By Suzanne Cassidy, MD

 

A syndrome is a group of signs and symptoms that occur together and characterize a disease or disorder.

Prader-Willi syndrome (“PWS“) was first described in 1956 by Swiss doctors Prader, Labhart, and Willi.  PWS is believed to be among the ten most common syndromes seen in birth defect clinics, and is the most common genetic syndrome causing morbid obesity in children. It exists throughout the world, but most people, including many physicians, are not familiar with this potentially life threatening, devastating, life-long disorder. Multiple studies in several countries in the developed world suggest that at least one in 15,000 to 30,000 people have the syndrome, which means that about 200,000 people worldwide are affected. In emerging countries very few patients are diagnosed. The following is a simplified description of the cause, manifestations and management of PWS. Additional details are available through IPWSO if desired.

 

CAUSE

Prader-Willi syndrome is a genetic condition whose cause is quite complex. It occurs when there is lack of expression of one or more genes in a specific region on the chromosome 15 that was inherited from the father, the precise location of the abnormality being designated as 15(q11-q13). There are 3 common ways that this lack of expression can occur: 1) there is a missing segment at this location from the chromosome 15 that was inherited from the father, called a deletion (found in about 70%); 2) the entire chromosome 15 contributed by the father is missing and instead there are two chromosome 15’s inherited from the mother, which is called maternal uniparental disomy 15, or UPD 15 (found in about 25%), or 3) there is a defect in the normal expression of the relevant genes due to an abnormality in control of gene expression, called an imprinting defect (found in 5% or less). The syndrome generally occurs as an isolated event in the family and risk is low that parents with one affected child will have another child with the same condition in the vast majority of families. There is nothing that either parent did or did not do, either before or during the pregnancy, that causes this genetic alteration.

 

DIAGNOSIS

Prader-Willi syndrome is usually suspected on the basis of the clinical signs and symptoms (see below) and confirmed by genetic testing. Clinical diagnostic criteria have been published in the medical literature and confirmed as accurate. However, because other disorders can have overlapping manifestations, the diagnosis should be confirmed by genetic testing, which is clinically available in many countries and is very accurate. Currently, the best test for Prader-Willi syndrome is called methylation analysis, and it is the best because it will be positive regardless of the genetic type. Other genetic tests can be used to determine the specific type, if that is desired, but it is not necessary to confirm the diagnosis.

Currently, IPWSO offers to cover the deeply discounted cost of genetic testing offered at the Baschirotto Institute for Rare Disorders in Italy for those living in countries where it is not available.

 

CLINICAL FEATURES

The pattern of characteristics associated with PWS is consistent among those affected by it, although there is significant variability in severity and not all affected individuals have every characteristic.

 

As a simplification, the disorder is marked by distinctly different presentation in infancy versus later in life.

Early phase: Initially, the neonate presents with slightly low or normal birth weight and poor suck with subsequent failure to gain weight and grow well, very limp muscles, and delayed developmental milestones.  Genitals are often small in both sexes, and one or both testes are undescended in males. Because of the weak, limp muscles and poor suck, infants are almost always unable to nurse and often require special feeding techniques such as special bottles or tube feeding (gavage).  The milestones of lifting the head, sitting up, crawling, walking, and speech all tend to be delayed.  On average, independent sitting is achieved at around 12-13 months, walking at 24-30 months, and tricycle riding at 4 years.  The first word may appear around 21 months and sentences around 3-1/2 years.

 

Second phase: There follows a period of normal eating behavior and improvement in muscle tone and activity. However, this in turn is followed by a phase that is usually marked by an increased appetite and often a  compulsion to eat. This often occurs in toddlers or young children. Life becomes dominated by a voracious appetite and drive for food. Individuals with Prader-Willi syndrome apparently do not feel full (lack a sense of satiety). They can eat a tremendous amount of food without becoming nauseated or having indigestion --and many have never vomited. This striving for food combined with a lower than normal calorie requirement and, frequently decreased activity related to the hypotonia will result in rapid weight gain if not controlled externally, leading to obesity and eventually the consequences of obesity: respiratory difficulties, heart disease, diabetes, and other problems.

 

CHARACTERISTICS

Physical characteristics: There is often a characteristic facial appearance with a narrow forehead, almond-shaped eyes, and a thin upper lip with downturned mouth. Scoliosis (S-shaped curvature of the spine) may develop. Many individuals have fairer coloring of hair, eyes and skin than other family members.

Growth deficiency: People with PWS typically have short stature for the family and small hands and feet. Early growth may be below normal, and there is failure to have a pubertal growth spurt. Recent studies have documented insufficiency in growth hormone, and treatment can correct this problem.

