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This article is for Medical Professionals

This article is for Medical Professionals

In This Article

In This Article

Prader-Willi syndrome (PWS) is a complex genetic disorder characterised by hypotonia and developmental delay as an infant and obesity, learning disability and behavioural problems (especially relating to food) in adolescence and adulthood.

Genetics

PWS was the first human disorder attributed to genomic imprinting. It is caused by:[1]

Deletion of the paternally inherited chromosomal 15q11.2-q13 region (occasionally a result of translocation). These are the majority.

Maternal uniparental disomy 15 caused by chromosomal nondisjunction (both copies are from the mother).

A defect in the imprinting process in the 15q11.2-q13 region on the paternally inherited chromosome.

The opposite, ie maternal deletion or paternal uniparental disomy, causes Angelman's syndrome.

Epidemiology

It is relatively common - prevalence 1/15,000-1/30,000.[1] Despite the genetic cause it appears to be sporadic rather than inherited in a Mendelian pattern. Sex ratio is equal and it occurs in all races.

Diagnostic criteria

As diagnostic tests are now available these should serve to raise suspicion and ensure that all appropriate people are tested, but avoid the expense and worry of unnecessary testing.[2]

From birth to age 3 requires 5 points including 4 major criteria.

Age 3 to adult requires 8 total points including 5 major criteria.

Major criteria (1 point each):

Neonatal or infantile central hypotonia with a poor suck. This gradually improves with age.

Feeding problems in infancy or failure to thrive.

Excessive weight gain between 1 and 6 years of age. Morphological and hormonal abnormalities of the pituitary gland are found in PWS. [3] Marked differences in obesity have been found between patients living in different countries. It is thought that these differences could be explained by differences in management. [4]

Marked differences in obesity have been found between patients living in different countries. It is thought that these differences could be explained by differences in management. Characteristic facial features (narrow face, almond-shaped eyes, etc).

Hypogonadism - genital hypoplasia and/or delayed or incomplete gonadal maturation (this is not always associated with infertility in boys). [5]

Cryptorchidism is common.

Global developmental delay (in child aged <6 years). They may not sit until 12 months, or walk until 24 months. Older children show mild-to-moderate learning difficulties and an IQ of 50 to 70.

Hyperphagia with excessive appetite or food obsession.

Chromosomal abnormality - deletion 15q 11-13 or other appropriate molecular abnormality in this chromosomal region.

Minor criteria (0.5 points each):

Decreased fetal movements, infantile lethargy or weak cry in infancy, which improves with age.

Characteristic behavioural problems (typically tantrums or obsessive/compulsive behaviour). [6] Adults may have psychotic episodes.

Adults may have psychotic episodes. Sleep disturbance/sleep apnoea.

Short stature in childhood and failure of pubertal growth spurt.

Hypopigmentation - fair skin and hair.

Small hands and feet.

Narrow hands with straight ulnar border.

Eye abnormalities (esotropia, myopia).

Thick, viscous saliva ± crusting at mouth corners.

Speech articulation defects.

Skin picking.

Other features which may be present, many of them related to problems of the hypothalamus:

High pain threshold.

Decreased vomiting.

Temperature instability or altered temperature sensitivity.

Scoliosis or kyphosis (66.7% at skeletal maturity in one series of 145 patients). [7]

Early adrenarche (pubic or axillary hair before age 8) despite retardation of other sexual development.

Obesity may cause type 2 diabetes at an early age, also called 'maturity onset diabetes of the young' (MODY).

Osteoporosis (because of hypogonadism). Along with a high pain threshold this can lead to pathological fractures that are not instantly recognised.

They display an unusual skill with jigsaw puzzles. [8]

IQ is usually in the range of 60 to 80 but with expected individual variation. Genetic subtypes of the condition have differing IQ strengths - verbal vs performance IQ.[9]

PWS patients have a different gait from individuals who are simply obese.[10]

Presentation

This may be seen as a disease in two stages:

After birth there is hypotonia, failure to thrive and sleepiness. The child usually has blue eyes and blond hair. They tend to lag behind other children in the transition to solid food.

