Endocrine disorders in PWS
- hyperphagia (excessive appetite) and resulting obesity
- short stature and growth hormone deficiency - low growth hormone levels lead to reduced muscle mass which can lead to low tone or stamina
- delayed puberty resulting from deficiency of gonadotrophins (luteinising hormone, LH and follicle stimulating hormone, FSH) which are the hormones produced by the pituitary that control puberty and sexual development. In some individuals the testes or ovaries are also unable to produce sufficient sex hormone; this is commoner in males.
- diabetes mellitus (not universal, and not common in children and teenagers - generally due to obesity)
- hypothyroidism (relatively rare) - due to thyrotrophin-stimulating-hormone (TSH) deficiency.
- sleep disordered breathing including central and obstructive sleep apnoea
It is fairly certain that dysfunction of the hypothalamus in the brain is the main cause of endocrine disorders in PWS. The most common are:
Other endocrine disorders, not directly related to the hypothalamus, are:
Partly related to the hypothalamus, but not endocrine in origin (included for information):
It is known that missing genetic material on the paternal chromosome 15 is the cause of the syndrome, but research is still ongoing as to which genes directly affect the endocrinological systems which are faulty in PWS.
This article explains how people with PWS are affected by these disorders, and current knowledge about treatment.
Hyperphagia
Excessive appetite is perhaps the most evident symptom of PWS. It is thought that this is caused by a faulty mechanism somewhere within the hypothalmic control systems that regulate feeding and body weight. People with PWS do not experience satiety (or fullness) and therefore continue to feel hungry even when, given the opportunity, they have eaten more food than other people. They may eventually feel full, but will start to feel hungry again much sooner than others. Although infants have problems with lack of sucking and weak or absent cry which may need a short period of nasogastric feeding, this may then be followed be a period of normal feeding and then development of overeating. However, the excessive appetite has become apparent in most people with PWS by the age of 4 years.
Recent research has focused on identifying the hormone(s) or protein(s) responsible for this rise in appetite. Researchers have found abnormally high levels of a hormone that comes from the stomach called ghrelin in people with PWS. This hormone is normally at a high level in people without PWS when they are fasting or before meals, and it makes them feel hungry. People with PWS also have low levels of a hormone called pancreatic polypeptide which normally reduces appetite. It remains unclear if these hormonal abnormalities contribute to the increased hunger in PWS. If drugs become available that lower or block the effects of ghrelin, or mimic the action of pancreatic polypeptide then they may be worthwhile investigating as possible treatments for overeating in PWS.
To date, conventional appetite suppressants have been found to have little benefit for people with PWS, and there have been many anecdotal examples of negative side effects. The only currently available drug for obesity is Orlistat (Xenical). However since this reduces the absorption of fat from the intestine rather than altering hunger it is not felt to be of benefit in people with PWS, especially as it will lead to diarrhoea if they eat excess fatty food. Other drugs previously available to reduce appetite in people without PWS e.g. Sibutramine (Reductil) and Rimonabant (Acomplia) have now been withdrawn from the market because of side effects, which were also seen in people with PWS.
Similarly, more drastic measures such as stapling or bypassing the stomach or wiring the jaws are not usually recommended.
Dietary control and management of their diet by others, and control of the food environment, together with increased exercise, are currently the only treatments available to people with PWS. Some are able to exercise some control around food, but most will be tempted to take extra food if the occasion arises. On a positive note, excellent control of diet in early childhood can result in the child with PWS remaining a reasonable weight through childhood.
Short stature and abnormal body composition
Short stature and small hands and feet are a feature of most people with PWS, and lack of growth hormone (GH) and delayed or absent puberty are probably contributory to this. In men, the average height without GH is around 156 cm (5' 2") and in women it is around 146 cm (4' 10") - though this is also dependent on the height of the parents. Growth hormone deficiency is also an important cause for their different body composition, which has a greater ratio of fat mass to muscle mass than the normal population. Growth hormone deficiency may be found in both obese and non-obese children with PWS.
Growth hormone therapy
Numerous research projects have been carried out in the past few years worldwide, looking at growth hormone deficiency in PWS, and the usefulness of growth hormone therapy (GHT). To date, most of this research has been focused on children.
Although very long-term effects of GHT are still not known, effects over 7-10 years may be good. It improves final height, physical strength, agility and respiratory muscle function, as well as increasing the overall muscle mass and reducing the fat mass in the body. Researchers have suggested that the best results can be achieved, particularly in terms of body composition, if GHT is started early, rather than in middle or late childhood. Current recommendation is that GHT should be started from at least 1-2 years old, but studies are examining if there may be benefits in starting at even younger ages between 6-12 months. Studies are also suggesting that GHT may help adults with PWS once they have reached their final height both in terms of peak bone mass and body composition.
GHT has now been approved for treatment of children with PWS in the UK by the National Institute for Clinical Excellence (NICE). It is important to note that, from May 2010, the treatment is for improvement in body composition in Prader-Willi syndrome, not growth hormone deficiency - and should therefore be available to any child with PWS. At the end of treatment as a young adult, it will be important to know whether the individual is still growth hormone deficient or not, and then they will require a pharmacological test of growth hormone secretion.
GHT will not necessarily help with obesity, nor is there any evidence to show that it decreases the feelings of hunger, so children with PWS will still need dietary controls in place to ensure that they do not over-eat and to maintain their energy intake to about 75% of the intake of children without PWS.
Early onset of puberty and increased risk of developing diabetes are possible side effects for anyone taking GH. However, these problems also occur in people with PWS who have never received GHT, so it is often difficult to ascertain whether, if these happen, they are as a result of GHT, or would have happened anyway. Your endocrinologist will monitor your child's progress to see if any of these symptoms are occuring.