Incomplete Sexual Development: The small genitalia that characterize affected individuals are more easily identified in males, but affects both sexes.  Males often have undescended testicles and a small, poorly delineated scrotum; females have small labia minora and clitoris. Pubertal development is typically delayed and incomplete, and fertility is extremely rare and has occurred only in females.

 

Intellectual disability: Learning and cognitive development are delayed. Although there is wide variability in abilities, the average IQ is in the 60’s. Most affected persons function in the mild intellectual disability range independent of tested IQ, and most are learning disabled.

 

Speech and language difficulties: Cognitive capacity and probably also the extent of hypotonia affect this ability. Speech therapy may be helpful.

 

Balance and Coordination: Fine motor skills usually are well developed, while gross motor skills remain limited.

High pain threshold and irregularities in body temperature control.  Most people with PWS are unaware of injury and infection because of blunted sensory mechanisms. Unexplained high or low temperatures may occur, and there is often insensitivity to environmental temperature.

 

Skin Scratching and Picking: Many individuals with PWS pick and scratch at sores and insect bites which, if not controlled, may become chronic sores and result in infection.

 

Behavior and Temperament: Affected children tend to be loving, happy and compliant in early years, and then subtle changes typically lead to mood swings and behavior difficulties over time.  This often includes temper outbursts, stubbornness, rigidity, argumentativeness, and repetitive thoughts and behaviors. Social skills are often impaired. True psychosis occurs in a minority of affected older teenagers and young adults, but it usually responds well to treatment. Depression may result in later years when self-image issues emerge, particularly over the conflict between the drive for independence and the need for management.

 

Other Findings: People with PWS may experience excessive daytime sleepiness and sleep apnea, particularly if obese. Eye abnormalities such as strabismus (cross-eyed), myopia (nearsightedness) or amblyopia (lazy eye) are common.

 

TREATMENT

There is currently no cure for Prader-Willi syndrome, nor is there a drug that can be prescribed to alleviate all of the symptoms. As of this writing, there is no known substance that has been demonstrated to lessen the drive to eat, although much research is being conducted to find such a substance.

Treatment is primarily symptomatic and most importantly consists of:

• Early diagnosis and intervention

• Lifetime weight control through diet, environmental controls (lack of access to food), and exercise

• Growth hormone replacement therapy, when available

•  Behavior management , with consistent limit-setting

•  Special education and sheltered or supported employment

 

 

Early Diagnosis: Early diagnosis of PWS gives parents an opportunity to manage their child‘s diet, prevent or treat infantile failure to thrive, avoid obesity from the start, and improve behavior. It may facilitate a family‘s access to critical early intervention services and help identify areas of need or risk. It allows families to know what to expect and institute appropriate preventative measures.

 

Weight Control: People with PWS have a flaw in the part of their brain that determines hunger and satiety that gives them a continuous urge to eat following their period of poor eating in the early years. In addition, they need fewer calories to maintain an appropriate weight. This is believed to be due to decreased muscle tone and bulk and lower physical activity. It is important to provide the needed nutrients while restricting calories in order to maintain a healthy weight. Access to food must be limited and regular (preferably daily) exercise should begin as early as possible. Weight management should be individualized and include weekly weighing, complete control of food intake, environmental barriers to food access (such as locks on kitchens) and diets acknowledging that fewer calories are required.

 

Growth Hormone: In recent years, numerous studies have demonstrated conclusively that growth hormone replacement therapy can very positively affect growth, body composition (the proportion of fat to muscle and bone), and activity level in people with PWS. It can also improve breathing and probably also speech and academic performance. Since it can improve body shape and physical abilities, it also improves self-image. However, growth hormone requires a daily subcutaneous injection, is expensive, and is not covered by all health programs in all countries..

 

Behavior Management: Behavior management is crucial for both weight and behavior problems. Behavior management should be oriented towards intervention and prevention.  Consistent enforcement of limits by all caregivers (including parents, the wider family, teachers, and residential carers)  is very important. For best results, pre-schedule, pre-plan, avoid arguments and anticipate. 

 

Special Education and Sheltered  or supported Employment:  Because of the developmental delay and intellectual disability combined with the behavioral problems, people with PWS require special assistance in school in order to learn as much as their abilities allow. Once they have completed school, they need assistance in finding employment that matches their abilities optimally, and supervision to control access to extra food and deal with behavioral outbursts when they occur. Adults with PWS who do not live with their family will require a residence that includes supportive supervision and accommodation to their dietary and behavior control issues while simultaneously allowing them as much success and social interaction as possible.