Prader-Willi Syndrome

Prader-Willi syndrome: description

The Prader-Willi syndrome (falsely synonymous Willi-Prader syndrome) was first described in 1956 by the pediatricians Andrea Prader, Alexis Labhart and Heinrich Willi. About one in 20,000 newborns suffers from Prader-Willi syndrome. The cause is a genetically induced dysfunction of the hypothalamus, an important switching center in the brain. The severity of Prader-Willi syndrome can be very diverse and complex.

Prader-Willi syndrome: symptoms

Already before the birth fall affected fetuses. They move noticeably little in the womb. The heart rate is lower than normal. At birth, fetuses with Prader-Willi syndrome are more likely to be in abnormal positions in the mother’s body. During and after birth babies need a lot of support.

Immediately after birth, affected newborns are affected by a lack of physical activity, (muscle) weakness and a low birth weight. Even the typical screaming after the birth may be missing or is only weak. Due to the pronounced weakness and the resulting suction and swallowing disorder, it is difficult for babies to drink.

Babies with Prader-Willi syndrome often show certain external features. The narrow face is characterized by almond-shaped eyes and a small mouth with a thin upper lip. The skull is often long (dolidochocephaly), hands and feet are small. The spine may be bent in an S-shape (scoliosis). The bone substance in the whole body shows damage and defects in the radiograph (osteoporosis / osteopenia). The pigmentation of the skin, hair and retina may be reduced. Even visual disturbances and strabismus (strabismus) of the eyes are possible. The scrotum is small and often empty (undescended testicles). Overall, the development of sick children is delayed.

At the end of the first year of life, the muscle weakness improves a bit. At least a mild weakness, however, always exists. Normal activities are quickly tiring and exhausting for patients with Prader-Willi syndrome. Nevertheless, children enjoy the same kind of typical activities of childhood. In infancy, the growth is significantly reduced.

Uninhibited food intake

In the course of the disease affected children eat more and more (hyperphagia) – without feeling a sense of satiety. Food is hoarded and stolen even in severe cases. The control of eating behavior is extremely difficult for the children. Therefore, they develop a marked obesity (obesity). They increase particularly fast, since there is a marked discrepancy between the high calorie intake and the low energy consumption.

Being overweight causes typical complications: The heart and lungs are suffering from the burden of obesity. One quarter of all those affected developed diabetes mellitus up to the age of 20 years. Sleep disorders, venous diseases (thrombophlebitis) and water retention are also among the multitude of possible consequences. In the course of the disease, sleep disorders may be added. In addition to repeated breathing pauses, disturbances of the day-night rhythm or even deep sleep are possible. Learning is difficult for affected children.

The development of puberty is disturbed

The typical growth spurt in puberty is low. Affected children are usually no larger than 140 to 160 centimeters. Although puberty may be premature (premature adrenalche), puberty is often never completed. Those affected usually remain barren. In boys, the penis and especially the testicles remain small. Pigmentation and wrinkles are missing on the scrotum. The voice break can fail. In girls labia (labia) and clitoris (clitoris) remain underdeveloped. The first menstrual bleeding does not occur at all, prematurely or belatedly, sometimes only between the 30th and 40th year of age.

Psychic and mental development

Both mental and psychomotor development are disturbed in Prader-Willi syndrome. Milestones of child development are often achieved later than in healthy peers. Linguistic and motor development sometimes take twice as long as with healthy peers.

The average intelligence quotient (IQ) is between 60 and 70, well below the norm. Due to the physical weakness speaking can be difficult. Speech development is delayed and speech understanding is disturbed, depending on the low IQ. Around 40 percent of sufferers are on the border with mental disability. Irrespective of the IQ, learning disorders such as arithmetical difficulties also show up. The school achievements are usually below average.

