Prader-Willi Syndrome

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Classification according to ICD-10
Q87.1 Congenital malformation syndromes that are predominantly associated with short stature (including: Prader-Willi syndrome)
ICD-10 online (WHO version 2019)

The Prader-Willi syndrome ( PWS ), also known by the synonyms Prader-Labhard-Willi-Fanconi syndrome , Urban syndrome and Urban-Rogers-Meyer syndrome , is a comparatively rare one caused by a damaged chromosome 15 in humans Disability . It is based on a congenital genetic mutation or a mutation induced errors in genomic imprinting mechanism of chromosome 15 ( microdeletion ) and is associated with physical , metabolic-related and cognitive symptoms accompanied by a malfunction of the diencephalon caused.

history

The Prader-Willi syndrome was first described in detail from a scientific point of view in 1956 by the Zurich pediatricians Andrea Prader , Alexis Labhard and Heinrich Willi . At that time, however, only the individual symptoms were explained and no statements could yet be made about the actual causes.

The original first description of the typical symptoms goes back to John Langdon Down , who at that time already described children with Williams-Beuren syndrome and became known for the detailed first description of Down syndrome named after him . A 21-year-old woman with Prader-Willi syndrome was described by him as early as 1864.

In 1981 it was found that the cause of the Prader-Willi syndrome is often a genetic peculiarity, namely an incompleteness of chromosome 15 from the father. This chromosome peculiarity is found in around 70% of all people with Prader-Willi syndrome.

frequency

The Prader-Willi syndrome usually occurs sporadically and on average in one in 10,000 to 15,000 children . Girls and boys are affected roughly equally. Familial clusters and sibling cases are described in individual cases.

causes

The cause of the syndrome is that the copy of the gene inherited from the father is incomplete or not functional. The chromosome segment 15q11-13 is subject to a so-called genomic imprint , which means that certain genes on this segment are only active on the chromosome originating from the father and others only on the chromosome originating from the mother. In Prader-Willi syndrome, certain paternal genes are not expressed and the corresponding genes on the maternal chromosome are shut down; thus the gene product is completely absent .

In recent years, more precise genetic marking techniques have been used to identify various causes at the chromosome level. A distinction is made between the paternal deletion already mentioned above , in which a piece of chromosome 15 inherited from the father is missing ( microdeletion ), the maternal disomy in which two maternal chromosomes 15 are present and that of the father is missing ( uniparental disomy 15) , or an error in the genomic imprint of the chromosome segment. The Prader-Willi syndrome is one of the peculiarities in which a functional failure of genes that are subject to genomic imprinting can usually be identified as the cause.

If the deletion in this area does not affect the paternal chromosome 15 but rather the chromosome from the mother, this leads to Angelman syndrome . This genetic peculiarity occurs more frequently in the relational environment of people with Prader-Willi syndrome. For the Prader-Willi syndrome, various genes that have been lost simultaneously through deletion are discussed as triggers, the SNRPN gene and the Necdin gene.

The observable effects of the Prader-Willi syndrome can be largely attributed to a lack of hormone release ( gonadotropin-releasing hormone ) in the hypothalamus , which is caused by the genetic characteristics described. The defective hormone release affects other hormone-producing glands, such as the thyroid , adrenal and gonads ( testicles and ovaries ).

One study suggested that a certain snoRNA (HBII-52) is not expressed in Prader-Willi syndrome patients and therefore the splice regulation of the serotonin receptor 5-HT 2CR is disturbed. This could be a possible reason for the good response of patients to selective serotonin reuptake inhibitors ( SSRIs ). However, another study shows that HBII-52 does not play an important role in Prader-Willi syndrome. The lack of the SNORD116 (formerly HBII-85) snoRNAs leads to the main symptoms of Prader-Willi syndrome and is believed to be the main cause.

Problems and therapeutic approaches in different ages

The consequences of the missing gene segments are diverse and can appear in people with Prader-Willi syndrome in different ways depending on age.

The fetal, neonatal, and infant period

Almost all newborns with Prader-Willi syndrome show pronounced muscle hypotonia (reduction in muscle tension), which is sometimes already noticeable during pregnancy. Many mothers report reduced child movements, 40–50% of them have to have a caesarean section because the child is in breech position , which is caused by increased amniotic fluid ( polyhydramnios ). 20–30% are born prematurely before the 37th week of pregnancy, 10–20% are too young for their age.

In the newborn age, pronounced muscle hypotonia ( floppy infant ) and the resulting weak drinking appear. 95% of this is so pronounced that a nasogastric tube must be inserted, as otherwise sufficient food intake is not guaranteed. The infant also sleeps a lot, moves comparatively little during the waking phase and cries less. The Prader-Willi syndrome is one of the most frequent differential diagnoses of marked muscular hypotension and drinking weakness after birth that initially persists for months; a corresponding genetic test (further information on the website of the Professional Association of German Human Geneticists) should therefore be part of the basic clarification of these symptoms. Furthermore, the eyes are usually almond-shaped, strabismus and nearsightedness are observed in half of the patients (an initial ophthalmological examination is necessary in the first year of life). Unusually further, the below-average formation of the sexual organs ( hypogenitalism ) in boys is often undescended observed.