Your child should also have an assessment for any respiratory problems or evidence of sleep apnoea prior to receiving GHT, as there may be risks associated with GHT for children with upper respiratory tract problems and sleep apnoea (see below).
Sleep apnoea
Sleep apnoea is a condition whereby the person stops breathing in their sleep for periods of 10 seconds or more. As the person starts to breathe again, the person can startle or snort in their sleep. Snoring is also present in sleep apnoea. In PWS it may be due to disturbances in the hypothalamus which controls breathing, but can also be caused or exacerbated by obstruction of the airway between the soft palate and the larynx. This can happen if the person is obese or if they have large tonsils or adenoids. It can be treated with CPAP (continuous positive airway pressure), which requires the person to wear a nasal mask, through which air is pumped from a machine by the bed.
From time to time your endocrinologist may organise a sleep study to check that sleep apnoea is not developing.
Gonadotrophin deficiency
Gonadotrophin deficiency is evident in the majority of males and females with PWS. However, individuals vary greatly and treatment should be on an individual basis. In women, periods may start late or not at all and be very irregular. Breasts may not fully mature, and pubertal hair may be scanty. In boys undescended testes are commonly present at birth, together with a small penis. Sometimes the voice may not break at puberty and facial and pubertal hair is scanty.
Some children with PWS develop pubic and axillary hair early but then go through true puberty much later. Early true puberty requiring treatment to hold up development, has been reported in a small number of children with PWS.
Until recently it was thought that both sexes were infertile, but to date five cases of women with PWS having babies have been reported worldwide - none in the UK. There are still no documented reports of men with PWS fathering children.
Sex hormones (oestrogen and testosterone) are not just important for sexual development; they also help prevent osteoporosis in both sexes, and should therefore be considered as a possible treatment, even if sexual issues and relationships are not very important to the person with PWS. Sex hormone replacement therapy can also help the person with PWS feel and look more like the rest of their peers.
Very little research has been carried out on the side effects of sex hormone replacement therapy in people with PWS. Anecdotally, parents have reported weight increases in women receiving sex hormone therapy (hormone replacement therapy) and an increase in aggressive behaviour (with one case of psychosis) in men receiving testosterone - but these reports have been contested by others. In summary, care should be taken with sex hormone replacement therapy and your child should be monitored during the course of treatment. Newer delivery methods of testosterone replacement in males such as gels applied to the skin and longer-acting injections may be of benefit in avoiding high peaks of testosterone levels and hence side effects. Slow increases in testosterone dose are recommended.
Diabetes mellitus
Early onset of type II diabetes (diabetes mellitus) is common in PWS, and is usually associated with obesity. It may develop before the person reaches 20 years of age. The best way to prevent the onset of diabetes is to maintain a healthy weight and encourage an active lifestyle. There is a greater tendency to diabetes in those who have a relation with the condition.
Treatment is normally initially with tablets (eg Metformin, Gliclazide, Pioglitazone), but in some cases insulin treatment may be needed. If weight is reduced, diabetic medications (tablets or insulin) can often be reduced or sometimes discontinued. With the exception of Metformin, most tablet treatments have a side effect in normal people - and quite possibly people with PWS - of mild weight gain.
Some newer drugs for diabetes such as Exenatide or Liraglutide have recently become available that mimic the action of the hormone GLP-1 which stimulates insulin secretion. In people without PWS they may have the benefit of reducing blood sugar levels without increasing weight or in fact helping patients lose small amounts of weight. It is not yet known if these benefits are also seen in people with PWS. Furthermore these drugs may also slow down the emptying of the stomach, which is already slow in people with PWS. This might increase the risk of rupture of the stomach in people with PWS if they were to binge overeat (which has been rarely reported in PWS without use of these drugs, probably due to reduced vomiting and high pain threshold in PWS). The benefits and safety of these GLP-1 drugs in people with PWS therefore needs further investigation before it can be generally recommended.
Diabetes can be very hard to manage in PWS, as the diet has to be very carefully monitored to provide both a health balance of nutrients and also a controlled energy intake. The propensity of the person with PWS to seek out "extras" without telling anyone can seriously upset any dietary regimen which is put in place. Not surprisingly, diabetes is often managed better in residential care homes where the person with PWS has restricted access to food.
Hypothyroidism
Individals with PWS have an increased chance of developing an underactive thyroid (low thyroid hormone levels). They should have regular blood tests to check for this throughout life. The treatment is thyroxine tablets.
Cortisol hormone insufficiency
There has been a suggestion that some people with PWS may be at increased risk of stress hormone (cortisol) deficiency due to hypothalamic problems but this has not been found in all studies and probably occurs only rarely. If there is a clinical suspicion of cortisol deficiency during an acute illness such as an infection (e.g. low blood sugar, low and variable blood pressure), then consideration should be made to urgently measure cortisol levels and if there is concern hydrocortisone could be administered until the results are available.
Further information
Further information about the management of hormonal aspects of the syndrome can be found from this consensus recommendations paper (J Clin Endocrinol Metab. 93:4183-97, 2008)
Some information about hormones in the syndrome and in general is also available from You and Your Hormones, a website created by the Society for Endocrinology:
Acknowledgements
Thanks to Prof Nick Finer, Dr Tony Goldstone, Dr Nicola Bridges, Dr Justin Davies and Dr Peter Clayton for their helpful comments and suggestions.
Thank you
This web page was made possible by a grant from the Society for Endocrinology and Clinical Endocrinology Trust.
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