Both the training of emotions and the behavior can be conspicuous. Those affected are sometimes described as obstinate and quick-tempered. Already in early childhood psychiatric abnormalities can occur: Forms of so-called opposition behavior as well as rigid and possessive behavior are described. Routine procedures can be difficult. In some cases, processes must be compulsively repeated. About 25 percent of patients have autistic features. Also the attention deficit syndrome (ADD) occurs frequently.

With age and overweight, the symptoms usually increase. In older adults, however, the symptoms of Prader-Willi syndrome can be reduced again. About ten percent suffer from psychosis. In addition, epilepsy and forms of “hypertension” (narcolepsy) are associated with Prader-Willi syndrome.

Prader-Willi syndrome: causes and risk factors

The cause of Prader-Willi syndrome is probably a dysfunction of part of the midbrain, the so-called hypothalamus. This causes, among other things, a deficiency of the important growth hormone. The disorder is caused in about three quarters of cases by the absence of a gene section on chromosome 15 (15q11-q13). In the case of Prader-Willi syndrome, especially a defect of the paternal chromosome copy seems to be of particular importance (70 to 75 Percent) so that there is only one copy of the gene. Another possibility is that both genes of the double set of chromosomes come only from the mother (uniparental disomy, 25 to 30 percent). Less often there is a so-called “imprinting defect” (one percent). The term “imprinting” is used to describe that genes are read as a function of their origin (maternal or paternal).

In most cases, the disorder is not inheritable. It usually develops only in the context of germ cell development or after fertilization. On the other hand, however, it is also possible that existing gene mutations (usually so-called balanced translocations) cause a Prader-Willi syndrome. In these cases, the inheritance risk is increased.

Prader-Willi syndrome: examinations and diagnosis

All newborns with persistent and unexplained weakness should be tested for PWS. Already the neonatal doctor (neonatologist) or pediatrician (pediatrician) will have the suspicion of a Prader-Willi syndrome after birth by the behavior of the child. Without evidence of the presence of this syndrome, no so-called predictive tests are performed. However, it is quite possible to diagnose a Prader-Willi syndrome even before birth.

Physical and apparative investigations

In most cases, there is already a high suspicion of Prader-Willi syndrome due to the physical examination (Holms criteria 1993, 2001). The main characteristic of the Prader-Willi syndrome is the pronounced weakness, which is especially evident in drinking. Also the appearance gives hints. Usually detectable reflexes are weak.

Diagnostically helpful is a measurable deficiency of growth hormone in the blood. Sex hormones (estrogen, testosterone, FSH, LH) are usually reduced in those affected. This is accompanied by an underdevelopment of the sexual organs. The function of the adrenal cortex is disturbed in many cases. Thus, the formation of sex hormones (androgens) can also begin prematurely (early adrenalche).

The examination of the brain waves (electroencephalogram, EEG) may also be noticeable.

Genetic examination

To confirm the suspicion of Prader-Willi syndrome genetic testing is carried out. In the first step, the methylation of the crucial site on chromosome 15 (15q11.2-q13, “SNRPN locus”) is investigated. Enzymes can bind so-called methyl groups to the DNA and thereby modify it. In more than 99 percent of cases, this examination provides the diagnosis. Otherwise, another common method for detecting chromosomal changes, fluorescence in situ hybridization (FISH), is performed.

Similar diseases are Martin Bell Syndrome or Angelmann Syndrome. The disorder in Martin-Bell syndrome lies on the X chromosome (fragile X syndrome). In the case of Angelmann syndrome and Prader-Willi syndrome, in most cases the same site on chromosome 15 is deleted – but in Angelmann syndrome only the one on the maternal chromosome.

Prader-Willi syndrome: treatment

The Prader-Willi syndrome can not be cured. However, with the help of a strictly guided, supportive therapy the symptoms can be alleviated. The main components of the treatment are nutritional control, hormone replacement therapy and treatment of behavioral problems.

nutrition

Especially if the muscle weakness is pronounced, adequate nutrition and sufficient growth must be ensured. To facilitate feeding, probes or special, artificial nipples can be used. In addition, a feeding plan with well-documented calorie intake and weight control should be prepared.