During this time physiotherapy according to Bobath or Vojta and orofacial stimulation therapy according to Castillo-Morales are recommended as treatment . Before the newborn is discharged from the hospital, breathing and pulse should be stable, which can be demonstrated by cardiorespirography .

The early childhood and childhood

In the first two years of life, the diet should be built up according to the usual recommendations. It is important to consistently refrain from sweetening with sugar, as this affects the taste unfavorably. The control of sufficient food intake is achieved by monthly measuring and weighing and comparing the values ​​with the usual percentile curves for the normal population. With increasing age (in the second year of life) the children become stronger and drink better, but the course of motor development (sitting, crawling, walking, etc.) remains delayed. Inadequate muscle control, despite optimal support, means that children with Prader-Willi syndrome learn motor skills late (free walking: (15) - 28 - (84) months, hopping: (36) - 73 - (105) months, One-legged stance for five seconds: (44) - 75 - (109) months). The intelligence performance is also limited, usually in the sense of a so-called learning disability , the effects of which are particularly evident in the areas of short-term memory and the ability to abstract . The start of speaking is often delayed (first words: (12) - 23 - (72) months), the use of language and expression are completely different in the following: In addition to PWS children who can articulate themselves well in two languages, some PWS children reach for a long time just a vocabulary that does not go beyond individual words. From the age of two, in addition to physiotherapy, connection to an early intervention center is recommended, as well as speech therapy support after having achieved free walking.

Growth hormone therapy is usually started from the age of two ; In addition to the final size, this improves muscle tension, trainability, psychological well-being and blood lipids . An undescended testicle should be treated in the second year of life. Flat arched feet occur to 90% and should be treated with appropriate insoles. Sleep-related breathing disorders can be caused by muscular hypotension, increased infections of the upper respiratory tract, adenoids or an enlarged tonsil ; Loud snoring with pauses in breathing should be clarified by a sleep medical examination.

In the course of the third year of life, an excessive, compulsive feeling of hunger develops , which has physical causes and cannot be consciously regulated. As long as it is not strictly controlled from the outside, this inevitably leads to excessive weight, which is exacerbated by the typical reluctance to move. The increasing independence makes it necessary to lock the kitchens and storage rooms. The average daily energy requirement is around 2/3 of the requirements of a normal-weight child of the same age. This problem of the lack of appetite control takes a significant part in everyday life with people with Prader-Willi syndrome from kindergarten age.

As soon as the common problem of muscle hypotonia takes a back seat, the supportive treatment of individual developmental disorders of balance and fine motor skills, language and social interaction comes to the fore. Disturbances in social interaction usually manifest themselves in phases of massive defiance and emotional instability.

School and youth age

The selection of a suitable type of school plays an important role in further development. The individual possibilities and the local conditions should be taken into account. Scoliosis (lateral curvature of the spine) can occur at the beginning of school age . Bed-wetting due to physical developmental delays (primary nocturnal enuresis ) can be a very stressful situation for families.

The underdeveloped sex organs as a direct consequence of the lack of hormone release lead to puberty, which usually begins later, but occasionally also premature and incomplete, which, with few exceptions, leads to infertility . The pubertal growth spurt does not occur, which is why a small body height (men on average 1.55 m; women on average 1.50 m), changed body proportions (sometimes extreme obesity , especially on the abdomen , hips and thighs ) and lower bone density are common. This is counteracted by the continued necessary nutritional management and by growth hormone therapy (which can usually be ended around the age of twelve), which is not always easy to achieve: Many adolescents are prone to fits of anger and temper outbursts , which , as the need for autonomy increases, also counteract them Direct measures.

A number of key qualifications are considered to be the strengths of children with Prader-Willi syndrome : They are often described as insightful, friendly, social, humorous, warm-hearted and helpful. The long-term memory usually works very well, and depending on the general level of intelligence many children develop with Prader-Willi Syndrome great pleasure in reading.

Adulthood

The life expectancy of people with Prader-Willi syndrome is shortened, which mainly by obesity and the consequential loss of often additionally occurring diabetes is (diabetes mellitus) due, but could here in the last 15-20 years is early onset, consistent Therapy achieves significant improvements. In adulthood, increasing neurological and psychiatric problems arise, which require close cooperation between internists and neuropsychiatrists.

Difficulties in social interaction

A common family point of contention in a child with Prader-Willi syndrome is the question of what to eat. The child's strong feeling of hunger cannot be dealt with rationally , as it is of biological origin. Often children with Prader-Willi syndrome steal other people's food and even eat rubbish or inedible food.

The sometimes very high emotionality of the children can turn out to be a further difficulty. Children with Prader-Willi syndrome are rarely able to express their feelings in a socially acceptable way. The result is an exaggerated and very strong expression of emotion. A low tolerance for frustration can be the main reason for a crisis.

