected to trauma, some PWS-like symptoms may result. She identifies this condition as hypothalamic obesity.

An interesting footnote to this discussion is that uniparental disomy, in which two paternal (and no maternal) chromosome 15s are present, results in another genetic disease: Angelman syndrome, which has markedly different symptoms from those of PWS.

What Are the Symptoms?
In the first stage, which typically begins at birth and lasts for up to about 3 years, PWS children demonstrate a notable “failure to thrive”, says Heinemann. As fetuses, they show little movement. Following birth, they show little or no inclination to nurse and are usually characterized by severe hypotonia with consequential weakness and so-called “floppiness”. The infants’ inability to suck may necessitate the use of feeding tubes.

In the second stage, beginning in early childhood and lasting for a lifetime, there is a shift to compulsive, excessive eating and fast weight gain. Unless parents and caregivers can control the overeating and the resultant caloric intake, the patients will typically tend to morbid obesity over time. As the patients pass through adolescence and puberty into adulthood, they are usually typified by short stature; small, narrow hands and feet; almond-shaped eyes; continuing hypotonia; and hypogonadism. In the vast majority of cases, they are infertile. Heinemann notes that only two known pregnancies have been reported worldwide.

Several genetic tests may be used to diagnose Prader-Willi Syndrome

Other characteristics of PWS patients may include some combination of learning disabilities, behavioral issues, reduced cognitive abilities ranging from normal to moderate mental retardation, a tendency to autism, respiratory problems, unusually high pain threshold, reduced ability to vomit, propensity to severe gastric illness, body-temperature abnormalities (ie, hypo- and hyperthermia), and skin lesions and bruises, which often result from compulsive skin picking or minor injuries.

Heinemann says that manifestations of PWS may vary significantly from patient to patient, depending on a number of factors; eg, the range and severity of symptoms, when during the patient’s early development the disease is correctly diagnosed, and how effectively it is managed after confirmation of the diagnosis.

Testing to Confirm the Diagnosis of PWS
The preliminary clinical diagnosis of PWS is typically the result of observations of the infant by physicians, caregivers, and parents. In the past—and still a possibility today, especially in the case of late diagnoses—it was not uncommon to consider children with PWS symptoms as being “slow” or to think that the parents were “neglectful”, says Heinemann. However, once suspicions regarding the possibility of the disease are aroused, several genetic tests may be used for verification.

In particular, Heinemann identifies the follow assays:

• The DNA methylation test (used to detect the imprinting pattern in the region 15q11–q13 and to confirm the presence or absence of PWS with 99% accuracy).
• DNA polymorphism studies (to determine the parental source of chromosome 15).
• The FISH (fluorescence in situ hybridization) test (to detect genetic deletions of all sizes and often performed in conjunction with chromosomal analysis).
• High-resolution chromosomal analysis (to detect large deletions and other chromosomal abnormalities).

Because of the differences in the types of information elicited from the tests, some or all of them are often employed in combination.

Various symptoms associated with PWS, notably obesity and cognitive difficulties, also may be associated with other unrelated diseases. Heinemann indicates that this can cause a degree of confusion during diagnosis, especially if the physicians and caregivers have had little or no experience with PWS, which is classed as a rare disease.

To further clarify this issue, she cites a 2001 paper entitled "Prader-Willi Look-Alike Disorders," by Celanie K. Christiansen and Bryan E. Hainline, MD, PhD, from the Departments of Medical and Molecular Genetics and Pediatrics at the Indiana University School of Medicine. The authors highlight the following medical conditions that may be confused with PWS: Albright’s hereditary osteodystrophy, Alstrom syndrome, Bardet-Biedl syndrome, Borjeson-Forssman-Lehmann syndrome, Cohen’s syndrome, and fragile X syndrome. The authors note, secondarily, that Down syndrome, Klinefelter’s syndrome, and Turner Syndrome also introduce a high risk of obesity.

How Is Prader-Willi Syndrome Managed?
The nature of PWS complicates patient management. Besides family members, a typical list of caregivers involved in managing a PWS patient may include the following disciplines: neonatologists, geneticists, endocrinologists, neurologists, developmental pediatricians, pathologists, radiologists, general practitioners, clinical lab technologists, nutritionists, pediatric social workers, physical therapists, and psychiatrists. With so many different people and specialties involved, Heinemann says that it has proven a challenge to build and maintain the databases needed to inform and educate all interested parties adequately.

Clinical diagnosis of PWS is typically a result of observation of the child by physicians, caregivers, and parents.

To flourish to the maximum extent possible, patients with PWS require more or less constant attention and a disciplined existence, whether they live with family or in professionally run and closely monitored group home environments specifically set up for PWS patients. Families and caregivers often go to the extreme of locking up food supplies to restrict access. Nevertheless, patients have been known to resort to imaginative schemes to obtain food, such as picking the locks or unscrewing the door hinges of secured cabinets

As the PWS child grows, caregivers must be alert to potential problems, such as hyperthyroidism, signs of early aging, osteoporosis, scoliosis, respiratory issues, sleep apnea, dental problems, and so on. Strict, extremely low-caloric dietary programs are essential for proper nutrition and weight control as appetite-suppressing drugs have not worked consistently in PWS patients.

Treatment strategies necessarily vary from patient to patient. Even children who appear healthy must be watched closely. Physical, speech, and occupational therapy programs are often employed to aid physical and cognitive development. Heinemann notes that growth hormone treatments by endocrinologists have proven beneficial with regard to physical factors such as increased stature, muscle development, fat reduction, and energy level, although such treatments must be closely observed and weighed against potential risks.

In addition, the intervention of psychiatrists and social workers is often needed as PWS patients frequently experience behavioral difficulties, such as obsessive/compulsive mannerisms and temper tantrums. For these and numerous other reasons associated with PWS, it is difficult to mainstream PWS children, according to Heinemann. They may want to attend regular schools, but it is difficult for them to handle it, and their behavioral and eating disorders sometimes result in expulsion and/or legal problems.

As patients move into adulthood and for the remainder of their lives, PWS must be closely monitored and managed on an ongoing basis. However, Heinemann says that with proper management, PWS patients can learn a great deal, achieve satisfying occupations, and enjoy rewarding personal lives.

What Does the Future Hold?
A great deal of ongoing research is helping to add to the PWS knowledge base, according to Heinemann. For example, she cites some recently published studies by David Cumming, MD, in The New England Journal of Medicine and by Andrea M. Hagg, et al, in The Journal of Clinical Endocrinology & Metabolism. These offer evidence that the concentration of ghrelin, which stimulates appetite and decreases metabolism, is significantly higher in PWS children than in normal children. Continuing research of this nature might offer hope of a new medication that could someday benefit PWS patients.

Other Prader-Willi Resources to Consider
For a more in-depth professional assessment of the management of PWS, Heinemann suggests visiting the Prader-Willi Syndrome Association (USA) Web site (www.pwsausa.com), which provides extensive reference information. A new comprehensive textbook Management of Prader-Willi Syndrome, Third Edition, is due to be published in about six months. In addition, there are numerous other Web sites for regional chapters of the association in the United States. and for the International Prader-Willi Syndrome Association.

For more information, contact Prader-Willi Syndrome Association (USA), 5700 Midnight Pass Road, Suite 6, Sarasota, Fla 34242. (800)926-4797. Fax: (941)312-0142. Email: national@pwsusa.org.

Gary Wolfe is a contributing writer for Clinical Lab Products.