The second stage becomes apparent at the age of 12-18 months, when an exceptional interest in food becomes apparent.[6] Hyperphagia, obesity, hypogonadism, short stature and sleep apnoea and cor pulmonale occur.[11] They have markedly elevated levels of ghrelin, a hormone associated with hunger.[12]

Diagnosis

DNA methylation analysis and fluorescent in situ hybridisation (FISH) techniques can diagnose PWS in all three types of PWS, as well as differentiate PWS from Angelman's syndrome in deletion cases.[1]

Other tests:

If the patient is obese, screening for glucose intolerance is advised.

Endocrine studies include insulin-like growth factor, lipids and thyroid function. LDL tends to be high and HDL low.

Body composition analysis by dual-energy X-ray absorptiometry (DEXA), anthropometry or another method. DEXA is used to assess fat mass rather than bone mineral density in this case.

Psychological and/or educational testing.

Differential diagnosis

Management

A multidisciplinary approach is essential:

Family support is essential to cope with the behavioural difficulties throughout childhood. The child must be kept away from excessive food intake to guard against subsequent obesity. [13] Their energy requirements are only about 75% of that of a normal child and hyperphagia can occasionally be dangerous, causing massive stomach dilation. Regular exercise is important.

Their energy requirements are only about 75% of that of a normal child and hyperphagia can occasionally be dangerous, causing massive stomach dilation. Regular exercise is important. Input from a paediatric gastroenterologist, endocrinologist, psychologist, psychiatrist, dietician, occupational therapists, speech therapists, exercise advisors and orthopaedic consultants may be helpful. Bariatric surgery has had poor results compared with normal, obese adolescents. [14]

Management of the transition period from childhood to adulthood is important and placement in a residential home may need to be considered. [15] The GP will continue to provide care throughout the transition and during adulthood. Specific points related to PWS to consider during a health check include: Sleep apnoea (obstructive, central or mixed) - even where obesity is not a problem. Scoliosis, kyphosis. Osteoporosis. Oedema. Cellulitis. Hypothyroidism. Gastroparesis. Type 2 diabetes. Skin infections (consequence of skin-picking). Squint, myopia.

The GP will continue to provide care throughout the transition and during adulthood. Specific points related to PWS to consider during a health check include:

Pharmacological

Growth hormone is essential to maintain normal growth, muscle development and avoid obesity. [11, 16] One study found that growth hormone also improved behavioural difficulties. [17] Growth hormone treatment was initially thought to make scoliosis worse but this has been refuted. [18]

One study found that growth hormone also improved behavioural difficulties. Growth hormone treatment was initially thought to make scoliosis worse but this has been refuted. Appetite suppressant drugs are of no value. Long-acting octreotide reduces ghrelin secretion but does not affect behaviour or weight. [19]

Many drugs have been used to modify behaviour but they tend to be ineffective or even counterproductive. Olanzapine may have an effect.

Haloperidol and fluoxetine are sometimes effective.

Selective serotonin reuptake inhibitors (SSRIs) seem to have a nonspecific behaviour-stabilising effect, with fewer outbursts, a marked reduction in irritability and less perseveration but with no antidepressant effect.

All these drugs may be tried with care. None is universally successful and they may even be counterproductive.

Genetic counselling

Recurrence risk depends on the mechanism causing PWS in the individual:[20]

Deletion is sporadic and has a recurrence rate of ≤1% (except in the rare cases where a chromosomal rearrangement is present in the father).

Maternal uniparental disomy 15 is typically de novo also with a recurrence rate of ≤1% (except if a Robertsonian translocation is present in either parent).

A proportion of those with an imprinting defect have a microdeletion in the imprinting centre; this can be familial and has a 50% recurrence risk when it is. However, the greater proportion of those with an imprinting defect have an epigenetic mutation and the recurrence risk is ≤1% for this group.

Prognosis

Obesity-related cardiovascular and respiratory disorders are the most frequent causes of death in children and adults. Based on a population study, the death rate has been estimated at 3% per year.[20]