The inability to accept changes in everyday life also gives rise to conflict over and over again. Even the vague prospect that the circadian rhythm could be disturbed can put a child with Prader-Willi syndrome under stress .

diagnosis

In order to be able to make a diagnosis based on clinical criteria, patients under three years of age must have at least five of the following criteria (including at least four main criteria). For patients over three years of age , a total of at least eight criteria (of which at least five main criteria) must be met.

The main criteria are:

Secondary criteria are:

Differential diagnosis

In terms of differential diagnosis, the Snyder-Robinson syndrome and trisomy Xq28 are to be distinguished .

therapy

The Prader-Willi syndrome cannot be cured. The therapy takes place therefore primarily symptomatic. It is still controversial among experts whether early intervention to compensate for the missing hormones can alleviate the severity of the Prader-Willi syndrome. However, such a growth hormone therapy is already considered successful in some circles; studies refer to a normalization of body size, body fat percentage and muscle mass. Furthermore, children treated in this way are said to have become more physically active and satisfied in the course of treatment, and behavioral problems decreased.

There are behavioral therapeutic methods that can have positive effects on the behavioral repertoire of people with Prader-Willi syndrome. The prerequisite for this, however, is the ability to have a certain self-control over the compulsive behavior. The problem, as always, in the practical application of learning theoretical knowledge that his indiscriminate use quickly into a kind of dressage can degenerate.

In 1998, a national focus for patients with Prader-Willi syndrome was set up at the pediatric center of the St. Bernward Hospital in Hildesheim in order to take into account the peculiarities of the disease in all age groups in an interdisciplinary manner; 146 patients from all over Germany were treated there (see literature: Lämmer and Weimann, 2007).

Radio

  • Thomas Gaevert : I don't know where it comes from. Südwestrundfunk, first broadcast on November 18, 2015, report for SWR2 Tandem - 25 minutes.

literature

  • Urs Eiholzer: The Prader-Willi Syndrome - About dealing with those affected. Karger, Basel 2005, ISBN 3-8055-7845-8 .
  • Marga Hogenboom: Understanding people with intellectual disabilities better. 2003, ISBN 3-497-01647-0 .
  • C. Lämmer, E. Weimann: Diagnosis, therapy and long-term care of patients with Prader-Willi syndrome - The Hildesheimer treatment model. In: Pediatrician. (02/2007) 38, pp. 87-96.
  • Klaus Sarimski: Developmental Psychology of Genetic Syndromes. 3. Edition. 2003, ISBN 3-8017-1764-X .
  • Claudia Färber: Analysis of gene sequences in the Prader-Willi / Angelman syndrome region. 2000, ISBN 3-89675-723-7 .
  • Urs Eiholzer: Prader-Willi Syndrome. 2001, ISBN 3-8055-7256-5 (English).
  • Winfried Schillinger: Health educational approaches in the Prader-Willi syndrome: Surveys on health-educational and behavior-modifying interventions for ... life satisfaction - an empirical study. Logos-Verlag, Berlin 2011, ISBN 978-3-8325-2931-4 .

Web links

Individual evidence

  1. ↑ A. Prader, A. Labhart, H. Willi: A syndrome of obesity, short stature, cryptorchidism and oligophrenia after myatonia-like condition in newborns. In: Switzerland Med Wchschr . tape 86 , 1956, pp. 1260-1261 .
  2. ^ OC Ward: Down's 1864 case of Prader-Willi syndrome . In: J Roy Soc Med . tape 90 , 1997, pp. 694-696 .
  3. ^ Prader-Willi syndrome.  In: Online Mendelian Inheritance in Man . (English)
  4. ↑ S. Kishore, S. Stamm: The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. In: Science. 2006, 311 (5758), pp. 230-232. PMID 16357227
  5. ↑ M. Runte, R. Varon, D. Horn, B. Horsthemke, K. Buiting: Exclusion of the C / D box snoRNA gene cluster HBII-52 from a major role in Prader-Willi syndrome. . In: Hum Genet . 116, No. 3, 2005, pp. 228-230. doi : 10.1007 / s00439-004-1219-2 . PMID 15565282 .
  6. ↑ AJ de Smith, C. Purmann, RG Walters et al .: A Deletion of the HBII-85 Class of Small Nucleolar RNAs (snoRNAs) is Associated with Hyperphagia, Obesity and Hypogonadism . In: Hum. Mol. Genet. . 18, No. 17, June 2009, pp. 3257-65. doi : 10.1093 / hmg / ddp263 . PMID 19498035 . PMC 2722987 (free full text).
  7. ↑ http://www.hgqn.org/
  8. ↑ Le syndrome de Prader-Willi
  9. ↑ National Institute of Health
  10. ^ DJ Driscoll, JL Miller, S. Schwartz, SB Cassidy: Prader-Willi Syndrome. In: RA Pagon, MP Adam, HH Ardinger et al .: (Editor) GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 1998 Oct 6 [updated 2016 Feb 4]. PMID 20301505