As children grow older, however, they develop an eating disorder with excessive food intake. Then a plan with a strict calorie restriction must be adhered to. Fat restriction is not always the goal, as fat is important for horn development. The eating disorder may require strict handling of access to food. The eating disorder in Prader-Willi syndrome has a particularly serious effect on the disease, since the affected little move and so there is a large discrepancy between calorie intake and need. It is crucial to involve the parents intensively and to provide the sick child with a solid structure.

At the same time, it must be ensured that sufficient vitamins and minerals are supplied. In the Prader-Willi syndrome disturbances of the bone metabolism often occur, which can be prevented with vitamin D and calcium intake. The skeletal development, especially of the spine, should be examined regularly.

The activity and motor development of the diseased child are regularly examined and possibly supported therapeutically with physiotherapy or similar methods.

growth hormone

From the second year of life can be additionally given the growth hormone HGH as a drug. This therapy should be stopped when closing the growth plates in the bone (X-ray control). Always the hormone therapy should be closely monitored. Hormone administration has a positive effect on body development, but side effects include foot edema, a worsening of spinal curvature (scoliosis) or an increase in pressure in the skull (pseudotumor cerebri). At the beginning of treatment it can lead to respiratory disorders. It is therefore important to monitor sleep at the beginning of therapy. Monitoring of HGH hormone therapy also includes the regular determination of thyroid levels and blood counts of the growth factor IGF-1.

In puberty disorders, sex hormones may be administered as depot injectors, hormone patches or gel. The behavioral problems can improve as a result. Estrogens also support bone formation but also have a variety of side effects.

Psychological promotion

To support behavioral development and achievement of development milestones, the affected child should receive help. In particular, the social skills must be trained in Prader-Willi syndrome. This should also encourage interaction with peers and caregivers. At school, one-to-one care may be necessary. If necessary, the living and working environment must be adapted. Psychiatric abnormalities may require drug therapy, for example with a serotonin antagonist. The goal of the intensive support is the best possible independence.

Surgical care

Any existing cleft lip and palate at birth can be treated early by surgeons. Even misalignments of the eyes, especially strabismus, can be treated surgically to prevent vision problems. First, the temporary cover of the healthy eye can help.

The underdevelopment of the reproductive organs may require surgery to relocate the testes from the lower abdomen into the scrotum. The administration of beta-hCG (human chorionic gonadotropin) may increase the scrotum and thus allow the testes to descend.

Also skeletal changes of Prader-Willi syndrome can be surgically treated. An S-position of the spine (scoliosis) requires in severe cases an operative correction, but is usually supplied without surgery (for example with a corset.

Prader-Willi syndrome: disease course and prognosis

The earliest possible diagnosis of “Prader-Willi syndrome” can positively influence the long-term prognosis. By positively influencing the (eating) behavior and the possible administration of growth hormones, the quality of life of the affected child can improve.

At regular intervals after the diagnosis, the eating behavior, weight and growth should be checked. Development, function, behavior as well as psychiatric abnormalities are controlled. Close monitoring and care by a specialist who can coordinate and ensure interdisciplinary care is very important.

Diseased people have an increased risk of recurring infections. Special care should be taken during surgery: After anesthesia, the recovery phase often lasts longer and there is an increased risk of respiratory disorders.

The biggest problem, however, is the increasing obesity. In the course of life outweigh the resulting complications. The mortality is increased by the sequelae. The increased mortality in Prader-Willi syndrome is therefore mainly caused by heart, vascular or lung diseases.

The inheritance risk is low. In most cases, the genetic change occurs spontaneously and not through heredity. The risk for parents to have a second child with Prader-Willi syndrome is low. The victims themselves often remain childless.

Only in rare cases is the Prader-Willi syndrome caused by rearrangements of the genetic information in the parental chromosome set, which are inheritable and also lead to a higher probability of heredity. Does a child have that? Prader-Willi SyndromeTherefore, the advice of human geneticists is recommended for parents with more children.